Many psychiatrists conceptualize mental illnesses, including psychotic disorders, across a continuum where their borders can be ambiguous.¹ The same can be said of individual symptoms such as delusions, where the line separating clear-cut pathology from nonpathological or subclinical “delusion-like beliefs” is often blurred.^2,3 However, the categorical distinction between mental illness and normality is fundamental to diagnostic reliability and crucial to clinical decisions about whether and how to intervene.

Conspiracy theory beliefs are delusion-like beliefs that are commonly encountered within today’s political landscape. Surveys have consistently revealed that approximately one-half of the population believes in at least 1 conspiracy theory, highlighting the normality of such beliefs despite their potential outlandishness.⁴ Here are 3 questions you can ask to help differentiate conspiracy theory beliefs from delusions.

1. What is the evidence for the belief?

Drawing from Karl Jaspers’ conceptualization of delusions as “impossible” and “unshareable,” the DSM-5 distinguishes delusions from culturally-sanctioned shared beliefs such as religious creeds.³ Whereas delusions often arise out of anomalous subjective experiences, individuals who come to believe in conspiracytheories have typically sought explanations and found them from secondary sources, often on the internet.⁵ Despite the familiar term “conspiracy theorist,” most who believe in conspiracy theories aren’t so much theorizing as they are adopting counter-narratives based on assimilated information. Unlike delusions, conspiracy theory beliefs are learned, with the “evidence” to support them easily located online.

2. Is the belief self-referential?

The stereotypical unshareability of delusions often hinges upon their self-referential content. For example, while it is easy to find others who believe in the Second Coming, it would be much harder to convince others that you are the Second Coming. Unlike delusions, conspiracy theories are beliefs about the world and explanations of real-life events; their content is rarely, if ever, directly related to the believer.

Conspiracy theory beliefs involve a negation of authoritative accounts that is rooted in “epistemic mistrust” of authoritative sources of information.⁵ While conspiratorial mistrust has been compared with paranoia, with paranoia found to be associated with belief in conspiracy theories,⁶ epistemic mistrust encompasses a range of justified cultural mistrust, unwarranted mistrust based on racial prejudice, and subclinical paranoia typical of schizotypy. The more self-referential the underlying paranoia, the more likely an associated belief is to cross the boundary from conspiracy theory to delusion.⁷

3. Is there overlap?

Conspiracy theory beliefs and delusions are not mutually exclusive. “Gang stalking” offers a vexing example of paranoia that is part shared conspiracy theory, part idiosyncratic delusion.⁸ Reliably disentangling these components requires identifying the conspiracy theory component as a widely-shared belief about government surveillance, while carefully analyzing the self-referential component to determine credibility and potential delusionality.

Many psychiatrists conceptualize mental illnesses, including psychotic disorders, across a continuum where their borders can be ambiguous.¹ The same can be said of individual symptoms such as delusions, where the line separating clear-cut pathology from nonpathological or subclinical “delusion-like beliefs” is often blurred.^2,3 However, the categorical distinction between mental illness and normality is fundamental to diagnostic reliability and crucial to clinical decisions about whether and how to intervene.

Conspiracy theory beliefs are delusion-like beliefs that are commonly encountered within today’s political landscape. Surveys have consistently revealed that approximately one-half of the population believes in at least 1 conspiracy theory, highlighting the normality of such beliefs despite their potential outlandishness.⁴ Here are 3 questions you can ask to help differentiate conspiracy theory beliefs from delusions.

1. What is the evidence for the belief?

Drawing from Karl Jaspers’ conceptualization of delusions as “impossible” and “unshareable,” the DSM-5 distinguishes delusions from culturally-sanctioned shared beliefs such as religious creeds.³ Whereas delusions often arise out of anomalous subjective experiences, individuals who come to believe in conspiracytheories have typically sought explanations and found them from secondary sources, often on the internet.⁵ Despite the familiar term “conspiracy theorist,” most who believe in conspiracy theories aren’t so much theorizing as they are adopting counter-narratives based on assimilated information. Unlike delusions, conspiracy theory beliefs are learned, with the “evidence” to support them easily located online.

2. Is the belief self-referential?

The stereotypical unshareability of delusions often hinges upon their self-referential content. For example, while it is easy to find others who believe in the Second Coming, it would be much harder to convince others that you are the Second Coming. Unlike delusions, conspiracy theories are beliefs about the world and explanations of real-life events; their content is rarely, if ever, directly related to the believer.

Conspiracy theory beliefs involve a negation of authoritative accounts that is rooted in “epistemic mistrust” of authoritative sources of information.⁵ While conspiratorial mistrust has been compared with paranoia, with paranoia found to be associated with belief in conspiracy theories,⁶ epistemic mistrust encompasses a range of justified cultural mistrust, unwarranted mistrust based on racial prejudice, and subclinical paranoia typical of schizotypy. The more self-referential the underlying paranoia, the more likely an associated belief is to cross the boundary from conspiracy theory to delusion.⁷

3. Is there overlap?

Conspiracy theory beliefs and delusions are not mutually exclusive. “Gang stalking” offers a vexing example of paranoia that is part shared conspiracy theory, part idiosyncratic delusion.⁸ Reliably disentangling these components requires identifying the conspiracy theory component as a widely-shared belief about government surveillance, while carefully analyzing the self-referential component to determine credibility and potential delusionality.

Many psychiatrists conceptualize mental illnesses, including psychotic disorders, across a continuum where their borders can be ambiguous.¹ The same can be said of individual symptoms such as delusions, where the line separating clear-cut pathology from nonpathological or subclinical “delusion-like beliefs” is often blurred.^2,3 However, the categorical distinction between mental illness and normality is fundamental to diagnostic reliability and crucial to clinical decisions about whether and how to intervene.

Conspiracy theory beliefs are delusion-like beliefs that are commonly encountered within today’s political landscape. Surveys have consistently revealed that approximately one-half of the population believes in at least 1 conspiracy theory, highlighting the normality of such beliefs despite their potential outlandishness.⁴ Here are 3 questions you can ask to help differentiate conspiracy theory beliefs from delusions.

1. What is the evidence for the belief?

Drawing from Karl Jaspers’ conceptualization of delusions as “impossible” and “unshareable,” the DSM-5 distinguishes delusions from culturally-sanctioned shared beliefs such as religious creeds.³ Whereas delusions often arise out of anomalous subjective experiences, individuals who come to believe in conspiracytheories have typically sought explanations and found them from secondary sources, often on the internet.⁵ Despite the familiar term “conspiracy theorist,” most who believe in conspiracy theories aren’t so much theorizing as they are adopting counter-narratives based on assimilated information. Unlike delusions, conspiracy theory beliefs are learned, with the “evidence” to support them easily located online.

2. Is the belief self-referential?

The stereotypical unshareability of delusions often hinges upon their self-referential content. For example, while it is easy to find others who believe in the Second Coming, it would be much harder to convince others that you are the Second Coming. Unlike delusions, conspiracy theories are beliefs about the world and explanations of real-life events; their content is rarely, if ever, directly related to the believer.

Conspiracy theory beliefs involve a negation of authoritative accounts that is rooted in “epistemic mistrust” of authoritative sources of information.⁵ While conspiratorial mistrust has been compared with paranoia, with paranoia found to be associated with belief in conspiracy theories,⁶ epistemic mistrust encompasses a range of justified cultural mistrust, unwarranted mistrust based on racial prejudice, and subclinical paranoia typical of schizotypy. The more self-referential the underlying paranoia, the more likely an associated belief is to cross the boundary from conspiracy theory to delusion.⁷

3. Is there overlap?

Conspiracy theory beliefs and delusions are not mutually exclusive. “Gang stalking” offers a vexing example of paranoia that is part shared conspiracy theory, part idiosyncratic delusion.⁸ Reliably disentangling these components requires identifying the conspiracy theory component as a widely-shared belief about government surveillance, while carefully analyzing the self-referential component to determine credibility and potential delusionality.

Mrs. D, age 67, has a history of major depressive disorder. She has had adequate treatment trials with duloxetine, mirtazapine, and sertraline; each failed to produce remission. She is currently prescribed paroxetine, 40 mg/d, and aripiprazole, 10 mg/d, with good efficacy. She also has a history of hypertension and seasonal allergies, for which she receives amlodipine, 10 mg/d, and loratadine, 10 mg/d, respectively.

Mrs. D’s depressive symptoms were well controlled until 2 months ago, when she fell and fractured her hip. With encouragement from her prescriber, she enrolled in a partial hospitalization program for more intensive psychotherapy. During a medication education session, she is surprised to learn that antidepressants may affect bone health.

During a medication management meeting with her prescriber, Mrs. D asks about the risk of osteoporosis, and whether her antidepressant could have contributed to her hip fracture.

Bone is a dynamic tissue that undergoes a continuous process of remodeling. Osteoblasts are responsible for bone formation, whereas osteoclasts are responsible for bone resorption. Osteocytes—the predominant cell type in bone—along with cytokines, hormones, and growth factors help to orchestrate these actions.¹ Serotonin is increasingly recognized as a factor in bone homeostasis. Bone synthesizes serotonin, expresses serotonin transporters, and contains a variety of serotonin receptors.²

Serotonin serves many physiologic functions outside of the CNS, and it appears to have opposing actions on bone metabolism (Table 1^1,3). Peripheral (gut-derived) serotonin inhibits bone formation through its effects on osteoblasts, whereas the actions of serotonin in the CNS promote bone growth through inhibitory effects on sympathetic output.² Selective serotonin reuptake inhibitor (SSRI) enhancement of peripheral serotonin and its negative effect on bone may outweigh the benefits caused by SSRI enhancement of central serotonin neurotransmission.¹ In vitro data suggest SSRIs inhibit osteoblast and osteoclast function, theoretically decreasing bone turnover and increasing fracture risk.⁴ Other data indicate SSRI treatment may decrease procollagen type 1 N-terminal propeptide, a peripheral marker of bone formation.⁵ Both SSRIs and serotonin-norepinephrine reuptake inhibitors (SNRIs) have been associated with lower cortical bone mineral density (BMD).⁶Table 2^7,8 details the relative affinity of select antidepressants for the serotonin transporter.

What the evidence says

Evidence for the correlation between fractures and serotonergic antidepressant use is mixed. One meta-analysis found a significant association between SSRIs and fractures, suggesting a 1.62-fold increased risk.¹³ Another meta-analysis investigated SSRIs and SNRIs and the risk of fracture.¹⁴ The SSRIs had a 1.67-fold increased risk; however, a lack of studies prohibited making conclusions about SNRIs. The number needed to harm was calculated at 85, 46, and 19 with 1, 2, and 5 years of SSRI exposure, respectively. A third meta-analysis found increased fracture risk related to depression and reported a hazard ratio of 1.26 after adjusting for confounders.⁹ This analysis suggests depression affects fracture risk and may limit the interpretation of causation from SSRI use. Studies included in these meta-analyses had significant heterogeneity.

Continue to: The effect of SSRIs...

The effect of SSRIs vs non-SSRIs on BMD also has been studied. The SSRIs were associated with significantly reduced BMD of the lumbar spine but not the total hip or femoral neck as compared to non-SSRIs; however, this BMD loss was not examined in relation to the presence of fractures. Older patients had more pronounced bone loss.¹⁵ Conversely, another meta-analysis examined BMD in women receiving SSRIs or tricyclic antidepressants.¹⁰ Neither medication class was associated with lower BMD at measured locations, including lumbar spine, femoral neck, and total hip. This analysis was limited by the lack of available trials; only 4 were included.

Other recent research has continued to explore the relationship between antidepressants and fracture in various patient populations. In a study of patients receiving maintenance dialysis treatment, short- and long-term SSRI use increased hip fracture risk. The authors speculated that short-term risk may be mediated by adverse effects that increase fall risk (eg, hyponatremia, orthostasis), whereas long-term risk may be influenced by changes in bone homeostasis.¹⁶ In two 6-month analyses of fluoxetine treatment in patients following an acute stroke, fluoxetine increased the risk of bone fractures.^17,18 Finally, in women with osteoporosis receiving risedronate or teriparatide, in both groups a higher fracture risk was observed for patients who were also receiving an SSRI or SNRI.¹⁹

Monitor BMD and educate patients about bone health

Available literature has not identified any clear risk factors for fracture with SSRI use. Guidelines suggest monitoring BMD in patients with risk factors for osteoporosis, if clinically indicated, as well as monitoring BMD in those receiving long-term antidepressant treatment.^20-22 Educate patients on strategies that promote optimal bone health, such as consuming a balanced diet that meets the recommended dietary allowance of calcium, vitamin D, and limits soda consumption. Teach patients to avoid tobacco and excessive alcohol use because both adversely impact BMD. Maintaining a healthy weight, physical activity, and adequate sleep also support bone health.¹¹ Instruct patients receiving antidepressants to report unexplained bone pain, tenderness, swelling, or bruising because these symptoms may be indicative of fracture.

CASE CONTINUED

Mrs. D’s age, sex, and depression place her at higher risk of fracture. Paroxetine is the only SSRI that has bone fracture listed as a precaution in its labeling.²³ In addition, it is the most anticholinergic SSRI and may have contributed to her fall. Switching to bupropion by cross titration may benefit Mrs. D because bupropion is not serotonergic. Little data exist regarding the effects of bupropion on bone. Her prescriber monitors Mrs. D’s BMD periodically, and educates her on dietary considerations. He also recommends calcium, 1,200 mg/d, and vitamin D, 800 IU/d, to help prevent fractures,²⁴ and that she continue physical therapy exercises and increase physical activity as tolerated.

Related Resources

• Cosman F, de Beur SJ, LeBoff MS, et al. Clinician’s guide to prevention and treatment of osteoporosis. Osteoporos Int. 2014;25(10):2359-2581.
• Dodd S, Mitchell PB, Bauer M, et al. Monitoring for antidepressant-associated adverse events in the treatment of patients with major depressive disorder: an international consensus statement. World J Biol Psychiatry. 2018;19(5):330-348.
• Fernandes BS, Hodge JM, Pasco JA, et al. Effects of depression and serotonergic antidepressants on bone: mechanisms and implications for the treatment of depression. Drugs Aging. 2016;33(1):21-25.
• US National Library of Medicine. DailyMed. https://dailymed.nlm.nih.gov/dailymed

Drug Brand Names

Amitriptyline • Elavil
Amlodipine • Norvasc
Aripiprazole • Abilify
Bupropion • Wellbutrin
Citalopram • Celexa
Clomipramine • Anafranil
Desipramine • Norpramin
Doxepin • Silenor, Sinequan
Duloxetine • Cymbalta
Escitalopram • Lexapro
Fluoxetine • Prozac
Fluvoxamine • Luvox
Imipramine • Tofranil
Levomilnacipran • Fetzima
Loratadine • Claritin
Mirtazapine • Remeron
Nortriptyline • Pamelor
Paroxetine • Paxil
Risedronate • Actonel
Sertraline • Zoloft
Teriparatide • Forteo
Trazodone • Desyrel
Venlafaxine • Effexor
Vortioxetine • Trintellix

Mrs. D, age 67, has a history of major depressive disorder. She has had adequate treatment trials with duloxetine, mirtazapine, and sertraline; each failed to produce remission. She is currently prescribed paroxetine, 40 mg/d, and aripiprazole, 10 mg/d, with good efficacy. She also has a history of hypertension and seasonal allergies, for which she receives amlodipine, 10 mg/d, and loratadine, 10 mg/d, respectively.

Mrs. D’s depressive symptoms were well controlled until 2 months ago, when she fell and fractured her hip. With encouragement from her prescriber, she enrolled in a partial hospitalization program for more intensive psychotherapy. During a medication education session, she is surprised to learn that antidepressants may affect bone health.

During a medication management meeting with her prescriber, Mrs. D asks about the risk of osteoporosis, and whether her antidepressant could have contributed to her hip fracture.

Bone is a dynamic tissue that undergoes a continuous process of remodeling. Osteoblasts are responsible for bone formation, whereas osteoclasts are responsible for bone resorption. Osteocytes—the predominant cell type in bone—along with cytokines, hormones, and growth factors help to orchestrate these actions.¹ Serotonin is increasingly recognized as a factor in bone homeostasis. Bone synthesizes serotonin, expresses serotonin transporters, and contains a variety of serotonin receptors.²

Serotonin serves many physiologic functions outside of the CNS, and it appears to have opposing actions on bone metabolism (Table 1^1,3). Peripheral (gut-derived) serotonin inhibits bone formation through its effects on osteoblasts, whereas the actions of serotonin in the CNS promote bone growth through inhibitory effects on sympathetic output.² Selective serotonin reuptake inhibitor (SSRI) enhancement of peripheral serotonin and its negative effect on bone may outweigh the benefits caused by SSRI enhancement of central serotonin neurotransmission.¹ In vitro data suggest SSRIs inhibit osteoblast and osteoclast function, theoretically decreasing bone turnover and increasing fracture risk.⁴ Other data indicate SSRI treatment may decrease procollagen type 1 N-terminal propeptide, a peripheral marker of bone formation.⁵ Both SSRIs and serotonin-norepinephrine reuptake inhibitors (SNRIs) have been associated with lower cortical bone mineral density (BMD).⁶Table 2^7,8 details the relative affinity of select antidepressants for the serotonin transporter.

