Commentary

Since the FDA approved intranasal esketamine, there has understandably been significant dialogue, debate, and discussion about the possible mechanisms of action of its antidepressant effects. Ketamine, the racemate of esketamine and arketamine, has been used off-label since the late 1990s. The first study of IV ketamine’s rapid antidepressant activity was published in 2000.¹ In that study, 7 patients with major depressive disorder (MDD) were treated in a double-blind/placebo-controlled manner with IV ketamine or placebo. Researchers found a significant antidepressant effect within 72 hours with the administration of IV ketamine.

There is a tremendous number of publications related to ketamine, which creates a large reservoir of information to review in an attempt to piece together what we currently know about the mechanisms of action of ketamine/esketamine (K/ESK). A search of PubMed using the search word “ketamine” (October 8, 2019; www.ncbi.nlm.nih.gov/pubmed) produced a list of 4,869 articles just in the last 5 years; and the search words “ketamine and depression” produced a list of 1,221 publications over the same time period.

The FDA approval of intranasal esketamine in March 2019 was based on 5 phase III clinical studies (albeit not all were positive studies) and >9 years of intensive preclinical and clinical research on the efficacy and safety of intranasal esketamine in treatment-resistant depression (TRD). At the time the FDA approved it, esketamine had been studied in 1,700 patients with TRD, with 1-year safety data on approximately 800 patients. Despite this established data portfolio, critics of K/ESK continue to opine that we do not have enough long-term experience with these drugs, and some key opinion leaders continue to voice caution about the clinical use of K/ESK until we obtain more information and experience.

An article in the September 2019 issue Currrent Psychiatryby Epstein and Farrell² exemplifies my concern regarding the misrepresentation of significant details about what we know about the mechanism of action of K/ESK. Both K/ESK are certainly not “miracle cures,” and although I understand the use of this term in the article’s title, the continued use of this term to describe K/ESK in the article is detrimental. The authors caution about “miracle cures” ultimately proving to be harmful, and suggest that K/ESK could end up in the trash heap with Freud’s 1884 positive description of cocaine for depression and inducing insulin comas to treat patients with schizophrenia, a treatment used until 1960. These rogue treatments were used in the infancy of psychiatry, at a time when there was a paucity of treatments available in psychiatry, and only a primitive understanding of the brain.

Of greater concern to me is the authors’ simplistic and flawed description of the mechanism of action of ketamine. They state “based on available research, ketamine’s long-lasting effects seem to come from 2 mechanisms… activation of endogenous opioid receptors… [and] blockade of N-methyl-D-aspartate receptors.” In the spirit of scientific inquiry, I would like to explore the current evidence base of the putative mechanisms of action of K/ESK.

Ketamine: A plethora of studies

An impressive body of literature is attempting to piece together the complex and multidimensional neurophysiological mechanisms that result in ketamine’s rapid-acting antidepressant (RAAD) effect, which occurs as soon as 4 hours post-dose. A plethora of pre-clinical and clinical studies, including functional connectivity MRI scans in individuals with MDD, have provided a rough outline, albeit incomplete, of ketamine’s mechanisms of action. Ketamine was discovered in 1962 by chemist Calvin L. Stevens, who was experimenting with novel molecular structures to find a replacement for phencyclidine as a safer dissociative anesthetic. After successful experiments in human prisoners in 1964, ketamine was further studied and became FDA-approved in 1970 as a dissociative anesthetic. Lacking respiratory depression and hypotension, which were common adverse effects of other anesthetics, ketamine became commonly used on the battlefield in the Vietnam War, and continues to be used as a dissociative anesthetic.