What the evidence says

Evidence for the correlation between fractures and serotonergic antidepressant use is mixed. One meta-analysis found a significant association between SSRIs and fractures, suggesting a 1.62-fold increased risk.¹³ Another meta-analysis investigated SSRIs and SNRIs and the risk of fracture.¹⁴ The SSRIs had a 1.67-fold increased risk; however, a lack of studies prohibited making conclusions about SNRIs. The number needed to harm was calculated at 85, 46, and 19 with 1, 2, and 5 years of SSRI exposure, respectively. A third meta-analysis found increased fracture risk related to depression and reported a hazard ratio of 1.26 after adjusting for confounders.⁹ This analysis suggests depression affects fracture risk and may limit the interpretation of causation from SSRI use. Studies included in these meta-analyses had significant heterogeneity.

Continue to: The effect of SSRIs...

The effect of SSRIs vs non-SSRIs on BMD also has been studied. The SSRIs were associated with significantly reduced BMD of the lumbar spine but not the total hip or femoral neck as compared to non-SSRIs; however, this BMD loss was not examined in relation to the presence of fractures. Older patients had more pronounced bone loss.¹⁵ Conversely, another meta-analysis examined BMD in women receiving SSRIs or tricyclic antidepressants.¹⁰ Neither medication class was associated with lower BMD at measured locations, including lumbar spine, femoral neck, and total hip. This analysis was limited by the lack of available trials; only 4 were included.

Other recent research has continued to explore the relationship between antidepressants and fracture in various patient populations. In a study of patients receiving maintenance dialysis treatment, short- and long-term SSRI use increased hip fracture risk. The authors speculated that short-term risk may be mediated by adverse effects that increase fall risk (eg, hyponatremia, orthostasis), whereas long-term risk may be influenced by changes in bone homeostasis.¹⁶ In two 6-month analyses of fluoxetine treatment in patients following an acute stroke, fluoxetine increased the risk of bone fractures.^17,18 Finally, in women with osteoporosis receiving risedronate or teriparatide, in both groups a higher fracture risk was observed for patients who were also receiving an SSRI or SNRI.¹⁹

Monitor BMD and educate patients about bone health

Available literature has not identified any clear risk factors for fracture with SSRI use. Guidelines suggest monitoring BMD in patients with risk factors for osteoporosis, if clinically indicated, as well as monitoring BMD in those receiving long-term antidepressant treatment.^20-22 Educate patients on strategies that promote optimal bone health, such as consuming a balanced diet that meets the recommended dietary allowance of calcium, vitamin D, and limits soda consumption. Teach patients to avoid tobacco and excessive alcohol use because both adversely impact BMD. Maintaining a healthy weight, physical activity, and adequate sleep also support bone health.¹¹ Instruct patients receiving antidepressants to report unexplained bone pain, tenderness, swelling, or bruising because these symptoms may be indicative of fracture.

CASE CONTINUED

Mrs. D’s age, sex, and depression place her at higher risk of fracture. Paroxetine is the only SSRI that has bone fracture listed as a precaution in its labeling.²³ In addition, it is the most anticholinergic SSRI and may have contributed to her fall. Switching to bupropion by cross titration may benefit Mrs. D because bupropion is not serotonergic. Little data exist regarding the effects of bupropion on bone. Her prescriber monitors Mrs. D’s BMD periodically, and educates her on dietary considerations. He also recommends calcium, 1,200 mg/d, and vitamin D, 800 IU/d, to help prevent fractures,²⁴ and that she continue physical therapy exercises and increase physical activity as tolerated.

Related Resources

• Cosman F, de Beur SJ, LeBoff MS, et al. Clinician’s guide to prevention and treatment of osteoporosis. Osteoporos Int. 2014;25(10):2359-2581.
• Dodd S, Mitchell PB, Bauer M, et al. Monitoring for antidepressant-associated adverse events in the treatment of patients with major depressive disorder: an international consensus statement. World J Biol Psychiatry. 2018;19(5):330-348.
• Fernandes BS, Hodge JM, Pasco JA, et al. Effects of depression and serotonergic antidepressants on bone: mechanisms and implications for the treatment of depression. Drugs Aging. 2016;33(1):21-25.
• US National Library of Medicine. DailyMed. https://dailymed.nlm.nih.gov/dailymed

Drug Brand Names

Amitriptyline • Elavil
Amlodipine • Norvasc
Aripiprazole • Abilify
Bupropion • Wellbutrin
Citalopram • Celexa
Clomipramine • Anafranil
Desipramine • Norpramin
Doxepin • Silenor, Sinequan
Duloxetine • Cymbalta
Escitalopram • Lexapro
Fluoxetine • Prozac
Fluvoxamine • Luvox
Imipramine • Tofranil
Levomilnacipran • Fetzima
Loratadine • Claritin
Mirtazapine • Remeron
Nortriptyline • Pamelor
Paroxetine • Paxil
Risedronate • Actonel
Sertraline • Zoloft
Teriparatide • Forteo
Trazodone • Desyrel
Venlafaxine • Effexor
Vortioxetine • Trintellix

Mrs. D, age 67, has a history of major depressive disorder. She has had adequate treatment trials with duloxetine, mirtazapine, and sertraline; each failed to produce remission. She is currently prescribed paroxetine, 40 mg/d, and aripiprazole, 10 mg/d, with good efficacy. She also has a history of hypertension and seasonal allergies, for which she receives amlodipine, 10 mg/d, and loratadine, 10 mg/d, respectively.

Mrs. D’s depressive symptoms were well controlled until 2 months ago, when she fell and fractured her hip. With encouragement from her prescriber, she enrolled in a partial hospitalization program for more intensive psychotherapy. During a medication education session, she is surprised to learn that antidepressants may affect bone health.

During a medication management meeting with her prescriber, Mrs. D asks about the risk of osteoporosis, and whether her antidepressant could have contributed to her hip fracture.

Bone is a dynamic tissue that undergoes a continuous process of remodeling. Osteoblasts are responsible for bone formation, whereas osteoclasts are responsible for bone resorption. Osteocytes—the predominant cell type in bone—along with cytokines, hormones, and growth factors help to orchestrate these actions.¹ Serotonin is increasingly recognized as a factor in bone homeostasis. Bone synthesizes serotonin, expresses serotonin transporters, and contains a variety of serotonin receptors.²

Serotonin serves many physiologic functions outside of the CNS, and it appears to have opposing actions on bone metabolism (Table 1^1,3). Peripheral (gut-derived) serotonin inhibits bone formation through its effects on osteoblasts, whereas the actions of serotonin in the CNS promote bone growth through inhibitory effects on sympathetic output.² Selective serotonin reuptake inhibitor (SSRI) enhancement of peripheral serotonin and its negative effect on bone may outweigh the benefits caused by SSRI enhancement of central serotonin neurotransmission.¹ In vitro data suggest SSRIs inhibit osteoblast and osteoclast function, theoretically decreasing bone turnover and increasing fracture risk.⁴ Other data indicate SSRI treatment may decrease procollagen type 1 N-terminal propeptide, a peripheral marker of bone formation.⁵ Both SSRIs and serotonin-norepinephrine reuptake inhibitors (SNRIs) have been associated with lower cortical bone mineral density (BMD).⁶Table 2^7,8 details the relative affinity of select antidepressants for the serotonin transporter.

What the evidence says

Evidence for the correlation between fractures and serotonergic antidepressant use is mixed. One meta-analysis found a significant association between SSRIs and fractures, suggesting a 1.62-fold increased risk.¹³ Another meta-analysis investigated SSRIs and SNRIs and the risk of fracture.¹⁴ The SSRIs had a 1.67-fold increased risk; however, a lack of studies prohibited making conclusions about SNRIs. The number needed to harm was calculated at 85, 46, and 19 with 1, 2, and 5 years of SSRI exposure, respectively. A third meta-analysis found increased fracture risk related to depression and reported a hazard ratio of 1.26 after adjusting for confounders.⁹ This analysis suggests depression affects fracture risk and may limit the interpretation of causation from SSRI use. Studies included in these meta-analyses had significant heterogeneity.

Continue to: The effect of SSRIs...

The effect of SSRIs vs non-SSRIs on BMD also has been studied. The SSRIs were associated with significantly reduced BMD of the lumbar spine but not the total hip or femoral neck as compared to non-SSRIs; however, this BMD loss was not examined in relation to the presence of fractures. Older patients had more pronounced bone loss.¹⁵ Conversely, another meta-analysis examined BMD in women receiving SSRIs or tricyclic antidepressants.¹⁰ Neither medication class was associated with lower BMD at measured locations, including lumbar spine, femoral neck, and total hip. This analysis was limited by the lack of available trials; only 4 were included.

Other recent research has continued to explore the relationship between antidepressants and fracture in various patient populations. In a study of patients receiving maintenance dialysis treatment, short- and long-term SSRI use increased hip fracture risk. The authors speculated that short-term risk may be mediated by adverse effects that increase fall risk (eg, hyponatremia, orthostasis), whereas long-term risk may be influenced by changes in bone homeostasis.¹⁶ In two 6-month analyses of fluoxetine treatment in patients following an acute stroke, fluoxetine increased the risk of bone fractures.^17,18 Finally, in women with osteoporosis receiving risedronate or teriparatide, in both groups a higher fracture risk was observed for patients who were also receiving an SSRI or SNRI.¹⁹

Monitor BMD and educate patients about bone health

Available literature has not identified any clear risk factors for fracture with SSRI use. Guidelines suggest monitoring BMD in patients with risk factors for osteoporosis, if clinically indicated, as well as monitoring BMD in those receiving long-term antidepressant treatment.^20-22 Educate patients on strategies that promote optimal bone health, such as consuming a balanced diet that meets the recommended dietary allowance of calcium, vitamin D, and limits soda consumption. Teach patients to avoid tobacco and excessive alcohol use because both adversely impact BMD. Maintaining a healthy weight, physical activity, and adequate sleep also support bone health.¹¹ Instruct patients receiving antidepressants to report unexplained bone pain, tenderness, swelling, or bruising because these symptoms may be indicative of fracture.

CASE CONTINUED

Mrs. D’s age, sex, and depression place her at higher risk of fracture. Paroxetine is the only SSRI that has bone fracture listed as a precaution in its labeling.²³ In addition, it is the most anticholinergic SSRI and may have contributed to her fall. Switching to bupropion by cross titration may benefit Mrs. D because bupropion is not serotonergic. Little data exist regarding the effects of bupropion on bone. Her prescriber monitors Mrs. D’s BMD periodically, and educates her on dietary considerations. He also recommends calcium, 1,200 mg/d, and vitamin D, 800 IU/d, to help prevent fractures,²⁴ and that she continue physical therapy exercises and increase physical activity as tolerated.

Related Resources

• Cosman F, de Beur SJ, LeBoff MS, et al. Clinician’s guide to prevention and treatment of osteoporosis. Osteoporos Int. 2014;25(10):2359-2581.
• Dodd S, Mitchell PB, Bauer M, et al. Monitoring for antidepressant-associated adverse events in the treatment of patients with major depressive disorder: an international consensus statement. World J Biol Psychiatry. 2018;19(5):330-348.
• Fernandes BS, Hodge JM, Pasco JA, et al. Effects of depression and serotonergic antidepressants on bone: mechanisms and implications for the treatment of depression. Drugs Aging. 2016;33(1):21-25.
• US National Library of Medicine. DailyMed. https://dailymed.nlm.nih.gov/dailymed

Drug Brand Names

Amitriptyline • Elavil
Amlodipine • Norvasc
Aripiprazole • Abilify
Bupropion • Wellbutrin
Citalopram • Celexa
Clomipramine • Anafranil
Desipramine • Norpramin
Doxepin • Silenor, Sinequan
Duloxetine • Cymbalta
Escitalopram • Lexapro
Fluoxetine • Prozac
Fluvoxamine • Luvox
Imipramine • Tofranil
Levomilnacipran • Fetzima
Loratadine • Claritin
Mirtazapine • Remeron
Nortriptyline • Pamelor
Paroxetine • Paxil
Risedronate • Actonel
Sertraline • Zoloft
Teriparatide • Forteo
Trazodone • Desyrel
Venlafaxine • Effexor
Vortioxetine • Trintellix

CASE Unresponsive after a presumed seizure

Mr. F, age 44, has schizophrenia. He is brought to the hospital by ambulance after he is found on the ground outside of his mother’s house following a presumed seizure and fall. On arrival to the emergency department, he is unresponsive. His laboratory values are significant for a sodium level of 110 mEq/L (reference range: 135 to 145 mEq/L), indicating hyponatremia.

HISTORY Fixated on purity

Mr. F’s mother reports that Mr. F had an unremarkable childhood. He was raised in a household with both parents and a younger sister. Mr. F did well academically and studied engineering and physics in college. There was no reported history of trauma or substance use.

During his senior year of college, Mr. F began experiencing paranoia, auditory hallucinations, and religious delusions. He required hospitalization and was diagnosed with schizophrenia. Following multiple hospitalizations over 5 years, he moved in with his mother, who was granted guardianship.

His mother said Mr. F’s religious delusions were of purity and cleansing the soul. He spent hours memorizing the Bible and would go for days without eating but would drink large amounts of water. She said she thought this was due to his desire to flush out imperfections.

In the past 3 years, Mr. F has been hospitalized several times for severe hyponatremia. At home, his mother attempted to restrict his water intake. However, Mr. F would still drink out of sinks and hoses. Mr. F’s mother reports that over the past month he had become more isolated. He would spend entire days reading the Bible, and his water intake had further increased.

Prior medication trials for Mr. F included haloperidol, up to 10 mg twice per day; aripiprazole, up to 20 mg/d; and risperidone, up to 6 mg nightly. These had been effective, but Mr. F had difficulty with adherence. He did not receive a long-acting injectable (LAI) antipsychotic initially due to lack of access at the rural clinic where he was treated, and later due to his mother’s preference for her son to receive oral medications. Prior to his current presentation, Mr. F’s medication regimen was olanzapine, 10 mg twice a day; perphenazine, 8 mg twice a day; and long-acting propranolol, 60 mg/d. Mr. F had no other chronic medical problems.

EVALUATION Hyponatremia, but why?

Mr. F is intubated and admitted to the surgical service for stabilization due to injuries from his fall. He has fractures of his right sinus and bilateral nasal bones, which are managed nonoperatively. He is delirious, with waxing and waning attention, memory disturbances, and disorientation. His psychotropic medications are held.

Continue to: Imaging of his head...

Imaging of his head does not reveal acute abnormalities suggesting a malignant or paraneoplastic process, and there are no concerns for ongoing seizures. An infection workup is negative. His urine toxicology is negative and blood alcohol level is 0. His sodium normalizes after 3 days of IV fluids and fluid restriction. Therefore, further tests to differentiate the causes of hyponatremia, such as urine electrolytes and urine osmolality, are not pursued.

[polldaddy:10910406]

The authors’ observations

The differential diagnosis for hyponatremia is broad in the setting of psychiatric illness. Low sodium levels could be due to psychotropic medications, psychiatrically-driven behaviors, or an underlying medical problem. Our differential diagnosis for Mr. F included iatrogenic syndrome of inappropriate antidiuretic hormone (SIADH), diabetes insipidus, or psychogenic polydipsia, a form of primary polydipsia. Other causes of primary polydipsia are related to substances, such as heavy beer intakeor use of 3,4-methylenedioxymethamphetamine (MDMA, also known as “ecstasy”), or brain lesions,¹ but these causes were less likely given Mr. F’s negative urine toxicology and head imaging.

While psychogenic polydipsia is due to increased water consumption, both SIADH and diabetes insipidus are due to alterations in fluid homeostasis.^2,3 Table 1^2-4 outlines distinguishing characteristics of SIADH, diabetes insipidus, and psychogenic polydipsia. Urine studies were not pursued because Mr. F’s sodium resolved and acute concerns, such as malignancy or infection, were ruled out. Mr. F’s hyponatremia was presumed to be due to psychogenic polydipsia because of his increased fluid intake and normalization of sodium with hypertonic fluids and subsequent fluid restriction. During this time, he was managed on the surgical service; the plan was to pursue urine studies and possibly a fluid challenge if his hyponatremia persisted.