Following the publication of the Berman article¹ in 2000 that demonstrated apparent RAAD activity of IV ketamine, interest in ketamine’s use for TRD—a huge unmet need in psychiatry—skyrocketed. Since the FDA approval of iproniazid (a monoamine oxidase inhibitor) as the first medication approved to treat major depression in 1958, and the FDA approval of imipramine in 1959, all subsequent FDA-approved antidepressants have shared iproniazid/imipramine’s properties of modulating the monoamines serotonin, dopamine, and norepinephrine. The infamous Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial concluded that only 37% of patients with a major depressive episode achieve remission with their first antidepressant trial, and only 49% respond (50% improvement in symptoms).³ Ketamine/esketamine offered a novel mechanism of action, presumed to be related to the glutamate system, that demonstrated a clinical improvement in depressive symptoms in as few as 4 hours, with benefits that lasted up to 1 week after a single dose.

Continue to: A model of how ketamine works

Numerous publications from preclinical and clinical research collectively have woven a putative model of how K/ESK may rapidly improve depression by ultimately increasing synaptogenesis in the human prefrontal cortex—a part of the brain known to atrophy in states of chronic stress and depression.⁴ What is well established is the noncompetitive antagonism of K/ESK at the N-methyl-D-aspartate (NMDA) glutamate receptor, but this pharmacodynamic property may or may not be responsible, or even required, for the ultimate antidepressant effect 4 hours after administration. It has been shown that unlike anesthetic doses of K/ESK that inhibit glutamate, subanesthetic doses activate neuronal glutamate transmission in the prefrontal cortex.⁵

A significant body of evidence supports agonism of the glutamate alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor as an important step in the cascade of events that ultimately increases levels of the mammalian target of rapamycin (mTOR), which unleashes protein synthesis in synapses facilitating synaptogenesis. Pretreatment with AMPA receptor antagonists blocks the downstream effect of synaptogenesis.^6,7 In support of this putative mechanism, hydroxynorketamine, a metabolite of racemic ketamine that has also demonstrated RAAD activity in a ketamine-like manner, is dependent upon AMPA glutamate receptor upregulation and activation, while not requiring activity at the NMDA-glutamate receptor.^8,9

A comprehensive model on the putative molecular cascade of events contributing to the antidepressant effect of ketamine has recently been published¹⁰ and mirrors the excellent previous review by Abdallah et al.¹¹ Hirota and Lambert¹⁰ propose that antagonism of interneuronal NMDA-glutamate receptors on GABAergic interneurons may result in a prefrontal cortex surge of glutamate, which increases agonism of the AMPA-glutamate receptor. This AMPA-glutamate receptor agonism has been shown to increase expression of brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF),¹² both of which converge on increasing levels of mTOR, and the subsequent activation of mTOR, which putatively plays a role in increased production of scaffolding proteins and increased synaptogenesis, especially in the prefrontal cortex. In support of this model, during infusion and at 24 hours after a single ketamine infusion in individuals with MDD, functional connectivity MRI demonstrated an increase in global brain connectivity in the prefrontal cortex.^13,14 The demonstration of increased global connectivity in the prefrontal cortex of patients with MDD, both during ketamine infusion and at 24 hours post-infusion, supports the clinical observations in clinics treating patients with K/ESK.

Opioid receptors and ketamine

During the past year, there has been significant discussion in psychiatry about the possible role of the mu opioid receptor and opioid system activation in ketamine’s RAAD effect. Remarkably, the literature supporting this hypothesis in humans is based on a single study by Williams et al.¹⁵ The authors’ claim: “We now present the first evidence in humans that opioid receptors are necessary for ketamine’s acute antidepressant effect.” In fact, in my opinion, this single study, which has not been replicated, is highly flawed. It included 30 adults with TRD, but only 12 of the 14 participants who qualified for the planned interim analysis completed the double-blind crossover. The population studied was quite treatment-refractory; the average duration of MDD was 24.1 years, the average age at onset was 17.3 years, and the duration of the current depressive episode at the time of the study was 8.6 years. Most significant to me was the reason the study was terminated: “At the interim analysis, given the finding that the combination of ketamine and naltrexone was not only ineffective but also noxious for many participants, we decided to stop enrolling patients in the study.” A distinct possibility is that the noxious adverse effects from the naltrexone impacted the participants’ experience in a negative manner, dampening down any antidepressant effect from ketamine.

In the August 2019 issue of Molecular Psychiatry, these same authors published a second article¹⁶ with conclusions based solely on “a secondary analysis of” the data from the same 12 participants in their first publication. Williams et al¹⁶ concluded that naltrexone also decreases the anti-suicidality effects of ketamine. Without any additional data or clinical research, these same authors extrapolated their hypothesized opioid receptor activity of ketamine to include it being responsible for ketamine’s established anti-suicidal effects.

Continue to: Mathew and Rivas-Grajales...

Mathew and Rivas-Grajales¹⁷ recently published a thoughtful critique and analysis of the study design and conclusions of the original Williams paper.¹⁵ They concluded that insufficient evidence exists to answer the question of how ketamine may interface with the opioid system, and they encourage further research into this important topic.

Two additional recent publications^18,19 reported that naltrexone pretreatment did not attenuate the antidepressant effects of ketamine in their participants. Additionally, a recent publication in the anesthesiology literature²⁰ concluded that esketamine reversed respiratory depression that was induced by remifentanil. From a clinical perspective, the most compelling argument against a direct mu opioid receptor mechanism for K/ESK is the lack of any craving, tolerance, or withdrawal in patients with TRD treated with K/ESK in numerous clinical publications comparing K/ESK with placebo. In the case of esketamine, during the 5 phase III clinical trials—including both short- and long-term studies—there was no signal for an opioid-like pharmacology. Significantly, both K/ESK are rapidly metabolized by the human body, and the typical dosing is 2 doses/week for the first month, then 1 dose/week for the next month, then 1 dose every week or less for the remainder of treatment.

Curiously, in the May 2019 issue of the American Journal of Psychiatry, Schatzberg²¹ (one of the co-authors of the prior 2 studies opining that ketamine has direct opioid system activation) wrote a “Reviews and Overviews” article in which he misrepresents the conclusions of an elegant study by Abdallah et al²² published in December 2018.

Abdallah et al²² added rapamycin, an immunosuppressant and a known inhibitor of mTOR, as a pretreatment to patients in a major depressive episode prior to infusion with IV ketamine. Their hypothesis was to see if the rapamycin decreased ketamine’s rapid antidepressant response—putatively by inhibiting the effect of mTOR. Rather than decreasing ketamine’s antidepressant effect, and in contrast to the placebo pretreatment group, at 2 weeks post IV ketamine infusion, patients treated with rapamycin-ketamine had a longer duration/greater improvement in their depressive symptoms compared with the patients receiving placebo-ketamine (improvement of 41% vs 13%, respectively, P = .04). Abdallah et al²² hypothesized that the pretreatment with rapamycin provides anti-inflammatory benefits to the synaptogenesis resulting from ketamine, which protects the newly formed synapses and prolongs ketamine’s antidepressant effect. Schatzberg²¹ came to a different conclusion than Abdallah et al,²² opining that because the rapamycin “failed to decrease ketamine response,” this result debunks the role of mTOR as a mediator in the antidepressant effect of ketamine through synaptogenesis.

Much more to learn

We still have a great deal to learn about the mechanism of action of K/ESK. However, clinics that are augmenting antidepressants with K/ESK in patients with TRD report significant and rapid symptom improvement in some patients (personal communications). We still do not understand the actual mechanisms of action of antidepressants and antipsychotics, but this does not curtail their use and clinical benefits to our patients. Ketamine has been extensively studied. In the current appropriate climate of concern about the pervasive and lethal opioid epidemic in the United States, we must remain on solid scientific ground before attributing an opioid mechanism to a novel treatment that has already benefitted many of our most depressed and refractory patients.

Continue to: Looking at the extensive...