EVALUATION Delirium resolves, delusions persist

While Mr. F is on the surgical service, the treatment team focuses on stabilizing his sodium level and assessing for causes of altered mental status that led to his fall. Psychiatry is consulted for management of his agitation. Following the gradual correction of his sodium level and extubation, his sensorium improves. By hospital Day 5, Mr. F’s delirium resolves.

During this time, Mr. F’s disorganization and religious delusions become apparent. He spends much of his time reading his Bible. He has poor hygiene and limited engagement in activities of daily living. Due to his psychosis and inability to care for himself, Mr. F is transferred to the psychiatric unit with consent from his mother.

Continue to: TREATMENT Olanzapine and fluid restriction

In the psychiatric unit, Mr. F is restarted on olanzapine, but not on perphenazine due to anticholinergic effects and not on propranolol due to continued orthostatic hypotension. Five days later, he is at his baseline level of functioning with residual psychosis. His fluid intake is restricted to <1.5 L per day and he is easily compliant.

Mr. F’s mother is comfortable with his discharge home on a regimen of olanzapine, 25 mg/d, and the team discusses the fluid restrictions with her. The treatment team suggests initiating an LAI before Mr. F is discharged, but this is not pursued because his mother thinks he is doing well with the oral medication. She wants to monitor him with the medication changes in the clinic before pursuing an LAI; however, she is open to it in the future.

The authors’ observations

Approximately 20% of patients with schizophrenia may experience psychogenic polydipsia.^4,5 The cause of psychogenic polydipsia in patients with serious mental illness is multifactorial. It may stem from malfunction of the hypothalamic-pituitary axis, which leads to alterations in antidiuretic hormone secretion and function.^4-6

Mr. F’s case highlights several challenges associated with treating psychogenic polydipsia in patients with serious mental illness. Antipsychotics with high dopamine affinity, such as risperidone and haloperidol, may increase the risk of psychogenic polydipsia, while antipsychotics with lower dopamine affinity, such as clozapine, may decrease the occurrence.⁵ Antipsychotics block postsynaptic dopamine receptors, which can induce supersensitivity by increasing presynaptic dopamine release in the hypothalamic areas, where thirst regulation occurs. This increase in dopamine leads to increased thirst drive and fluid intake.³

Quetiapine or clozapine may have been a better antipsychotic choice because these agents have lower D2 receptor affinity, whereas olanzapine has intermediate binding to D2 receptors.^6,7 However, quetiapine and clozapine are more strongly associated with orthostasis, which was a concern during Mr. F’s hospitalization. The weekly laboratory testing required with clozapine use would have been an unfeasible burden for Mr. F because he lived in a rural environment. Perphenazine was not continued due to higher D2 affinity and anticholinergic effects, which can increase thirst.⁶

Continue to: In addition to switching...

In addition to switching to an antipsychotic with looser D2 binding, other medications for treating polydipsia have been studied. It is hypothesized that the alpha-2 adrenergic system may play a role in thirst regulation. For example, mianserin, an alpha-2 antagonist, may decrease water intake. However, studies have been small and inconsistent.^8,9 Propranolol,¹⁰ a beta adrenergic receptor blocker; irbesartan,¹¹ an angiotensin-II receptor blocker; demeclocycline,¹² a tetracycline that inhibits antidiuretic hormone action; and naltrexone,⁹ a mu opioid antagonist, have been studied with inconclusive results and a variety of adverse effects^5,7,13 (Table 2^8-13).

Behavioral interventions for patients with psychogenic polydipsia include fluid restriction, twice-daily weight checks, cognitive-behavioral therapy, and reinforcement schedules, which may be useful but less realistic due to need for increased supervision.^11,12 Patient and family education on the signs of hyponatremia are important to prevent serious complications, such as those Mr. F experienced.

OUTCOME Repeated hospitalizations

Mr. F is discharged with follow-up in our psychiatry clinic and attends 1 appointment. At that time, his mother reports that Mr. F is compliant with his medication and has limited fluid intake. However, over the next 2 months, he is admitted to our psychiatric unit twice with similar presentations. Each time, the treatment team has extensive discussions with Mr. F’s mother about strategies to limit his water intake and the possibility of residential placement due to his need for a higher level of care. Although she acknowledges that nursing home placement may be needed in the future, she is not ready to take this step.

Three months later, Mr. F returns to our hospital with severe abdominal pain and is found to have a perforated bowel obstruction. His sodium is within normal limits on presentation, and the psychiatry team is not involved during this hospitalization. Mr. F is treated for sepsis and undergoes 3 exploratory laparotomies with continued decline in his health. He dies during this hospitalization. The cause of Mr. F’s perforated bowel obstruction is not determined, and his family does not pursue an autopsy.

The authors’ observations

At Mr. F’s final hospital presentation, his sodium was normal. It is possible Mr. F and his mother had found an acceptable fluid restriction routine, and he may have been doing better from a psychiatric perspective, but this will remain unknown.

Continue to: This case highlights...

This case highlights the clinical and ethical complexity of treating patients with psychogenic polydipsia. Because Mr. F no longer had autonomy, we had to determine if his mother was acting in his best interest as his guardian. Guardianship requirements and expectations vary by state. In our state of Missouri, a guardian is appointed by the court to act in the best interest of the ward, and may be a family member (preferred) or state-appointed. The guardian is responsible for providing the ward’s care and is in charge of financial and medical decisions. In Missouri, the guardian must assure the ward resides in the “least restrictive setting reasonably available,” which is the minimum necessary to provide the ward safe care and housing.¹⁴ Full guardianship, as in Mr. F’s case, is different from limited guardianship, which is an option in states such as Missouri. In limited guardianship, the court decides the extent of the guardian’s role in decisions for the ward.^14,15

Mr. F’s mother believed she was acting in her son’s best interest by having him home with his family. She believed by living at home, he would derive more enjoyment from life than living in a nursing home. By the time Mr. F presented to our hospital, he had been living with decompensated schizophrenia for years, so some level of psychosis was likely to persist, even with treatment. Given his increasingly frequent hospitalizations for hyponatremia due to increased water intake, more intense supervision may have been needed to maintain his safety, in line with nonmaleficence. The treatment team considered Mr. F’s best interest when discussing placement and worked to understand his mother’s preferences.

His mother continued to acknowledge the need for changes and adjustments at home. She was receptive to the need for fluid restriction and increased structure at home. Therefore, we felt she continued to be acting in his best interest, and his home would be the least restrictive setting for his care. If Mr. F had continued to require repeated hospitalizations and had not passed away, we would have pursued an ethics consult to discuss the need for nursing home placement and how to best approach this with Mr. F’s mother.

Bottom Line

Patients with serious mental illness who present with hyponatremia should be evaluated for psychogenic polydipsia by assessing their dietary and fluid intakes, along with collateral from family. The use of antipsychotics with high dopamine affinity may increase the risk of psychogenic polydipsia. Behavioral interventions include fluid restriction, weight checks, cognitive-behavioral therapy, and reinforcement schedules.

Related Resources

• Sharp CS, Wilson MP. Hyponatremia. In: Nordstrom KD, Wilson MP, eds. Quick guide to psychiatric emergencies. Springer International Publishing; 2018:115-119. doi:10.1007/ 978-3-319-58260-3_21
• Sailer C, Winzeler B, Christ-Crain M. Primary polydipsia in the medical and psychiatric patient: characteristics, complications and therapy. Swiss Med Wkly. 2017;147:w14514. doi:10.4414/ smw.2017.14514

Drug Brand Names

Amiloride • Midamor
Aripiprazole • Abilify
Clonidine • Catapres
Clozapine • Clozaril
Demeclocycline • Declomycin
Desmopressin • DDAVP
Haloperidol • Haldol
Irbesartan • Avapro
Lithium • Eskalith, Lithobid
Losartan • Cozaar
Mianserin • Tolvon
Naloxone • Narcan
Naltrexone • Revia
Olanzapine • Zyprexa
Perphenazine • Trilafon
Propranolol • Inderal LA
Quetiapine • Seroquel
Risperidone • Risperda

CASE Unresponsive after a presumed seizure

Mr. F, age 44, has schizophrenia. He is brought to the hospital by ambulance after he is found on the ground outside of his mother’s house following a presumed seizure and fall. On arrival to the emergency department, he is unresponsive. His laboratory values are significant for a sodium level of 110 mEq/L (reference range: 135 to 145 mEq/L), indicating hyponatremia.

HISTORY Fixated on purity

Mr. F’s mother reports that Mr. F had an unremarkable childhood. He was raised in a household with both parents and a younger sister. Mr. F did well academically and studied engineering and physics in college. There was no reported history of trauma or substance use.

During his senior year of college, Mr. F began experiencing paranoia, auditory hallucinations, and religious delusions. He required hospitalization and was diagnosed with schizophrenia. Following multiple hospitalizations over 5 years, he moved in with his mother, who was granted guardianship.

His mother said Mr. F’s religious delusions were of purity and cleansing the soul. He spent hours memorizing the Bible and would go for days without eating but would drink large amounts of water. She said she thought this was due to his desire to flush out imperfections.

In the past 3 years, Mr. F has been hospitalized several times for severe hyponatremia. At home, his mother attempted to restrict his water intake. However, Mr. F would still drink out of sinks and hoses. Mr. F’s mother reports that over the past month he had become more isolated. He would spend entire days reading the Bible, and his water intake had further increased.

Prior medication trials for Mr. F included haloperidol, up to 10 mg twice per day; aripiprazole, up to 20 mg/d; and risperidone, up to 6 mg nightly. These had been effective, but Mr. F had difficulty with adherence. He did not receive a long-acting injectable (LAI) antipsychotic initially due to lack of access at the rural clinic where he was treated, and later due to his mother’s preference for her son to receive oral medications. Prior to his current presentation, Mr. F’s medication regimen was olanzapine, 10 mg twice a day; perphenazine, 8 mg twice a day; and long-acting propranolol, 60 mg/d. Mr. F had no other chronic medical problems.

EVALUATION Hyponatremia, but why?

Mr. F is intubated and admitted to the surgical service for stabilization due to injuries from his fall. He has fractures of his right sinus and bilateral nasal bones, which are managed nonoperatively. He is delirious, with waxing and waning attention, memory disturbances, and disorientation. His psychotropic medications are held.

Continue to: Imaging of his head...

Imaging of his head does not reveal acute abnormalities suggesting a malignant or paraneoplastic process, and there are no concerns for ongoing seizures. An infection workup is negative. His urine toxicology is negative and blood alcohol level is 0. His sodium normalizes after 3 days of IV fluids and fluid restriction. Therefore, further tests to differentiate the causes of hyponatremia, such as urine electrolytes and urine osmolality, are not pursued.

[polldaddy:10910406]

The authors’ observations

The differential diagnosis for hyponatremia is broad in the setting of psychiatric illness. Low sodium levels could be due to psychotropic medications, psychiatrically-driven behaviors, or an underlying medical problem. Our differential diagnosis for Mr. F included iatrogenic syndrome of inappropriate antidiuretic hormone (SIADH), diabetes insipidus, or psychogenic polydipsia, a form of primary polydipsia. Other causes of primary polydipsia are related to substances, such as heavy beer intakeor use of 3,4-methylenedioxymethamphetamine (MDMA, also known as “ecstasy”), or brain lesions,¹ but these causes were less likely given Mr. F’s negative urine toxicology and head imaging.

While psychogenic polydipsia is due to increased water consumption, both SIADH and diabetes insipidus are due to alterations in fluid homeostasis.^2,3 Table 1^2-4 outlines distinguishing characteristics of SIADH, diabetes insipidus, and psychogenic polydipsia. Urine studies were not pursued because Mr. F’s sodium resolved and acute concerns, such as malignancy or infection, were ruled out. Mr. F’s hyponatremia was presumed to be due to psychogenic polydipsia because of his increased fluid intake and normalization of sodium with hypertonic fluids and subsequent fluid restriction. During this time, he was managed on the surgical service; the plan was to pursue urine studies and possibly a fluid challenge if his hyponatremia persisted.

EVALUATION Delirium resolves, delusions persist

While Mr. F is on the surgical service, the treatment team focuses on stabilizing his sodium level and assessing for causes of altered mental status that led to his fall. Psychiatry is consulted for management of his agitation. Following the gradual correction of his sodium level and extubation, his sensorium improves. By hospital Day 5, Mr. F’s delirium resolves.

During this time, Mr. F’s disorganization and religious delusions become apparent. He spends much of his time reading his Bible. He has poor hygiene and limited engagement in activities of daily living. Due to his psychosis and inability to care for himself, Mr. F is transferred to the psychiatric unit with consent from his mother.

Continue to: TREATMENT Olanzapine and fluid restriction

In the psychiatric unit, Mr. F is restarted on olanzapine, but not on perphenazine due to anticholinergic effects and not on propranolol due to continued orthostatic hypotension. Five days later, he is at his baseline level of functioning with residual psychosis. His fluid intake is restricted to <1.5 L per day and he is easily compliant.

Mr. F’s mother is comfortable with his discharge home on a regimen of olanzapine, 25 mg/d, and the team discusses the fluid restrictions with her. The treatment team suggests initiating an LAI before Mr. F is discharged, but this is not pursued because his mother thinks he is doing well with the oral medication. She wants to monitor him with the medication changes in the clinic before pursuing an LAI; however, she is open to it in the future.

The authors’ observations

Approximately 20% of patients with schizophrenia may experience psychogenic polydipsia.^4,5 The cause of psychogenic polydipsia in patients with serious mental illness is multifactorial. It may stem from malfunction of the hypothalamic-pituitary axis, which leads to alterations in antidiuretic hormone secretion and function.^4-6

Mr. F’s case highlights several challenges associated with treating psychogenic polydipsia in patients with serious mental illness. Antipsychotics with high dopamine affinity, such as risperidone and haloperidol, may increase the risk of psychogenic polydipsia, while antipsychotics with lower dopamine affinity, such as clozapine, may decrease the occurrence.⁵ Antipsychotics block postsynaptic dopamine receptors, which can induce supersensitivity by increasing presynaptic dopamine release in the hypothalamic areas, where thirst regulation occurs. This increase in dopamine leads to increased thirst drive and fluid intake.³

Quetiapine or clozapine may have been a better antipsychotic choice because these agents have lower D2 receptor affinity, whereas olanzapine has intermediate binding to D2 receptors.^6,7 However, quetiapine and clozapine are more strongly associated with orthostasis, which was a concern during Mr. F’s hospitalization. The weekly laboratory testing required with clozapine use would have been an unfeasible burden for Mr. F because he lived in a rural environment. Perphenazine was not continued due to higher D2 affinity and anticholinergic effects, which can increase thirst.⁶

Continue to: In addition to switching...

In addition to switching to an antipsychotic with looser D2 binding, other medications for treating polydipsia have been studied. It is hypothesized that the alpha-2 adrenergic system may play a role in thirst regulation. For example, mianserin, an alpha-2 antagonist, may decrease water intake. However, studies have been small and inconsistent.^8,9 Propranolol,¹⁰ a beta adrenergic receptor blocker; irbesartan,¹¹ an angiotensin-II receptor blocker; demeclocycline,¹² a tetracycline that inhibits antidiuretic hormone action; and naltrexone,⁹ a mu opioid antagonist, have been studied with inconclusive results and a variety of adverse effects^5,7,13 (Table 2^8-13).

Behavioral interventions for patients with psychogenic polydipsia include fluid restriction, twice-daily weight checks, cognitive-behavioral therapy, and reinforcement schedules, which may be useful but less realistic due to need for increased supervision.^11,12 Patient and family education on the signs of hyponatremia are important to prevent serious complications, such as those Mr. F experienced.

OUTCOME Repeated hospitalizations

Mr. F is discharged with follow-up in our psychiatry clinic and attends 1 appointment. At that time, his mother reports that Mr. F is compliant with his medication and has limited fluid intake. However, over the next 2 months, he is admitted to our psychiatric unit twice with similar presentations. Each time, the treatment team has extensive discussions with Mr. F’s mother about strategies to limit his water intake and the possibility of residential placement due to his need for a higher level of care. Although she acknowledges that nursing home placement may be needed in the future, she is not ready to take this step.

Three months later, Mr. F returns to our hospital with severe abdominal pain and is found to have a perforated bowel obstruction. His sodium is within normal limits on presentation, and the psychiatry team is not involved during this hospitalization. Mr. F is treated for sepsis and undergoes 3 exploratory laparotomies with continued decline in his health. He dies during this hospitalization. The cause of Mr. F’s perforated bowel obstruction is not determined, and his family does not pursue an autopsy.

The authors’ observations

At Mr. F’s final hospital presentation, his sodium was normal. It is possible Mr. F and his mother had found an acceptable fluid restriction routine, and he may have been doing better from a psychiatric perspective, but this will remain unknown.

Continue to: This case highlights...