Looking at the extensive published data over the past 20 years, a consistent model has emerged whereby glutamate agonism of the AMPA-glutamate receptor, both with and without antagonism of the NMDA-glutamate receptor, appears to set in motion a molecular cascade involving BDNF and VEGF, and ultimately increasing the activity of mTOR, with resulting synaptogenicity that increases global brain connectivity in the human prefrontal cortex. As we continue to understand the complexities and additional circuitries that are involved in the RAAD effect of K/ESK, the hope is that novel molecular targets for future drug development will emerge.

Bottom Line

Extensive published data over the past 20 years has produced a consistent model to explain the putative mechanisms of action for the rapid antidepressant effects of ketamine and esketamine. We must remain on solid scientific ground before attributing an opioid mechanism to a novel treatment that has already benefitted many of our patients with treatment-resistant depression.

Related Resources

• Mattingly GW, Anderson RH. Intranasal esketamine. Current Psychiatry. 2019;18(5):31-38.
• Thase M. Ketamine and esketamine for treating unipolar depression in adults: Administration, efficacy, and adverse effects. UpToDate. www.uptodate.com/contents/ketamine-and-esketamine-for-treating-unipolar-depression-in-adults-administration-efficacy-and-adverse-effects.

Drug Brand Names

Esketamine nasal spray • Spravato
Imipramine • Tofranil
Ketamine • Ketalar
Naltrexone • Vivitrol, ReVia
Rapamycin • Rapamune
Remifentanil • Ultiva

Since the FDA approved intranasal esketamine, there has understandably been significant dialogue, debate, and discussion about the possible mechanisms of action of its antidepressant effects. Ketamine, the racemate of esketamine and arketamine, has been used off-label since the late 1990s. The first study of IV ketamine’s rapid antidepressant activity was published in 2000.¹ In that study, 7 patients with major depressive disorder (MDD) were treated in a double-blind/placebo-controlled manner with IV ketamine or placebo. Researchers found a significant antidepressant effect within 72 hours with the administration of IV ketamine.

There is a tremendous number of publications related to ketamine, which creates a large reservoir of information to review in an attempt to piece together what we currently know about the mechanisms of action of ketamine/esketamine (K/ESK). A search of PubMed using the search word “ketamine” (October 8, 2019; www.ncbi.nlm.nih.gov/pubmed) produced a list of 4,869 articles just in the last 5 years; and the search words “ketamine and depression” produced a list of 1,221 publications over the same time period.

The FDA approval of intranasal esketamine in March 2019 was based on 5 phase III clinical studies (albeit not all were positive studies) and >9 years of intensive preclinical and clinical research on the efficacy and safety of intranasal esketamine in treatment-resistant depression (TRD). At the time the FDA approved it, esketamine had been studied in 1,700 patients with TRD, with 1-year safety data on approximately 800 patients. Despite this established data portfolio, critics of K/ESK continue to opine that we do not have enough long-term experience with these drugs, and some key opinion leaders continue to voice caution about the clinical use of K/ESK until we obtain more information and experience.

An article in the September 2019 issue Currrent Psychiatryby Epstein and Farrell² exemplifies my concern regarding the misrepresentation of significant details about what we know about the mechanism of action of K/ESK. Both K/ESK are certainly not “miracle cures,” and although I understand the use of this term in the article’s title, the continued use of this term to describe K/ESK in the article is detrimental. The authors caution about “miracle cures” ultimately proving to be harmful, and suggest that K/ESK could end up in the trash heap with Freud’s 1884 positive description of cocaine for depression and inducing insulin comas to treat patients with schizophrenia, a treatment used until 1960. These rogue treatments were used in the infancy of psychiatry, at a time when there was a paucity of treatments available in psychiatry, and only a primitive understanding of the brain.

Of greater concern to me is the authors’ simplistic and flawed description of the mechanism of action of ketamine. They state “based on available research, ketamine’s long-lasting effects seem to come from 2 mechanisms… activation of endogenous opioid receptors… [and] blockade of N-methyl-D-aspartate receptors.” In the spirit of scientific inquiry, I would like to explore the current evidence base of the putative mechanisms of action of K/ESK.