This case highlights the clinical and ethical complexity of treating patients with psychogenic polydipsia. Because Mr. F no longer had autonomy, we had to determine if his mother was acting in his best interest as his guardian. Guardianship requirements and expectations vary by state. In our state of Missouri, a guardian is appointed by the court to act in the best interest of the ward, and may be a family member (preferred) or state-appointed. The guardian is responsible for providing the ward’s care and is in charge of financial and medical decisions. In Missouri, the guardian must assure the ward resides in the “least restrictive setting reasonably available,” which is the minimum necessary to provide the ward safe care and housing.¹⁴ Full guardianship, as in Mr. F’s case, is different from limited guardianship, which is an option in states such as Missouri. In limited guardianship, the court decides the extent of the guardian’s role in decisions for the ward.^14,15

Mr. F’s mother believed she was acting in her son’s best interest by having him home with his family. She believed by living at home, he would derive more enjoyment from life than living in a nursing home. By the time Mr. F presented to our hospital, he had been living with decompensated schizophrenia for years, so some level of psychosis was likely to persist, even with treatment. Given his increasingly frequent hospitalizations for hyponatremia due to increased water intake, more intense supervision may have been needed to maintain his safety, in line with nonmaleficence. The treatment team considered Mr. F’s best interest when discussing placement and worked to understand his mother’s preferences.

His mother continued to acknowledge the need for changes and adjustments at home. She was receptive to the need for fluid restriction and increased structure at home. Therefore, we felt she continued to be acting in his best interest, and his home would be the least restrictive setting for his care. If Mr. F had continued to require repeated hospitalizations and had not passed away, we would have pursued an ethics consult to discuss the need for nursing home placement and how to best approach this with Mr. F’s mother.

Bottom Line

Patients with serious mental illness who present with hyponatremia should be evaluated for psychogenic polydipsia by assessing their dietary and fluid intakes, along with collateral from family. The use of antipsychotics with high dopamine affinity may increase the risk of psychogenic polydipsia. Behavioral interventions include fluid restriction, weight checks, cognitive-behavioral therapy, and reinforcement schedules.

Related Resources

• Sharp CS, Wilson MP. Hyponatremia. In: Nordstrom KD, Wilson MP, eds. Quick guide to psychiatric emergencies. Springer International Publishing; 2018:115-119. doi:10.1007/ 978-3-319-58260-3_21
• Sailer C, Winzeler B, Christ-Crain M. Primary polydipsia in the medical and psychiatric patient: characteristics, complications and therapy. Swiss Med Wkly. 2017;147:w14514. doi:10.4414/ smw.2017.14514

Drug Brand Names

Amiloride • Midamor
Aripiprazole • Abilify
Clonidine • Catapres
Clozapine • Clozaril
Demeclocycline • Declomycin
Desmopressin • DDAVP
Haloperidol • Haldol
Irbesartan • Avapro
Lithium • Eskalith, Lithobid
Losartan • Cozaar
Mianserin • Tolvon
Naloxone • Narcan
Naltrexone • Revia
Olanzapine • Zyprexa
Perphenazine • Trilafon
Propranolol • Inderal LA
Quetiapine • Seroquel
Risperidone • Risperda

CASE Unresponsive after a presumed seizure

Mr. F, age 44, has schizophrenia. He is brought to the hospital by ambulance after he is found on the ground outside of his mother’s house following a presumed seizure and fall. On arrival to the emergency department, he is unresponsive. His laboratory values are significant for a sodium level of 110 mEq/L (reference range: 135 to 145 mEq/L), indicating hyponatremia.

HISTORY Fixated on purity

Mr. F’s mother reports that Mr. F had an unremarkable childhood. He was raised in a household with both parents and a younger sister. Mr. F did well academically and studied engineering and physics in college. There was no reported history of trauma or substance use.

During his senior year of college, Mr. F began experiencing paranoia, auditory hallucinations, and religious delusions. He required hospitalization and was diagnosed with schizophrenia. Following multiple hospitalizations over 5 years, he moved in with his mother, who was granted guardianship.

His mother said Mr. F’s religious delusions were of purity and cleansing the soul. He spent hours memorizing the Bible and would go for days without eating but would drink large amounts of water. She said she thought this was due to his desire to flush out imperfections.

In the past 3 years, Mr. F has been hospitalized several times for severe hyponatremia. At home, his mother attempted to restrict his water intake. However, Mr. F would still drink out of sinks and hoses. Mr. F’s mother reports that over the past month he had become more isolated. He would spend entire days reading the Bible, and his water intake had further increased.

Prior medication trials for Mr. F included haloperidol, up to 10 mg twice per day; aripiprazole, up to 20 mg/d; and risperidone, up to 6 mg nightly. These had been effective, but Mr. F had difficulty with adherence. He did not receive a long-acting injectable (LAI) antipsychotic initially due to lack of access at the rural clinic where he was treated, and later due to his mother’s preference for her son to receive oral medications. Prior to his current presentation, Mr. F’s medication regimen was olanzapine, 10 mg twice a day; perphenazine, 8 mg twice a day; and long-acting propranolol, 60 mg/d. Mr. F had no other chronic medical problems.

EVALUATION Hyponatremia, but why?

Mr. F is intubated and admitted to the surgical service for stabilization due to injuries from his fall. He has fractures of his right sinus and bilateral nasal bones, which are managed nonoperatively. He is delirious, with waxing and waning attention, memory disturbances, and disorientation. His psychotropic medications are held.

Continue to: Imaging of his head...

Imaging of his head does not reveal acute abnormalities suggesting a malignant or paraneoplastic process, and there are no concerns for ongoing seizures. An infection workup is negative. His urine toxicology is negative and blood alcohol level is 0. His sodium normalizes after 3 days of IV fluids and fluid restriction. Therefore, further tests to differentiate the causes of hyponatremia, such as urine electrolytes and urine osmolality, are not pursued.

[polldaddy:10910406]

The authors’ observations

The differential diagnosis for hyponatremia is broad in the setting of psychiatric illness. Low sodium levels could be due to psychotropic medications, psychiatrically-driven behaviors, or an underlying medical problem. Our differential diagnosis for Mr. F included iatrogenic syndrome of inappropriate antidiuretic hormone (SIADH), diabetes insipidus, or psychogenic polydipsia, a form of primary polydipsia. Other causes of primary polydipsia are related to substances, such as heavy beer intakeor use of 3,4-methylenedioxymethamphetamine (MDMA, also known as “ecstasy”), or brain lesions,¹ but these causes were less likely given Mr. F’s negative urine toxicology and head imaging.

While psychogenic polydipsia is due to increased water consumption, both SIADH and diabetes insipidus are due to alterations in fluid homeostasis.^2,3 Table 1^2-4 outlines distinguishing characteristics of SIADH, diabetes insipidus, and psychogenic polydipsia. Urine studies were not pursued because Mr. F’s sodium resolved and acute concerns, such as malignancy or infection, were ruled out. Mr. F’s hyponatremia was presumed to be due to psychogenic polydipsia because of his increased fluid intake and normalization of sodium with hypertonic fluids and subsequent fluid restriction. During this time, he was managed on the surgical service; the plan was to pursue urine studies and possibly a fluid challenge if his hyponatremia persisted.

EVALUATION Delirium resolves, delusions persist

While Mr. F is on the surgical service, the treatment team focuses on stabilizing his sodium level and assessing for causes of altered mental status that led to his fall. Psychiatry is consulted for management of his agitation. Following the gradual correction of his sodium level and extubation, his sensorium improves. By hospital Day 5, Mr. F’s delirium resolves.

During this time, Mr. F’s disorganization and religious delusions become apparent. He spends much of his time reading his Bible. He has poor hygiene and limited engagement in activities of daily living. Due to his psychosis and inability to care for himself, Mr. F is transferred to the psychiatric unit with consent from his mother.

Continue to: TREATMENT Olanzapine and fluid restriction

In the psychiatric unit, Mr. F is restarted on olanzapine, but not on perphenazine due to anticholinergic effects and not on propranolol due to continued orthostatic hypotension. Five days later, he is at his baseline level of functioning with residual psychosis. His fluid intake is restricted to <1.5 L per day and he is easily compliant.

Mr. F’s mother is comfortable with his discharge home on a regimen of olanzapine, 25 mg/d, and the team discusses the fluid restrictions with her. The treatment team suggests initiating an LAI before Mr. F is discharged, but this is not pursued because his mother thinks he is doing well with the oral medication. She wants to monitor him with the medication changes in the clinic before pursuing an LAI; however, she is open to it in the future.

The authors’ observations

Approximately 20% of patients with schizophrenia may experience psychogenic polydipsia.^4,5 The cause of psychogenic polydipsia in patients with serious mental illness is multifactorial. It may stem from malfunction of the hypothalamic-pituitary axis, which leads to alterations in antidiuretic hormone secretion and function.^4-6

Mr. F’s case highlights several challenges associated with treating psychogenic polydipsia in patients with serious mental illness. Antipsychotics with high dopamine affinity, such as risperidone and haloperidol, may increase the risk of psychogenic polydipsia, while antipsychotics with lower dopamine affinity, such as clozapine, may decrease the occurrence.⁵ Antipsychotics block postsynaptic dopamine receptors, which can induce supersensitivity by increasing presynaptic dopamine release in the hypothalamic areas, where thirst regulation occurs. This increase in dopamine leads to increased thirst drive and fluid intake.³

Quetiapine or clozapine may have been a better antipsychotic choice because these agents have lower D2 receptor affinity, whereas olanzapine has intermediate binding to D2 receptors.^6,7 However, quetiapine and clozapine are more strongly associated with orthostasis, which was a concern during Mr. F’s hospitalization. The weekly laboratory testing required with clozapine use would have been an unfeasible burden for Mr. F because he lived in a rural environment. Perphenazine was not continued due to higher D2 affinity and anticholinergic effects, which can increase thirst.⁶

Continue to: In addition to switching...

In addition to switching to an antipsychotic with looser D2 binding, other medications for treating polydipsia have been studied. It is hypothesized that the alpha-2 adrenergic system may play a role in thirst regulation. For example, mianserin, an alpha-2 antagonist, may decrease water intake. However, studies have been small and inconsistent.^8,9 Propranolol,¹⁰ a beta adrenergic receptor blocker; irbesartan,¹¹ an angiotensin-II receptor blocker; demeclocycline,¹² a tetracycline that inhibits antidiuretic hormone action; and naltrexone,⁹ a mu opioid antagonist, have been studied with inconclusive results and a variety of adverse effects^5,7,13 (Table 2^8-13).

Behavioral interventions for patients with psychogenic polydipsia include fluid restriction, twice-daily weight checks, cognitive-behavioral therapy, and reinforcement schedules, which may be useful but less realistic due to need for increased supervision.^11,12 Patient and family education on the signs of hyponatremia are important to prevent serious complications, such as those Mr. F experienced.

OUTCOME Repeated hospitalizations

Mr. F is discharged with follow-up in our psychiatry clinic and attends 1 appointment. At that time, his mother reports that Mr. F is compliant with his medication and has limited fluid intake. However, over the next 2 months, he is admitted to our psychiatric unit twice with similar presentations. Each time, the treatment team has extensive discussions with Mr. F’s mother about strategies to limit his water intake and the possibility of residential placement due to his need for a higher level of care. Although she acknowledges that nursing home placement may be needed in the future, she is not ready to take this step.

Three months later, Mr. F returns to our hospital with severe abdominal pain and is found to have a perforated bowel obstruction. His sodium is within normal limits on presentation, and the psychiatry team is not involved during this hospitalization. Mr. F is treated for sepsis and undergoes 3 exploratory laparotomies with continued decline in his health. He dies during this hospitalization. The cause of Mr. F’s perforated bowel obstruction is not determined, and his family does not pursue an autopsy.

The authors’ observations

At Mr. F’s final hospital presentation, his sodium was normal. It is possible Mr. F and his mother had found an acceptable fluid restriction routine, and he may have been doing better from a psychiatric perspective, but this will remain unknown.

Continue to: This case highlights...

This case highlights the clinical and ethical complexity of treating patients with psychogenic polydipsia. Because Mr. F no longer had autonomy, we had to determine if his mother was acting in his best interest as his guardian. Guardianship requirements and expectations vary by state. In our state of Missouri, a guardian is appointed by the court to act in the best interest of the ward, and may be a family member (preferred) or state-appointed. The guardian is responsible for providing the ward’s care and is in charge of financial and medical decisions. In Missouri, the guardian must assure the ward resides in the “least restrictive setting reasonably available,” which is the minimum necessary to provide the ward safe care and housing.¹⁴ Full guardianship, as in Mr. F’s case, is different from limited guardianship, which is an option in states such as Missouri. In limited guardianship, the court decides the extent of the guardian’s role in decisions for the ward.^14,15

Mr. F’s mother believed she was acting in her son’s best interest by having him home with his family. She believed by living at home, he would derive more enjoyment from life than living in a nursing home. By the time Mr. F presented to our hospital, he had been living with decompensated schizophrenia for years, so some level of psychosis was likely to persist, even with treatment. Given his increasingly frequent hospitalizations for hyponatremia due to increased water intake, more intense supervision may have been needed to maintain his safety, in line with nonmaleficence. The treatment team considered Mr. F’s best interest when discussing placement and worked to understand his mother’s preferences.

His mother continued to acknowledge the need for changes and adjustments at home. She was receptive to the need for fluid restriction and increased structure at home. Therefore, we felt she continued to be acting in his best interest, and his home would be the least restrictive setting for his care. If Mr. F had continued to require repeated hospitalizations and had not passed away, we would have pursued an ethics consult to discuss the need for nursing home placement and how to best approach this with Mr. F’s mother.

Bottom Line

Patients with serious mental illness who present with hyponatremia should be evaluated for psychogenic polydipsia by assessing their dietary and fluid intakes, along with collateral from family. The use of antipsychotics with high dopamine affinity may increase the risk of psychogenic polydipsia. Behavioral interventions include fluid restriction, weight checks, cognitive-behavioral therapy, and reinforcement schedules.

Related Resources

• Sharp CS, Wilson MP. Hyponatremia. In: Nordstrom KD, Wilson MP, eds. Quick guide to psychiatric emergencies. Springer International Publishing; 2018:115-119. doi:10.1007/ 978-3-319-58260-3_21
• Sailer C, Winzeler B, Christ-Crain M. Primary polydipsia in the medical and psychiatric patient: characteristics, complications and therapy. Swiss Med Wkly. 2017;147:w14514. doi:10.4414/ smw.2017.14514

Drug Brand Names

Amiloride • Midamor
Aripiprazole • Abilify
Clonidine • Catapres
Clozapine • Clozaril
Demeclocycline • Declomycin
Desmopressin • DDAVP
Haloperidol • Haldol
Irbesartan • Avapro
Lithium • Eskalith, Lithobid
Losartan • Cozaar
Mianserin • Tolvon
Naloxone • Narcan
Naltrexone • Revia
Olanzapine • Zyprexa
Perphenazine • Trilafon
Propranolol • Inderal LA
Quetiapine • Seroquel
Risperidone • Risperda

In the modern-day practice of medicine, turf wars are more common than one may realize. Presently, an ongoing battle over who should be prescribing and administering ketamine for novel treatment uses is being waged among psychiatrists, anesthesiologists, family physicians, and emergency physicians. Whoever emerges victorious will determine whether psychiatric care is administered in a safe and cost-effective manner, or if it will merely benefit the bottom line of the prescriber. In this article, we discuss how ketamine may have a role for treatment-resistant depression (TRD), and why psychiatrists are uniquely qualified to prescribe and administer this medication for this purpose.

New approaches to treatment-resistant depression

Antidepressant medications, long the mainstay of depression treatment, have been shown to be safe and relatively equally effective, with varying tolerability. However, 33% percent of patients do not achieve remission after 4 trials of antidepressant therapy.¹ Most antidepressant efficacy studies report remission rates of 35% to 40%,² which means many patients require subsequent switching and/or augmentation of their treatment.³ The STAR*D trial demonstrated that after 2 adequate antidepressant trials, the likelihood of remission diminishes.⁴

After a patient’s depression is found to be treatment-resistant, the onus of guiding treatment shifts away from the patient’s primary care physician to the more specialized psychiatrist. Few would question the suitability of a psychiatrist’s expertise in handling complicated and nuanced mental illness. In order to manage TRD, psychiatrists enter a terrain of emerging novel therapies with rapid onset, different mechanisms of action, and parenteral routes of administration.

One such therapy is esketamine, the S-enantiomer of ketamine. The FDA approved the intranasal (IN) formulation of esketamine in March 2019 after the medication had been designated as a breakthrough therapy for TRD in 2013 and studied in 6 Phase III clinical trials.⁵ The S-enantiomer of ketamine is known to bind to the N-methyl-D-aspartate receptor stronger than the R-enantiomer.⁶ The mechanism of action of both stereoisomers on other receptors, such as opioid and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), is the focus of intensive research and remains to be fully elucidated, but initial studies indicate rapid neuroplasticity and synaptogenesis.⁷ What is clear is that this new intervention can provide relief to patients with TRD via a pharmacologically distinct mechanism.⁸

Ketamine may be administered intranasally, intravenously, or orally. A meta-analysis aimed at assessing differences in ketamine efficacy for depression based on route of administration have shown that both IV and IN ketamine are effective, though it is not possible to draw conclusions regarding a direct comparison based on available data.⁹ Despite several landmark published studies, such as those by Zarate et al,¹⁰ IV ketamine is not FDA-approved for TRD.

Continue to: Why psychiatrists?

Psychiatrists have been prescribing IN esketamine, which is covered by most commercial insurances and administered in certified healthcare settings under a Risk Evaluation and Mitigation Strategy program.⁵ However, anesthesiologists and emergency physicians have opened a crop of boutique and concierge health clinics offering various “packages” of IV ketamine infusions for a slew of mental ailments, including depression, anxiety, bipolar disorder, and posttraumatic stress disorder.¹¹ Minimal investigation reveals that these services are being prescribed mainly by practitioners in fields other than psychiatry. Intravenous ketamine has long been used off-label as a treatment for depression not by psychiatrists but by practitioners of anesthesiology or emergency medicine. Although these clinicians are likely familiar with ketamine as an anesthetic, they have no foundation or expertise in the diagnosis and treatment of complex mood disorders. The FDA-approved indication for esketamine falls firmly in the realm of psychiatric treatment. Physicians who have not completed a psychiatry residency have neither the training nor experience necessary to determine whether a patient is a candidate for this treatment.

One potential adverse effect of ketamine is an emergence phenomenon, colloquially named a “K-hole,” that can induce symptoms of psychosis such as disturbing hallucinations. Patients who have a history of psychosis need to be carefully evaluated for appropriateness to receive this treatment.

Furthermore, ketamine treatments administered by physicians who are not psychiatrists are billed not through insurance but mostly via private pay. A patient may therefore be charged $350 to $1,000 per infusion, to be paid out of pocket.¹¹ Tally that up over the standard 6 to 12 initial treatment infusions, followed by maintenance infusions, and these patients with profound depression are potentially building up significant debt. Does this practice align with the ethical principles of autonomy, justice, beneficence, and nonmaleficence that all physicians swore to uphold? Will psychiatrists take a stand against the financial exploitation of a vulnerable group that is desperate to find any potential relief from their depression?

In the modern-day practice of medicine, turf wars are more common than one may realize. Presently, an ongoing battle over who should be prescribing and administering ketamine for novel treatment uses is being waged among psychiatrists, anesthesiologists, family physicians, and emergency physicians. Whoever emerges victorious will determine whether psychiatric care is administered in a safe and cost-effective manner, or if it will merely benefit the bottom line of the prescriber. In this article, we discuss how ketamine may have a role for treatment-resistant depression (TRD), and why psychiatrists are uniquely qualified to prescribe and administer this medication for this purpose.

New approaches to treatment-resistant depression

Antidepressant medications, long the mainstay of depression treatment, have been shown to be safe and relatively equally effective, with varying tolerability. However, 33% percent of patients do not achieve remission after 4 trials of antidepressant therapy.¹ Most antidepressant efficacy studies report remission rates of 35% to 40%,² which means many patients require subsequent switching and/or augmentation of their treatment.³ The STAR*D trial demonstrated that after 2 adequate antidepressant trials, the likelihood of remission diminishes.⁴

After a patient’s depression is found to be treatment-resistant, the onus of guiding treatment shifts away from the patient’s primary care physician to the more specialized psychiatrist. Few would question the suitability of a psychiatrist’s expertise in handling complicated and nuanced mental illness. In order to manage TRD, psychiatrists enter a terrain of emerging novel therapies with rapid onset, different mechanisms of action, and parenteral routes of administration.

One such therapy is esketamine, the S-enantiomer of ketamine. The FDA approved the intranasal (IN) formulation of esketamine in March 2019 after the medication had been designated as a breakthrough therapy for TRD in 2013 and studied in 6 Phase III clinical trials.⁵ The S-enantiomer of ketamine is known to bind to the N-methyl-D-aspartate receptor stronger than the R-enantiomer.⁶ The mechanism of action of both stereoisomers on other receptors, such as opioid and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), is the focus of intensive research and remains to be fully elucidated, but initial studies indicate rapid neuroplasticity and synaptogenesis.⁷ What is clear is that this new intervention can provide relief to patients with TRD via a pharmacologically distinct mechanism.⁸

Ketamine may be administered intranasally, intravenously, or orally. A meta-analysis aimed at assessing differences in ketamine efficacy for depression based on route of administration have shown that both IV and IN ketamine are effective, though it is not possible to draw conclusions regarding a direct comparison based on available data.⁹ Despite several landmark published studies, such as those by Zarate et al,¹⁰ IV ketamine is not FDA-approved for TRD.

Continue to: Why psychiatrists?

Psychiatrists have been prescribing IN esketamine, which is covered by most commercial insurances and administered in certified healthcare settings under a Risk Evaluation and Mitigation Strategy program.⁵ However, anesthesiologists and emergency physicians have opened a crop of boutique and concierge health clinics offering various “packages” of IV ketamine infusions for a slew of mental ailments, including depression, anxiety, bipolar disorder, and posttraumatic stress disorder.¹¹ Minimal investigation reveals that these services are being prescribed mainly by practitioners in fields other than psychiatry. Intravenous ketamine has long been used off-label as a treatment for depression not by psychiatrists but by practitioners of anesthesiology or emergency medicine. Although these clinicians are likely familiar with ketamine as an anesthetic, they have no foundation or expertise in the diagnosis and treatment of complex mood disorders. The FDA-approved indication for esketamine falls firmly in the realm of psychiatric treatment. Physicians who have not completed a psychiatry residency have neither the training nor experience necessary to determine whether a patient is a candidate for this treatment.

One potential adverse effect of ketamine is an emergence phenomenon, colloquially named a “K-hole,” that can induce symptoms of psychosis such as disturbing hallucinations. Patients who have a history of psychosis need to be carefully evaluated for appropriateness to receive this treatment.

Furthermore, ketamine treatments administered by physicians who are not psychiatrists are billed not through insurance but mostly via private pay. A patient may therefore be charged $350 to $1,000 per infusion, to be paid out of pocket.¹¹ Tally that up over the standard 6 to 12 initial treatment infusions, followed by maintenance infusions, and these patients with profound depression are potentially building up significant debt. Does this practice align with the ethical principles of autonomy, justice, beneficence, and nonmaleficence that all physicians swore to uphold? Will psychiatrists take a stand against the financial exploitation of a vulnerable group that is desperate to find any potential relief from their depression?

In the modern-day practice of medicine, turf wars are more common than one may realize. Presently, an ongoing battle over who should be prescribing and administering ketamine for novel treatment uses is being waged among psychiatrists, anesthesiologists, family physicians, and emergency physicians. Whoever emerges victorious will determine whether psychiatric care is administered in a safe and cost-effective manner, or if it will merely benefit the bottom line of the prescriber. In this article, we discuss how ketamine may have a role for treatment-resistant depression (TRD), and why psychiatrists are uniquely qualified to prescribe and administer this medication for this purpose.

New approaches to treatment-resistant depression

Antidepressant medications, long the mainstay of depression treatment, have been shown to be safe and relatively equally effective, with varying tolerability. However, 33% percent of patients do not achieve remission after 4 trials of antidepressant therapy.¹ Most antidepressant efficacy studies report remission rates of 35% to 40%,² which means many patients require subsequent switching and/or augmentation of their treatment.³ The STAR*D trial demonstrated that after 2 adequate antidepressant trials, the likelihood of remission diminishes.⁴

After a patient’s depression is found to be treatment-resistant, the onus of guiding treatment shifts away from the patient’s primary care physician to the more specialized psychiatrist. Few would question the suitability of a psychiatrist’s expertise in handling complicated and nuanced mental illness. In order to manage TRD, psychiatrists enter a terrain of emerging novel therapies with rapid onset, different mechanisms of action, and parenteral routes of administration.

One such therapy is esketamine, the S-enantiomer of ketamine. The FDA approved the intranasal (IN) formulation of esketamine in March 2019 after the medication had been designated as a breakthrough therapy for TRD in 2013 and studied in 6 Phase III clinical trials.⁵ The S-enantiomer of ketamine is known to bind to the N-methyl-D-aspartate receptor stronger than the R-enantiomer.⁶ The mechanism of action of both stereoisomers on other receptors, such as opioid and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), is the focus of intensive research and remains to be fully elucidated, but initial studies indicate rapid neuroplasticity and synaptogenesis.⁷ What is clear is that this new intervention can provide relief to patients with TRD via a pharmacologically distinct mechanism.⁸

Ketamine may be administered intranasally, intravenously, or orally. A meta-analysis aimed at assessing differences in ketamine efficacy for depression based on route of administration have shown that both IV and IN ketamine are effective, though it is not possible to draw conclusions regarding a direct comparison based on available data.⁹ Despite several landmark published studies, such as those by Zarate et al,¹⁰ IV ketamine is not FDA-approved for TRD.

Continue to: Why psychiatrists?

Psychiatrists have been prescribing IN esketamine, which is covered by most commercial insurances and administered in certified healthcare settings under a Risk Evaluation and Mitigation Strategy program.⁵ However, anesthesiologists and emergency physicians have opened a crop of boutique and concierge health clinics offering various “packages” of IV ketamine infusions for a slew of mental ailments, including depression, anxiety, bipolar disorder, and posttraumatic stress disorder.¹¹ Minimal investigation reveals that these services are being prescribed mainly by practitioners in fields other than psychiatry. Intravenous ketamine has long been used off-label as a treatment for depression not by psychiatrists but by practitioners of anesthesiology or emergency medicine. Although these clinicians are likely familiar with ketamine as an anesthetic, they have no foundation or expertise in the diagnosis and treatment of complex mood disorders. The FDA-approved indication for esketamine falls firmly in the realm of psychiatric treatment. Physicians who have not completed a psychiatry residency have neither the training nor experience necessary to determine whether a patient is a candidate for this treatment.

One potential adverse effect of ketamine is an emergence phenomenon, colloquially named a “K-hole,” that can induce symptoms of psychosis such as disturbing hallucinations. Patients who have a history of psychosis need to be carefully evaluated for appropriateness to receive this treatment.

Furthermore, ketamine treatments administered by physicians who are not psychiatrists are billed not through insurance but mostly via private pay. A patient may therefore be charged $350 to $1,000 per infusion, to be paid out of pocket.¹¹ Tally that up over the standard 6 to 12 initial treatment infusions, followed by maintenance infusions, and these patients with profound depression are potentially building up significant debt. Does this practice align with the ethical principles of autonomy, justice, beneficence, and nonmaleficence that all physicians swore to uphold? Will psychiatrists take a stand against the financial exploitation of a vulnerable group that is desperate to find any potential relief from their depression?

Editor’s note: Readers’ Forum is a department for correspondence from readers that is not in response to articles published in Current Psychiatry. All submissions to Readers’ Forum undergo peer review and are subject to editing for length and style. For more information, contact [email protected].

The Accreditation Council for Graduate Medical Education (ACGME) is en­trusted with assuring that upon graduation every resident is a competent doctor, a trained professional, and prepared to practice in their own field at a level that assures patient safety and meets the standard of care. The American Board of Psychiatry and Neurology (ABPN) is a private company that sells certificates claiming to attest the capacity or competence of the doctor but does not make public the test questions or algorithms used to win its qualifications or approval. The certifying business and the newer Maintenance of Certification (MOC) process developed by ABPN have unfortunately been embraced by ACGME and many hospitals, despite the lack of any good scientific support that board certification or MOC are meaningful for quality of patient care or outcomes. By that I mean there is no evidence that the voluntary board certification process or MOC have been shown to produce better outcomes for patients, save money for the country drowning in an ocean of health care costs, or allow doctors to get paid at a higher level by insurers for the same billing codes compared with those who bill without possessing these qualifications. The only entity that “profits” from the board certification/MOC process is ABPN, a private corporation that is supposed to be a nonprofit, but was sitting on a treasury of more than $140M in assets in 2019,¹ with revenues growing annually. Including the interest earned on the investment and added revenues every year, the estimated total assets of ABPN will be in the range of $150M at the end of 2021!

Collaboration between ACGME and ABPN

The collaboration between ACGME and ABPN for graduate education for designing training programs for residents and fellows, with progressively increasing competencies and their assessments to dovetail with the board examinations offered by ABPN, sounds very legitimate. This arrangement is designed to enhance the quality of training and establish a minimum level of competence in each trainee who completes the training program. However, ACGME is catering to a monopoly recognized by the US Department of Justice (DOJ) Antitrust Division.² ACGME has not entertained other evaluators of competence to discourage competition to the monopolistic ABPN. ACGME is only involved with the accredited training programs and has no business in assessing the continued competence of graduated trainees after they leave the program, although most will voluntarily opt to become board-certified by ABPN. Maintenance of Certification definitely does not come within the purview of “graduate medical education” for ACGME to be getting drawn into this collaboration.

ACGME and ABPN are unregulated and are not member-driven. As such, they operate outside of any real oversight. Their power derives from the status given to them by hospitals, some insurers, and many of our colleagues, who fail to see the reality that they are nothing more than diploma shops.

I am board-certified in psychiatry and child and adolescent psychiatry, and I have participated in obtaining board certification by ABPN in 3 other subspecialties (geriatric, addiction, and forensic). I decided to not participate in MOC for the latter 3 subspecialty certifications beyond 10 and 20 years for my own practical reasons. Obviously, then, I am not at all against initial certifications in any specialty, nor am I opposed to practitioners keeping up with progress in their fields and maintaining their competence. I am opposed to the continued efforts to engage professionals to pay a high price for the repeated MOC, riding on the hard work and earnings of the graduated specialists and continuously suctioning their income over their careers, with no evidence that MOC measures clinical competence or patient outcomes of their subscribers, who pay a chunk of money to the American Board of Medical Specialties (ABMS)/ABPN annually and every 10 years.

MOC and the APA

Many American Psychiatric Association (APA) members are opposed to the APA giving ABPN a piggyback ride to accomplish this profit seeking. This is becoming obvious to many APA members, who see this as a great exploitation.

Over the last 6 years, physicians have begun to question the validity of board certification and MOC by ABPN, mostly as a response to ever-increasing costs to them and ever-increasing revenues to ABPN. While APA members have long pressed the APA to push back against ABPN, the APA Board of Trustees has done the opposite by accepting yearly “unrestricted educational grants” from ABPN. In this manner, ABPN has essentially silenced the APA and has made it ineffective as our member organization in what has become a fight against ABPN’s unchecked power, influence, and intrusion. Every poll conducted by every APA District Branch or subspecialty organization has shown widespread discontent and anger at the ABPN/MOC process and APA’s deliberate inaction. Even when the APA commissioned its own member survey on the topic, wrote the questions, picked who would get the survey, decided which responses to count, and determined what statistics to apply, the results were damning. Despite its obviously transparent machinations, the APA failed to glorify the MOC process.

Continue to: The APA's membership...

The APA’s membership is declining, and the Board of Trustee’s position on MOC is partly to blame. The APA is once again not listening to its members! As a membership-driven organization, the APA must not exclusively support and promote this commercial educational product termed MOC when other, less expensive alternatives are now available. The APA can easily endorse these alternatives, in addition to offering its own less expensive products for attesting maintenance of competence. The latter effort will help eliminate the monopoly held by ABMS/ABPN in this domain and please all members as well as the DOJ.

The APA’s failure to provide less expensive alternatives or at least endorse existing ones despite repeated requests from a large number of APA members has led to frustration and a surge of strong feelings that are expressed on the APA email listservs, and especially that of the MOC caucus. These expressions are legitimate and need to be publicized to the general membership. I have collected the opinions of various loyal, long-standing APA members and put together a separate, yet-unpublished article to drive home the point that APA has resisted breaking the monopoly of ABPN, which the DOJ would encourage organizations such as the APA to do. Instead, APA is acting as an enabler to ABPN to create a multi-million dollar (and eventually a billion dollar) monopolistic industry at their members’ expense, literally endangering the careers of members if they fail to participate when employed by institutions that overvalue the MOC offered by ABPN.

I believe the recent exhibition of “collaboration” between the APA and ABPN is not similar to that between ACGME and ABPN, but is a most blatant effort on the part of the APA to help ABPN build a billion-dollar educational industry over the next 10 to 15 years. One can easily lose sight of this and get lost in the intricacies of how candidates can maintain their competency by obtaining free CME credits. The APA is distracting its members by citing this. They will continue to pay a high price for certification and recertification, with no real discount.

Most of the APA’s 38,000 members are in the dark about the above-mentioned process. They need to do their own research, especially when there are alternatives to the ABPN’s MOC program. They need to insist that the APA stop exclusively promoting ABPN products, and publicize other, much cheaper, alternatives. It will please all APA members to see the ABPN’s monopoly vanish. This is especially the case for younger psychiatrists, who average nearly $250,000 in educational loans. They need to prevent the APA/ABPN collaboration from having a far-reaching effect on their careers and finances, with potentially destructive consequences for their families, employers and—most importantly—their patients. Even some state licensing boards are being tempted to buy into the illusion.

Stop this MOCkery.

Editor’s note: Readers’ Forum is a department for correspondence from readers that is not in response to articles published in Current Psychiatry. All submissions to Readers’ Forum undergo peer review and are subject to editing for length and style. For more information, contact [email protected].

The Accreditation Council for Graduate Medical Education (ACGME) is en­trusted with assuring that upon graduation every resident is a competent doctor, a trained professional, and prepared to practice in their own field at a level that assures patient safety and meets the standard of care. The American Board of Psychiatry and Neurology (ABPN) is a private company that sells certificates claiming to attest the capacity or competence of the doctor but does not make public the test questions or algorithms used to win its qualifications or approval. The certifying business and the newer Maintenance of Certification (MOC) process developed by ABPN have unfortunately been embraced by ACGME and many hospitals, despite the lack of any good scientific support that board certification or MOC are meaningful for quality of patient care or outcomes. By that I mean there is no evidence that the voluntary board certification process or MOC have been shown to produce better outcomes for patients, save money for the country drowning in an ocean of health care costs, or allow doctors to get paid at a higher level by insurers for the same billing codes compared with those who bill without possessing these qualifications. The only entity that “profits” from the board certification/MOC process is ABPN, a private corporation that is supposed to be a nonprofit, but was sitting on a treasury of more than $140M in assets in 2019,¹ with revenues growing annually. Including the interest earned on the investment and added revenues every year, the estimated total assets of ABPN will be in the range of $150M at the end of 2021!

Collaboration between ACGME and ABPN

The collaboration between ACGME and ABPN for graduate education for designing training programs for residents and fellows, with progressively increasing competencies and their assessments to dovetail with the board examinations offered by ABPN, sounds very legitimate. This arrangement is designed to enhance the quality of training and establish a minimum level of competence in each trainee who completes the training program. However, ACGME is catering to a monopoly recognized by the US Department of Justice (DOJ) Antitrust Division.² ACGME has not entertained other evaluators of competence to discourage competition to the monopolistic ABPN. ACGME is only involved with the accredited training programs and has no business in assessing the continued competence of graduated trainees after they leave the program, although most will voluntarily opt to become board-certified by ABPN. Maintenance of Certification definitely does not come within the purview of “graduate medical education” for ACGME to be getting drawn into this collaboration.

ACGME and ABPN are unregulated and are not member-driven. As such, they operate outside of any real oversight. Their power derives from the status given to them by hospitals, some insurers, and many of our colleagues, who fail to see the reality that they are nothing more than diploma shops.

I am board-certified in psychiatry and child and adolescent psychiatry, and I have participated in obtaining board certification by ABPN in 3 other subspecialties (geriatric, addiction, and forensic). I decided to not participate in MOC for the latter 3 subspecialty certifications beyond 10 and 20 years for my own practical reasons. Obviously, then, I am not at all against initial certifications in any specialty, nor am I opposed to practitioners keeping up with progress in their fields and maintaining their competence. I am opposed to the continued efforts to engage professionals to pay a high price for the repeated MOC, riding on the hard work and earnings of the graduated specialists and continuously suctioning their income over their careers, with no evidence that MOC measures clinical competence or patient outcomes of their subscribers, who pay a chunk of money to the American Board of Medical Specialties (ABMS)/ABPN annually and every 10 years.

MOC and the APA

Many American Psychiatric Association (APA) members are opposed to the APA giving ABPN a piggyback ride to accomplish this profit seeking. This is becoming obvious to many APA members, who see this as a great exploitation.

Over the last 6 years, physicians have begun to question the validity of board certification and MOC by ABPN, mostly as a response to ever-increasing costs to them and ever-increasing revenues to ABPN. While APA members have long pressed the APA to push back against ABPN, the APA Board of Trustees has done the opposite by accepting yearly “unrestricted educational grants” from ABPN. In this manner, ABPN has essentially silenced the APA and has made it ineffective as our member organization in what has become a fight against ABPN’s unchecked power, influence, and intrusion. Every poll conducted by every APA District Branch or subspecialty organization has shown widespread discontent and anger at the ABPN/MOC process and APA’s deliberate inaction. Even when the APA commissioned its own member survey on the topic, wrote the questions, picked who would get the survey, decided which responses to count, and determined what statistics to apply, the results were damning. Despite its obviously transparent machinations, the APA failed to glorify the MOC process.

Continue to: The APA's membership...

The APA’s membership is declining, and the Board of Trustee’s position on MOC is partly to blame. The APA is once again not listening to its members! As a membership-driven organization, the APA must not exclusively support and promote this commercial educational product termed MOC when other, less expensive alternatives are now available. The APA can easily endorse these alternatives, in addition to offering its own less expensive products for attesting maintenance of competence. The latter effort will help eliminate the monopoly held by ABMS/ABPN in this domain and please all members as well as the DOJ.

The APA’s failure to provide less expensive alternatives or at least endorse existing ones despite repeated requests from a large number of APA members has led to frustration and a surge of strong feelings that are expressed on the APA email listservs, and especially that of the MOC caucus. These expressions are legitimate and need to be publicized to the general membership. I have collected the opinions of various loyal, long-standing APA members and put together a separate, yet-unpublished article to drive home the point that APA has resisted breaking the monopoly of ABPN, which the DOJ would encourage organizations such as the APA to do. Instead, APA is acting as an enabler to ABPN to create a multi-million dollar (and eventually a billion dollar) monopolistic industry at their members’ expense, literally endangering the careers of members if they fail to participate when employed by institutions that overvalue the MOC offered by ABPN.

I believe the recent exhibition of “collaboration” between the APA and ABPN is not similar to that between ACGME and ABPN, but is a most blatant effort on the part of the APA to help ABPN build a billion-dollar educational industry over the next 10 to 15 years. One can easily lose sight of this and get lost in the intricacies of how candidates can maintain their competency by obtaining free CME credits. The APA is distracting its members by citing this. They will continue to pay a high price for certification and recertification, with no real discount.

Most of the APA’s 38,000 members are in the dark about the above-mentioned process. They need to do their own research, especially when there are alternatives to the ABPN’s MOC program. They need to insist that the APA stop exclusively promoting ABPN products, and publicize other, much cheaper, alternatives. It will please all APA members to see the ABPN’s monopoly vanish. This is especially the case for younger psychiatrists, who average nearly $250,000 in educational loans. They need to prevent the APA/ABPN collaboration from having a far-reaching effect on their careers and finances, with potentially destructive consequences for their families, employers and—most importantly—their patients. Even some state licensing boards are being tempted to buy into the illusion.

Stop this MOCkery.

Editor’s note: Readers’ Forum is a department for correspondence from readers that is not in response to articles published in Current Psychiatry. All submissions to Readers’ Forum undergo peer review and are subject to editing for length and style. For more information, contact [email protected].

The Accreditation Council for Graduate Medical Education (ACGME) is en­trusted with assuring that upon graduation every resident is a competent doctor, a trained professional, and prepared to practice in their own field at a level that assures patient safety and meets the standard of care. The American Board of Psychiatry and Neurology (ABPN) is a private company that sells certificates claiming to attest the capacity or competence of the doctor but does not make public the test questions or algorithms used to win its qualifications or approval. The certifying business and the newer Maintenance of Certification (MOC) process developed by ABPN have unfortunately been embraced by ACGME and many hospitals, despite the lack of any good scientific support that board certification or MOC are meaningful for quality of patient care or outcomes. By that I mean there is no evidence that the voluntary board certification process or MOC have been shown to produce better outcomes for patients, save money for the country drowning in an ocean of health care costs, or allow doctors to get paid at a higher level by insurers for the same billing codes compared with those who bill without possessing these qualifications. The only entity that “profits” from the board certification/MOC process is ABPN, a private corporation that is supposed to be a nonprofit, but was sitting on a treasury of more than $140M in assets in 2019,¹ with revenues growing annually. Including the interest earned on the investment and added revenues every year, the estimated total assets of ABPN will be in the range of $150M at the end of 2021!

Collaboration between ACGME and ABPN

The collaboration between ACGME and ABPN for graduate education for designing training programs for residents and fellows, with progressively increasing competencies and their assessments to dovetail with the board examinations offered by ABPN, sounds very legitimate. This arrangement is designed to enhance the quality of training and establish a minimum level of competence in each trainee who completes the training program. However, ACGME is catering to a monopoly recognized by the US Department of Justice (DOJ) Antitrust Division.² ACGME has not entertained other evaluators of competence to discourage competition to the monopolistic ABPN. ACGME is only involved with the accredited training programs and has no business in assessing the continued competence of graduated trainees after they leave the program, although most will voluntarily opt to become board-certified by ABPN. Maintenance of Certification definitely does not come within the purview of “graduate medical education” for ACGME to be getting drawn into this collaboration.

ACGME and ABPN are unregulated and are not member-driven. As such, they operate outside of any real oversight. Their power derives from the status given to them by hospitals, some insurers, and many of our colleagues, who fail to see the reality that they are nothing more than diploma shops.

I am board-certified in psychiatry and child and adolescent psychiatry, and I have participated in obtaining board certification by ABPN in 3 other subspecialties (geriatric, addiction, and forensic). I decided to not participate in MOC for the latter 3 subspecialty certifications beyond 10 and 20 years for my own practical reasons. Obviously, then, I am not at all against initial certifications in any specialty, nor am I opposed to practitioners keeping up with progress in their fields and maintaining their competence. I am opposed to the continued efforts to engage professionals to pay a high price for the repeated MOC, riding on the hard work and earnings of the graduated specialists and continuously suctioning their income over their careers, with no evidence that MOC measures clinical competence or patient outcomes of their subscribers, who pay a chunk of money to the American Board of Medical Specialties (ABMS)/ABPN annually and every 10 years.

MOC and the APA

Many American Psychiatric Association (APA) members are opposed to the APA giving ABPN a piggyback ride to accomplish this profit seeking. This is becoming obvious to many APA members, who see this as a great exploitation.

Over the last 6 years, physicians have begun to question the validity of board certification and MOC by ABPN, mostly as a response to ever-increasing costs to them and ever-increasing revenues to ABPN. While APA members have long pressed the APA to push back against ABPN, the APA Board of Trustees has done the opposite by accepting yearly “unrestricted educational grants” from ABPN. In this manner, ABPN has essentially silenced the APA and has made it ineffective as our member organization in what has become a fight against ABPN’s unchecked power, influence, and intrusion. Every poll conducted by every APA District Branch or subspecialty organization has shown widespread discontent and anger at the ABPN/MOC process and APA’s deliberate inaction. Even when the APA commissioned its own member survey on the topic, wrote the questions, picked who would get the survey, decided which responses to count, and determined what statistics to apply, the results were damning. Despite its obviously transparent machinations, the APA failed to glorify the MOC process.

Continue to: The APA's membership...

The APA’s membership is declining, and the Board of Trustee’s position on MOC is partly to blame. The APA is once again not listening to its members! As a membership-driven organization, the APA must not exclusively support and promote this commercial educational product termed MOC when other, less expensive alternatives are now available. The APA can easily endorse these alternatives, in addition to offering its own less expensive products for attesting maintenance of competence. The latter effort will help eliminate the monopoly held by ABMS/ABPN in this domain and please all members as well as the DOJ.

The APA’s failure to provide less expensive alternatives or at least endorse existing ones despite repeated requests from a large number of APA members has led to frustration and a surge of strong feelings that are expressed on the APA email listservs, and especially that of the MOC caucus. These expressions are legitimate and need to be publicized to the general membership. I have collected the opinions of various loyal, long-standing APA members and put together a separate, yet-unpublished article to drive home the point that APA has resisted breaking the monopoly of ABPN, which the DOJ would encourage organizations such as the APA to do. Instead, APA is acting as an enabler to ABPN to create a multi-million dollar (and eventually a billion dollar) monopolistic industry at their members’ expense, literally endangering the careers of members if they fail to participate when employed by institutions that overvalue the MOC offered by ABPN.

I believe the recent exhibition of “collaboration” between the APA and ABPN is not similar to that between ACGME and ABPN, but is a most blatant effort on the part of the APA to help ABPN build a billion-dollar educational industry over the next 10 to 15 years. One can easily lose sight of this and get lost in the intricacies of how candidates can maintain their competency by obtaining free CME credits. The APA is distracting its members by citing this. They will continue to pay a high price for certification and recertification, with no real discount.

Most of the APA’s 38,000 members are in the dark about the above-mentioned process. They need to do their own research, especially when there are alternatives to the ABPN’s MOC program. They need to insist that the APA stop exclusively promoting ABPN products, and publicize other, much cheaper, alternatives. It will please all APA members to see the ABPN’s monopoly vanish. This is especially the case for younger psychiatrists, who average nearly $250,000 in educational loans. They need to prevent the APA/ABPN collaboration from having a far-reaching effect on their careers and finances, with potentially destructive consequences for their families, employers and—most importantly—their patients. Even some state licensing boards are being tempted to buy into the illusion.

Stop this MOCkery.

This month, the current Editor-in-Chief and his Editorial Board will conclude our 5-year term. Megan Adams MD, JD, MSc, from the University of Michigan School of Medicine will assume my position. She has a stellar academic, research, and teaching record and is one of the best writers I know. She and her Board of Editors will carry on the tradition of GIHN.

The idea of an official newspaper of the AGA came from AGA staff in 2006. The goals of the newspaper were twofold: to communicate the latest news and information to practitioners to help them stay at the forefront of patient care and to develop another revenue stream for our society. The newspaper was launched in January 2007 with Charles Lightdale MD, AGAF, as the first editor and Colin W. Howden MD, AGAF, as the second (each with 5-year terms). While they wrote occasional editorials, I began writing 300-word essays for each issue. I have tried diligently to maintain a balanced viewpoint for all my editorials, although this has been difficult in the recent past and current national environment.

The paper evolved from a simple print publication to a multimedia communications vehicle that includes online-only content, videos, supplements, quizzes, and more. Last year, we published our first “Data Trends,” a supplement containing 10 or so brief articles written by content experts, covering current topics of high interest. As the paper evolved, we broadened our target audience to include research scientists, international practitioners and others interested in digestive diseases.

As I did last month, I would like to thank the AGA and Frontline Medical Communications staff for their dedication and constant work to bring you this newspaper.

Finally, I would like to pay tribute to Tadataka “Tachi” Yamada, who died this last month at the age of 76 years. He was one of the premier advocates for global health. His contributions to our field thru research, philanthropy, and leadership were enormous. We will miss him greatly.

John I Allen, MD, MBA, AGAF
Editor in Chief

This month, the current Editor-in-Chief and his Editorial Board will conclude our 5-year term. Megan Adams MD, JD, MSc, from the University of Michigan School of Medicine will assume my position. She has a stellar academic, research, and teaching record and is one of the best writers I know. She and her Board of Editors will carry on the tradition of GIHN.

The idea of an official newspaper of the AGA came from AGA staff in 2006. The goals of the newspaper were twofold: to communicate the latest news and information to practitioners to help them stay at the forefront of patient care and to develop another revenue stream for our society. The newspaper was launched in January 2007 with Charles Lightdale MD, AGAF, as the first editor and Colin W. Howden MD, AGAF, as the second (each with 5-year terms). While they wrote occasional editorials, I began writing 300-word essays for each issue. I have tried diligently to maintain a balanced viewpoint for all my editorials, although this has been difficult in the recent past and current national environment.

The paper evolved from a simple print publication to a multimedia communications vehicle that includes online-only content, videos, supplements, quizzes, and more. Last year, we published our first “Data Trends,” a supplement containing 10 or so brief articles written by content experts, covering current topics of high interest. As the paper evolved, we broadened our target audience to include research scientists, international practitioners and others interested in digestive diseases.

As I did last month, I would like to thank the AGA and Frontline Medical Communications staff for their dedication and constant work to bring you this newspaper.

Finally, I would like to pay tribute to Tadataka “Tachi” Yamada, who died this last month at the age of 76 years. He was one of the premier advocates for global health. His contributions to our field thru research, philanthropy, and leadership were enormous. We will miss him greatly.

John I Allen, MD, MBA, AGAF
Editor in Chief

This month, the current Editor-in-Chief and his Editorial Board will conclude our 5-year term. Megan Adams MD, JD, MSc, from the University of Michigan School of Medicine will assume my position. She has a stellar academic, research, and teaching record and is one of the best writers I know. She and her Board of Editors will carry on the tradition of GIHN.

The idea of an official newspaper of the AGA came from AGA staff in 2006. The goals of the newspaper were twofold: to communicate the latest news and information to practitioners to help them stay at the forefront of patient care and to develop another revenue stream for our society. The newspaper was launched in January 2007 with Charles Lightdale MD, AGAF, as the first editor and Colin W. Howden MD, AGAF, as the second (each with 5-year terms). While they wrote occasional editorials, I began writing 300-word essays for each issue. I have tried diligently to maintain a balanced viewpoint for all my editorials, although this has been difficult in the recent past and current national environment.

The paper evolved from a simple print publication to a multimedia communications vehicle that includes online-only content, videos, supplements, quizzes, and more. Last year, we published our first “Data Trends,” a supplement containing 10 or so brief articles written by content experts, covering current topics of high interest. As the paper evolved, we broadened our target audience to include research scientists, international practitioners and others interested in digestive diseases.

As I did last month, I would like to thank the AGA and Frontline Medical Communications staff for their dedication and constant work to bring you this newspaper.

Finally, I would like to pay tribute to Tadataka “Tachi” Yamada, who died this last month at the age of 76 years. He was one of the premier advocates for global health. His contributions to our field thru research, philanthropy, and leadership were enormous. We will miss him greatly.

John I Allen, MD, MBA, AGAF
Editor in Chief

Our first study comes out of Sheffield, UK, and Halle, Germany, and looks at the correlation between sarcopenia and EPI (Jalal et al). Notably sarcopenia, or reduction in muscle mass, is a known complication of malnutrition and conditions like EPI. It has traditionally been difficult to diagnose because traditional methods have suffered from low accuracy (i.e., mid-arm circumference). In recent years, commercially available software has been developed to digitally assess skeletal muscle mass on axial CT imaging. Digital imaging allows for granular assessments of metrics such as myosteatosis and sacropenic obesity, both of which remained relatively elusive metrics in prior ways of assessing sarcopenia.

In this study, researchers postulate that, since CT scans are recently performed in the evaluation of those patients with suspected pancreatic pathology, it would be natural to assess for sarcopenia on said CT imaging. Identifying sarcopenia might allow clinicians to identify those patients with or at risk for EPI.

Patients referred to EUS for suspected pancreatic pathology were included in the study (except those found to have pancreatic cancer). This prospective study included 102 patients with suspected or proven benign pancreatic pathology, chronic pancreatitis, or recurrent pancreatic type pain. Fecal elastase testing was used to determine those with EPI, and digital CT analysis was used to recognize patients with sarcopenia.

Overall, EPI was present in 45.1% of patients. The prevalence of sarcopenia (67.4% vs. 37.55%; P < .003), myosteatosis (52.2% vs. 10.7%; P = .046), and sarcopenic obesity (66.7% vs. 24.3%; P = .002) was significantly higher in patients with vs without EPI. Sarcopenia (odds ratio [OR], 4.8; P = .02) was strongly associated with EPI. The authors conclude that digital skeletal mass analysis can be performed on patients already undergoing CT scans for suspected pancreatic pathology for possible further diagnosis, risk assessment and to better inform clinical management.

Another notable study came out of Baylor College of Medicine that looked at the clinical significance of fatty pancreas (FP) (Krill et al). Diffuse echogenicity of the pancreas is a common finding on endoscopic ultrasound (EUS), but of unknown clinical significance. Krill’s group aimed to determine if diffuse fatty infiltration of the pancreas had any clinical implication on pancreatic function. They conducted a retrospective case-control study comparing adult patients with diffuse echogenicity of the pancreas to those without known pancreatic disease with chronic diarrhea. Notably, the incidence of EPI (47% vs. 6%) and chronic pancreatitis (18% vs. 0%) was significantly higher (both P < .001) in the fatty pancreas group vs. the control group. 

The authors conclude “Our findings suggest that FP may not merely be a benign sonographic finding, but rather imply underlying parenchymal dysfunction, such as that seen when fat deposition occurs in the liver (i.e., nonalcoholic fatty liver disease).” Additionally the paper states that recent literature has found an association between fatty pancreas and increasing body mass index (BMI), hyperlipidemia, insulin resistance, and metabolic syndrome. Perhaps we will further appreciate the likely prominent and under-appreciated role of metabolic syndrome in the development of acute and chronic pancreatitis.

References:

Jalal M, Rosendahl J, Campbell JA, Vinayagam R, Al-Mukhtar A, Hopper AD. Identification of “digital sarcopenia” can aid the detection of pancreatic exocrine insufficiency and malnutrition assessment in patients with suspected pancreatic pathology. Dig Dis 2021 (Jun 8), (in press).

Krill JT, Szafron D, Elhanafi S, et al. Endoscopic ultrasound finding of diffuse echogenicity in the pancreas, is it relevant? Dig Dis Sci 2021 (Aug 4), (in press).

Our first study comes out of Sheffield, UK, and Halle, Germany, and looks at the correlation between sarcopenia and EPI (Jalal et al). Notably sarcopenia, or reduction in muscle mass, is a known complication of malnutrition and conditions like EPI. It has traditionally been difficult to diagnose because traditional methods have suffered from low accuracy (i.e., mid-arm circumference). In recent years, commercially available software has been developed to digitally assess skeletal muscle mass on axial CT imaging. Digital imaging allows for granular assessments of metrics such as myosteatosis and sacropenic obesity, both of which remained relatively elusive metrics in prior ways of assessing sarcopenia.

In this study, researchers postulate that, since CT scans are recently performed in the evaluation of those patients with suspected pancreatic pathology, it would be natural to assess for sarcopenia on said CT imaging. Identifying sarcopenia might allow clinicians to identify those patients with or at risk for EPI.

Patients referred to EUS for suspected pancreatic pathology were included in the study (except those found to have pancreatic cancer). This prospective study included 102 patients with suspected or proven benign pancreatic pathology, chronic pancreatitis, or recurrent pancreatic type pain. Fecal elastase testing was used to determine those with EPI, and digital CT analysis was used to recognize patients with sarcopenia.

Overall, EPI was present in 45.1% of patients. The prevalence of sarcopenia (67.4% vs. 37.55%; P < .003), myosteatosis (52.2% vs. 10.7%; P = .046), and sarcopenic obesity (66.7% vs. 24.3%; P = .002) was significantly higher in patients with vs without EPI. Sarcopenia (odds ratio [OR], 4.8; P = .02) was strongly associated with EPI. The authors conclude that digital skeletal mass analysis can be performed on patients already undergoing CT scans for suspected pancreatic pathology for possible further diagnosis, risk assessment and to better inform clinical management.

Another notable study came out of Baylor College of Medicine that looked at the clinical significance of fatty pancreas (FP) (Krill et al). Diffuse echogenicity of the pancreas is a common finding on endoscopic ultrasound (EUS), but of unknown clinical significance. Krill’s group aimed to determine if diffuse fatty infiltration of the pancreas had any clinical implication on pancreatic function. They conducted a retrospective case-control study comparing adult patients with diffuse echogenicity of the pancreas to those without known pancreatic disease with chronic diarrhea. Notably, the incidence of EPI (47% vs. 6%) and chronic pancreatitis (18% vs. 0%) was significantly higher (both P < .001) in the fatty pancreas group vs. the control group. 

The authors conclude “Our findings suggest that FP may not merely be a benign sonographic finding, but rather imply underlying parenchymal dysfunction, such as that seen when fat deposition occurs in the liver (i.e., nonalcoholic fatty liver disease).” Additionally the paper states that recent literature has found an association between fatty pancreas and increasing body mass index (BMI), hyperlipidemia, insulin resistance, and metabolic syndrome. Perhaps we will further appreciate the likely prominent and under-appreciated role of metabolic syndrome in the development of acute and chronic pancreatitis.

References:

Jalal M, Rosendahl J, Campbell JA, Vinayagam R, Al-Mukhtar A, Hopper AD. Identification of “digital sarcopenia” can aid the detection of pancreatic exocrine insufficiency and malnutrition assessment in patients with suspected pancreatic pathology. Dig Dis 2021 (Jun 8), (in press).

Krill JT, Szafron D, Elhanafi S, et al. Endoscopic ultrasound finding of diffuse echogenicity in the pancreas, is it relevant? Dig Dis Sci 2021 (Aug 4), (in press).

Our first study comes out of Sheffield, UK, and Halle, Germany, and looks at the correlation between sarcopenia and EPI (Jalal et al). Notably sarcopenia, or reduction in muscle mass, is a known complication of malnutrition and conditions like EPI. It has traditionally been difficult to diagnose because traditional methods have suffered from low accuracy (i.e., mid-arm circumference). In recent years, commercially available software has been developed to digitally assess skeletal muscle mass on axial CT imaging. Digital imaging allows for granular assessments of metrics such as myosteatosis and sacropenic obesity, both of which remained relatively elusive metrics in prior ways of assessing sarcopenia.

In this study, researchers postulate that, since CT scans are recently performed in the evaluation of those patients with suspected pancreatic pathology, it would be natural to assess for sarcopenia on said CT imaging. Identifying sarcopenia might allow clinicians to identify those patients with or at risk for EPI.

Patients referred to EUS for suspected pancreatic pathology were included in the study (except those found to have pancreatic cancer). This prospective study included 102 patients with suspected or proven benign pancreatic pathology, chronic pancreatitis, or recurrent pancreatic type pain. Fecal elastase testing was used to determine those with EPI, and digital CT analysis was used to recognize patients with sarcopenia.

Overall, EPI was present in 45.1% of patients. The prevalence of sarcopenia (67.4% vs. 37.55%; P < .003), myosteatosis (52.2% vs. 10.7%; P = .046), and sarcopenic obesity (66.7% vs. 24.3%; P = .002) was significantly higher in patients with vs without EPI. Sarcopenia (odds ratio [OR], 4.8; P = .02) was strongly associated with EPI. The authors conclude that digital skeletal mass analysis can be performed on patients already undergoing CT scans for suspected pancreatic pathology for possible further diagnosis, risk assessment and to better inform clinical management.

Another notable study came out of Baylor College of Medicine that looked at the clinical significance of fatty pancreas (FP) (Krill et al). Diffuse echogenicity of the pancreas is a common finding on endoscopic ultrasound (EUS), but of unknown clinical significance. Krill’s group aimed to determine if diffuse fatty infiltration of the pancreas had any clinical implication on pancreatic function. They conducted a retrospective case-control study comparing adult patients with diffuse echogenicity of the pancreas to those without known pancreatic disease with chronic diarrhea. Notably, the incidence of EPI (47% vs. 6%) and chronic pancreatitis (18% vs. 0%) was significantly higher (both P < .001) in the fatty pancreas group vs. the control group. 

The authors conclude “Our findings suggest that FP may not merely be a benign sonographic finding, but rather imply underlying parenchymal dysfunction, such as that seen when fat deposition occurs in the liver (i.e., nonalcoholic fatty liver disease).” Additionally the paper states that recent literature has found an association between fatty pancreas and increasing body mass index (BMI), hyperlipidemia, insulin resistance, and metabolic syndrome. Perhaps we will further appreciate the likely prominent and under-appreciated role of metabolic syndrome in the development of acute and chronic pancreatitis.

References:

Jalal M, Rosendahl J, Campbell JA, Vinayagam R, Al-Mukhtar A, Hopper AD. Identification of “digital sarcopenia” can aid the detection of pancreatic exocrine insufficiency and malnutrition assessment in patients with suspected pancreatic pathology. Dig Dis 2021 (Jun 8), (in press).

Krill JT, Szafron D, Elhanafi S, et al. Endoscopic ultrasound finding of diffuse echogenicity in the pancreas, is it relevant? Dig Dis Sci 2021 (Aug 4), (in press).

Identifying risk factors for onset of Psoriatic Arthritis (PsA) is a major unmet need. Comparing potential risk factors for the diagnosis of PsA, rheumatoid arthritis (RA), and ankylosing spondylitis (AS) is of interest. Such studies may help us identify shared and unique risk factors of onset of chronic inflammatory arthritis. Meer E et al compared potential risk factors for the diagnosis of PsA, psoriasis, RA, and AS. They conducted four parallel case-control studies using data collected between 1994 and 2015 in The Health Improvement Network, an anonymized longitudinal patient dataset collected at primary care clinics throughout the United Kingdom. PsA was associated with obesity, pharyngitis, skin infections, moderate alcohol intake, gout, and uveitis. As expected, PsA and AS were associated with uveitis. Interestingly, PsA and RA were associated with preceding gout. Smoking was a risk factor for all disease and statin use was inversely associated with all 4 diseases. This study has identified potential risk factors for inflammatory diseases including PsA and may help in early identification as well as risk mitigation.

Most patients develop psoriatic arthritis (PsA) after or simultaneously with cutaneous psoriasis. The mechanisms underlying progression from cutaneous psoriasis to arthritis psoriasis are currently unclear. An important question is whether modern targeted treatment of cutaneous psoriasis reduces the risk of developing PsA. To address this, Acosta Felquer ML et al  conducted a retrospective cohort study to compare the incidence of PsA in 1719 patients with psoriasis (14,721 patient/years of follow up) grouped according to different treatments for their skin psoriasis: topicals, phototherapy or no treatment (n= 1387), conventional disease-modifying antirheumatic drugs (cDMARDs) or biological DMARDs (bDMARDs). During follow-up, 239 patients (14%) developed PsA. The risk of developing PsA in patients treated with bDMARDs was significantly lower (incidence rate ratio (IRR)=0.26; 95% CI 0.03 to 0.94), compared with topicals, but not compared with cDMARDs (IRR=0.35; 95% CI 0.035 to 1.96). Male sex, nail involvement and higher body mass index were associated with increased risk of developing PsA, while bDMARD use was protective. Thus, this study provides some evidence that systemic treatment might ‘protect’ against development if PsA. Appropriately designed prospective studies are required.

One important clinical question is whether patients with oligoarthritis (involvement of <5 joints) progress to polyarthritis. In an observational study Gladman DD et al  reported that in 407 patients evaluated within 12 months of diagnosis, 192 (47%) presented with oligoarthritis. More patients with polyarthritis presented with dactylitis, enthesitis, higher HAQ and lower SF-36 scores. Of the 192 patients with oligoarthritis, 75 (39%) progressed to polyarthritis. Lower SF-36 mental component summary score was the predictor for progressing to polyarthritis. Thus, except for the burden of musculoskeletal involvement, oligoarticular PsA resembles polyarticular PsA and therefore the two PsA subclasses should simply be classified together as peripheral arthritis.

Identifying risk factors for onset of Psoriatic Arthritis (PsA) is a major unmet need. Comparing potential risk factors for the diagnosis of PsA, rheumatoid arthritis (RA), and ankylosing spondylitis (AS) is of interest. Such studies may help us identify shared and unique risk factors of onset of chronic inflammatory arthritis. Meer E et al compared potential risk factors for the diagnosis of PsA, psoriasis, RA, and AS. They conducted four parallel case-control studies using data collected between 1994 and 2015 in The Health Improvement Network, an anonymized longitudinal patient dataset collected at primary care clinics throughout the United Kingdom. PsA was associated with obesity, pharyngitis, skin infections, moderate alcohol intake, gout, and uveitis. As expected, PsA and AS were associated with uveitis. Interestingly, PsA and RA were associated with preceding gout. Smoking was a risk factor for all disease and statin use was inversely associated with all 4 diseases. This study has identified potential risk factors for inflammatory diseases including PsA and may help in early identification as well as risk mitigation.

Most patients develop psoriatic arthritis (PsA) after or simultaneously with cutaneous psoriasis. The mechanisms underlying progression from cutaneous psoriasis to arthritis psoriasis are currently unclear. An important question is whether modern targeted treatment of cutaneous psoriasis reduces the risk of developing PsA. To address this, Acosta Felquer ML et al  conducted a retrospective cohort study to compare the incidence of PsA in 1719 patients with psoriasis (14,721 patient/years of follow up) grouped according to different treatments for their skin psoriasis: topicals, phototherapy or no treatment (n= 1387), conventional disease-modifying antirheumatic drugs (cDMARDs) or biological DMARDs (bDMARDs). During follow-up, 239 patients (14%) developed PsA. The risk of developing PsA in patients treated with bDMARDs was significantly lower (incidence rate ratio (IRR)=0.26; 95% CI 0.03 to 0.94), compared with topicals, but not compared with cDMARDs (IRR=0.35; 95% CI 0.035 to 1.96). Male sex, nail involvement and higher body mass index were associated with increased risk of developing PsA, while bDMARD use was protective. Thus, this study provides some evidence that systemic treatment might ‘protect’ against development if PsA. Appropriately designed prospective studies are required.

One important clinical question is whether patients with oligoarthritis (involvement of <5 joints) progress to polyarthritis. In an observational study Gladman DD et al  reported that in 407 patients evaluated within 12 months of diagnosis, 192 (47%) presented with oligoarthritis. More patients with polyarthritis presented with dactylitis, enthesitis, higher HAQ and lower SF-36 scores. Of the 192 patients with oligoarthritis, 75 (39%) progressed to polyarthritis. Lower SF-36 mental component summary score was the predictor for progressing to polyarthritis. Thus, except for the burden of musculoskeletal involvement, oligoarticular PsA resembles polyarticular PsA and therefore the two PsA subclasses should simply be classified together as peripheral arthritis.

Identifying risk factors for onset of Psoriatic Arthritis (PsA) is a major unmet need. Comparing potential risk factors for the diagnosis of PsA, rheumatoid arthritis (RA), and ankylosing spondylitis (AS) is of interest. Such studies may help us identify shared and unique risk factors of onset of chronic inflammatory arthritis. Meer E et al compared potential risk factors for the diagnosis of PsA, psoriasis, RA, and AS. They conducted four parallel case-control studies using data collected between 1994 and 2015 in The Health Improvement Network, an anonymized longitudinal patient dataset collected at primary care clinics throughout the United Kingdom. PsA was associated with obesity, pharyngitis, skin infections, moderate alcohol intake, gout, and uveitis. As expected, PsA and AS were associated with uveitis. Interestingly, PsA and RA were associated with preceding gout. Smoking was a risk factor for all disease and statin use was inversely associated with all 4 diseases. This study has identified potential risk factors for inflammatory diseases including PsA and may help in early identification as well as risk mitigation.

Most patients develop psoriatic arthritis (PsA) after or simultaneously with cutaneous psoriasis. The mechanisms underlying progression from cutaneous psoriasis to arthritis psoriasis are currently unclear. An important question is whether modern targeted treatment of cutaneous psoriasis reduces the risk of developing PsA. To address this, Acosta Felquer ML et al  conducted a retrospective cohort study to compare the incidence of PsA in 1719 patients with psoriasis (14,721 patient/years of follow up) grouped according to different treatments for their skin psoriasis: topicals, phototherapy or no treatment (n= 1387), conventional disease-modifying antirheumatic drugs (cDMARDs) or biological DMARDs (bDMARDs). During follow-up, 239 patients (14%) developed PsA. The risk of developing PsA in patients treated with bDMARDs was significantly lower (incidence rate ratio (IRR)=0.26; 95% CI 0.03 to 0.94), compared with topicals, but not compared with cDMARDs (IRR=0.35; 95% CI 0.035 to 1.96). Male sex, nail involvement and higher body mass index were associated with increased risk of developing PsA, while bDMARD use was protective. Thus, this study provides some evidence that systemic treatment might ‘protect’ against development if PsA. Appropriately designed prospective studies are required.

One important clinical question is whether patients with oligoarthritis (involvement of <5 joints) progress to polyarthritis. In an observational study Gladman DD et al  reported that in 407 patients evaluated within 12 months of diagnosis, 192 (47%) presented with oligoarthritis. More patients with polyarthritis presented with dactylitis, enthesitis, higher HAQ and lower SF-36 scores. Of the 192 patients with oligoarthritis, 75 (39%) progressed to polyarthritis. Lower SF-36 mental component summary score was the predictor for progressing to polyarthritis. Thus, except for the burden of musculoskeletal involvement, oligoarticular PsA resembles polyarticular PsA and therefore the two PsA subclasses should simply be classified together as peripheral arthritis.

Chiuve et al published a large cohort study in the Journal of Epidemiology and Community Health that evaluated the association between uterine fibroids and diagnosed depression, anxiety and self-directed violence. Women aged 18-50 years with diagnosed uterine fibroids (n=313,754) were identified in the Optum Clinformatics commercial insurance claims database and matched 1:2 on age and calendar time to women without (n=627,539). After adjusting for confounders, women with uterine fibroids had a higher rate of depression, anxiety and self-directed violence then women not diagnosed with fibroids. Among women with pain symptoms and heavy menstrual bleeding, the hazard ratio comparing women with fibroids to women without was 1.21 for depression, 1.18 for anxiety and 1.68 for self-directed violence. Among women with fibroids, those who underwent hysterectomy had higher rates of depression, anxiety and self-directed violence.

A third study by Wesselink et al in Human Reproduction examined ambient air pollution exposure and the risk of developing uterine fibroids. This was a prospective cohort study of 21,998 premenopausal Black women in 56 US metropolitan areas from 1997 to 2011. During the follow up, 28.4% of participants (n=6238) reported uterine fibroid diagnosis by ultrasound or surgery. Increased ozone concentrations were associated with an increased risk of being diagnosed with uterine fibroids, with a stronger association among women less than 35 years of age and parous women. Other pollutants, specifically particulate matter <2.5 microns and nitrogen dioxide, were not associated with an increased risk of uterine fibroids.

Chiuve et al published a large cohort study in the Journal of Epidemiology and Community Health that evaluated the association between uterine fibroids and diagnosed depression, anxiety and self-directed violence. Women aged 18-50 years with diagnosed uterine fibroids (n=313,754) were identified in the Optum Clinformatics commercial insurance claims database and matched 1:2 on age and calendar time to women without (n=627,539). After adjusting for confounders, women with uterine fibroids had a higher rate of depression, anxiety and self-directed violence then women not diagnosed with fibroids. Among women with pain symptoms and heavy menstrual bleeding, the hazard ratio comparing women with fibroids to women without was 1.21 for depression, 1.18 for anxiety and 1.68 for self-directed violence. Among women with fibroids, those who underwent hysterectomy had higher rates of depression, anxiety and self-directed violence.

A third study by Wesselink et al in Human Reproduction examined ambient air pollution exposure and the risk of developing uterine fibroids. This was a prospective cohort study of 21,998 premenopausal Black women in 56 US metropolitan areas from 1997 to 2011. During the follow up, 28.4% of participants (n=6238) reported uterine fibroid diagnosis by ultrasound or surgery. Increased ozone concentrations were associated with an increased risk of being diagnosed with uterine fibroids, with a stronger association among women less than 35 years of age and parous women. Other pollutants, specifically particulate matter <2.5 microns and nitrogen dioxide, were not associated with an increased risk of uterine fibroids.

Chiuve et al published a large cohort study in the Journal of Epidemiology and Community Health that evaluated the association between uterine fibroids and diagnosed depression, anxiety and self-directed violence. Women aged 18-50 years with diagnosed uterine fibroids (n=313,754) were identified in the Optum Clinformatics commercial insurance claims database and matched 1:2 on age and calendar time to women without (n=627,539). After adjusting for confounders, women with uterine fibroids had a higher rate of depression, anxiety and self-directed violence then women not diagnosed with fibroids. Among women with pain symptoms and heavy menstrual bleeding, the hazard ratio comparing women with fibroids to women without was 1.21 for depression, 1.18 for anxiety and 1.68 for self-directed violence. Among women with fibroids, those who underwent hysterectomy had higher rates of depression, anxiety and self-directed violence.

A third study by Wesselink et al in Human Reproduction examined ambient air pollution exposure and the risk of developing uterine fibroids. This was a prospective cohort study of 21,998 premenopausal Black women in 56 US metropolitan areas from 1997 to 2011. During the follow up, 28.4% of participants (n=6238) reported uterine fibroid diagnosis by ultrasound or surgery. Increased ozone concentrations were associated with an increased risk of being diagnosed with uterine fibroids, with a stronger association among women less than 35 years of age and parous women. Other pollutants, specifically particulate matter <2.5 microns and nitrogen dioxide, were not associated with an increased risk of uterine fibroids.

Patients with hepatocellular carcinoma (HCC) that has not spread outside the liver have several treatment options available. This month we will review articles that analyze outcomes after liver transplantation, liver resection, as well as radiofrequency ablation.

In HCC patients within the Milan criteria, the 5-year overall survival rate after transplant is about 70%, and the 5-year HCC recurrence rate is about 10%. Patients with tumors beyond the Milan criteria are frequently down staged with locoregional therapies to fall within the Milan criteria. The incidence of HCC recurrence in these patients is around 15.5% at 5 years. In this study, Lee et al demonstrated that statin use substantially reduced the risk of HCC recurrence. In this retrospective analysis of a longitudinal cohort of 430 patients transplanted between September 1995 and December 2019, 323 patients (75.1%) were statin non-users and 107 (24.9%) were statin  users. Statin use was defined as at least 90 days of statin therapy, prescribed according to the treatment guidelines for dyslipidemia for primary or secondary prevention of CVD.   At a median follow-up of 64.9 months, HCC recurred in 79 patients (18.4%), including 72 (22.3%) in the statin non-user group and 7 (6.5%) in the statin user group. Of those, 61 (77.2%) patients had HCC recurrence that initially presented at extrahepatic site regardless of the presence of intrahepatic tumors.  Sixty-three patients (79.7%) had recurrence within 2 years of liver transplantation. The cumulative incidence of HCC recurrence at 2 and 5 years was 18.9% and 22.3% in the statin non-user group, and 3.8% and 5.7% in the statin user group, respectively (P < 0.001).

Liang et al evaluated the importance of tumor size in predicting the likelihood of HCC recurrence following surgical resection. In this retrospective study, a total of 813 cirrhotic patients who underwent curative-intent hepatectomy for solitary HCC without macrovascular invasion between 2001 and 2014 were evaluated. Overall, 464 patients had tumor size ≤ 5 cm, and 349 had tumor size > 5 cm. The 5-year RFS and OS rates were 38.3% and 61.5% in the ≤ 5 cm group, compared with 25.1% and 59.9% in the > 5 cm group. Long-term survival outcomes were significantly worse as tumor size increased. Multivariate analysis indicated that tumor size > 5 cm was an independent risk factor for tumor recurrence and long-term survival.

Finally, Sulaiman et al reported the survival rate of the early and intermediate stage HCC patients who underwent radiofrequency ablation (RFA). In this retrospective analysis, patients with BCLC A and B HCC who underwent RFA treatments between January 2015 to December 2017 were evaluated. Out of 62 patients 46 (74.2%) were reported to have RFA as their only first line of treatment, while 12 (25.8%) were reported to have a combination of RFA and other therapeutic modalities. At a mean follow up of 27 months, the survival rate at 12 and 36 months in patients who received RFA was 82.3% and 57.8%, respectively. A relatively high 36-month survival rate was seen in patients who had a response to RFA compared to the non-response group (100% vs 44.8%, P = 0.021). In terms of prognosis, BCLC staging of liver cancer and response after RFA were significantly associated with survival.

Patients with hepatocellular carcinoma (HCC) that has not spread outside the liver have several treatment options available. This month we will review articles that analyze outcomes after liver transplantation, liver resection, as well as radiofrequency ablation.

In HCC patients within the Milan criteria, the 5-year overall survival rate after transplant is about 70%, and the 5-year HCC recurrence rate is about 10%. Patients with tumors beyond the Milan criteria are frequently down staged with locoregional therapies to fall within the Milan criteria. The incidence of HCC recurrence in these patients is around 15.5% at 5 years. In this study, Lee et al demonstrated that statin use substantially reduced the risk of HCC recurrence. In this retrospective analysis of a longitudinal cohort of 430 patients transplanted between September 1995 and December 2019, 323 patients (75.1%) were statin non-users and 107 (24.9%) were statin  users. Statin use was defined as at least 90 days of statin therapy, prescribed according to the treatment guidelines for dyslipidemia for primary or secondary prevention of CVD.   At a median follow-up of 64.9 months, HCC recurred in 79 patients (18.4%), including 72 (22.3%) in the statin non-user group and 7 (6.5%) in the statin user group. Of those, 61 (77.2%) patients had HCC recurrence that initially presented at extrahepatic site regardless of the presence of intrahepatic tumors.  Sixty-three patients (79.7%) had recurrence within 2 years of liver transplantation. The cumulative incidence of HCC recurrence at 2 and 5 years was 18.9% and 22.3% in the statin non-user group, and 3.8% and 5.7% in the statin user group, respectively (P < 0.001).

Liang et al evaluated the importance of tumor size in predicting the likelihood of HCC recurrence following surgical resection. In this retrospective study, a total of 813 cirrhotic patients who underwent curative-intent hepatectomy for solitary HCC without macrovascular invasion between 2001 and 2014 were evaluated. Overall, 464 patients had tumor size ≤ 5 cm, and 349 had tumor size > 5 cm. The 5-year RFS and OS rates were 38.3% and 61.5% in the ≤ 5 cm group, compared with 25.1% and 59.9% in the > 5 cm group. Long-term survival outcomes were significantly worse as tumor size increased. Multivariate analysis indicated that tumor size > 5 cm was an independent risk factor for tumor recurrence and long-term survival.

Finally, Sulaiman et al reported the survival rate of the early and intermediate stage HCC patients who underwent radiofrequency ablation (RFA). In this retrospective analysis, patients with BCLC A and B HCC who underwent RFA treatments between January 2015 to December 2017 were evaluated. Out of 62 patients 46 (74.2%) were reported to have RFA as their only first line of treatment, while 12 (25.8%) were reported to have a combination of RFA and other therapeutic modalities. At a mean follow up of 27 months, the survival rate at 12 and 36 months in patients who received RFA was 82.3% and 57.8%, respectively. A relatively high 36-month survival rate was seen in patients who had a response to RFA compared to the non-response group (100% vs 44.8%, P = 0.021). In terms of prognosis, BCLC staging of liver cancer and response after RFA were significantly associated with survival.

Patients with hepatocellular carcinoma (HCC) that has not spread outside the liver have several treatment options available. This month we will review articles that analyze outcomes after liver transplantation, liver resection, as well as radiofrequency ablation.

In HCC patients within the Milan criteria, the 5-year overall survival rate after transplant is about 70%, and the 5-year HCC recurrence rate is about 10%. Patients with tumors beyond the Milan criteria are frequently down staged with locoregional therapies to fall within the Milan criteria. The incidence of HCC recurrence in these patients is around 15.5% at 5 years. In this study, Lee et al demonstrated that statin use substantially reduced the risk of HCC recurrence. In this retrospective analysis of a longitudinal cohort of 430 patients transplanted between September 1995 and December 2019, 323 patients (75.1%) were statin non-users and 107 (24.9%) were statin  users. Statin use was defined as at least 90 days of statin therapy, prescribed according to the treatment guidelines for dyslipidemia for primary or secondary prevention of CVD.   At a median follow-up of 64.9 months, HCC recurred in 79 patients (18.4%), including 72 (22.3%) in the statin non-user group and 7 (6.5%) in the statin user group. Of those, 61 (77.2%) patients had HCC recurrence that initially presented at extrahepatic site regardless of the presence of intrahepatic tumors.  Sixty-three patients (79.7%) had recurrence within 2 years of liver transplantation. The cumulative incidence of HCC recurrence at 2 and 5 years was 18.9% and 22.3% in the statin non-user group, and 3.8% and 5.7% in the statin user group, respectively (P < 0.001).

Liang et al evaluated the importance of tumor size in predicting the likelihood of HCC recurrence following surgical resection. In this retrospective study, a total of 813 cirrhotic patients who underwent curative-intent hepatectomy for solitary HCC without macrovascular invasion between 2001 and 2014 were evaluated. Overall, 464 patients had tumor size ≤ 5 cm, and 349 had tumor size > 5 cm. The 5-year RFS and OS rates were 38.3% and 61.5% in the ≤ 5 cm group, compared with 25.1% and 59.9% in the > 5 cm group. Long-term survival outcomes were significantly worse as tumor size increased. Multivariate analysis indicated that tumor size > 5 cm was an independent risk factor for tumor recurrence and long-term survival.

Finally, Sulaiman et al reported the survival rate of the early and intermediate stage HCC patients who underwent radiofrequency ablation (RFA). In this retrospective analysis, patients with BCLC A and B HCC who underwent RFA treatments between January 2015 to December 2017 were evaluated. Out of 62 patients 46 (74.2%) were reported to have RFA as their only first line of treatment, while 12 (25.8%) were reported to have a combination of RFA and other therapeutic modalities. At a mean follow up of 27 months, the survival rate at 12 and 36 months in patients who received RFA was 82.3% and 57.8%, respectively. A relatively high 36-month survival rate was seen in patients who had a response to RFA compared to the non-response group (100% vs 44.8%, P = 0.021). In terms of prognosis, BCLC staging of liver cancer and response after RFA were significantly associated with survival.