Ketamine: A plethora of studies

An impressive body of literature is attempting to piece together the complex and multidimensional neurophysiological mechanisms that result in ketamine’s rapid-acting antidepressant (RAAD) effect, which occurs as soon as 4 hours post-dose. A plethora of pre-clinical and clinical studies, including functional connectivity MRI scans in individuals with MDD, have provided a rough outline, albeit incomplete, of ketamine’s mechanisms of action. Ketamine was discovered in 1962 by chemist Calvin L. Stevens, who was experimenting with novel molecular structures to find a replacement for phencyclidine as a safer dissociative anesthetic. After successful experiments in human prisoners in 1964, ketamine was further studied and became FDA-approved in 1970 as a dissociative anesthetic. Lacking respiratory depression and hypotension, which were common adverse effects of other anesthetics, ketamine became commonly used on the battlefield in the Vietnam War, and continues to be used as a dissociative anesthetic.

Following the publication of the Berman article¹ in 2000 that demonstrated apparent RAAD activity of IV ketamine, interest in ketamine’s use for TRD—a huge unmet need in psychiatry—skyrocketed. Since the FDA approval of iproniazid (a monoamine oxidase inhibitor) as the first medication approved to treat major depression in 1958, and the FDA approval of imipramine in 1959, all subsequent FDA-approved antidepressants have shared iproniazid/imipramine’s properties of modulating the monoamines serotonin, dopamine, and norepinephrine. The infamous Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial concluded that only 37% of patients with a major depressive episode achieve remission with their first antidepressant trial, and only 49% respond (50% improvement in symptoms).³ Ketamine/esketamine offered a novel mechanism of action, presumed to be related to the glutamate system, that demonstrated a clinical improvement in depressive symptoms in as few as 4 hours, with benefits that lasted up to 1 week after a single dose.

Continue to: A model of how ketamine works

Numerous publications from preclinical and clinical research collectively have woven a putative model of how K/ESK may rapidly improve depression by ultimately increasing synaptogenesis in the human prefrontal cortex—a part of the brain known to atrophy in states of chronic stress and depression.⁴ What is well established is the noncompetitive antagonism of K/ESK at the N-methyl-D-aspartate (NMDA) glutamate receptor, but this pharmacodynamic property may or may not be responsible, or even required, for the ultimate antidepressant effect 4 hours after administration. It has been shown that unlike anesthetic doses of K/ESK that inhibit glutamate, subanesthetic doses activate neuronal glutamate transmission in the prefrontal cortex.⁵

A significant body of evidence supports agonism of the glutamate alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor as an important step in the cascade of events that ultimately increases levels of the mammalian target of rapamycin (mTOR), which unleashes protein synthesis in synapses facilitating synaptogenesis. Pretreatment with AMPA receptor antagonists blocks the downstream effect of synaptogenesis.^6,7 In support of this putative mechanism, hydroxynorketamine, a metabolite of racemic ketamine that has also demonstrated RAAD activity in a ketamine-like manner, is dependent upon AMPA glutamate receptor upregulation and activation, while not requiring activity at the NMDA-glutamate receptor.^8,9

A comprehensive model on the putative molecular cascade of events contributing to the antidepressant effect of ketamine has recently been published¹⁰ and mirrors the excellent previous review by Abdallah et al.¹¹ Hirota and Lambert¹⁰ propose that antagonism of interneuronal NMDA-glutamate receptors on GABAergic interneurons may result in a prefrontal cortex surge of glutamate, which increases agonism of the AMPA-glutamate receptor. This AMPA-glutamate receptor agonism has been shown to increase expression of brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF),¹² both of which converge on increasing levels of mTOR, and the subsequent activation of mTOR, which putatively plays a role in increased production of scaffolding proteins and increased synaptogenesis, especially in the prefrontal cortex. In support of this model, during infusion and at 24 hours after a single ketamine infusion in individuals with MDD, functional connectivity MRI demonstrated an increase in global brain connectivity in the prefrontal cortex.^13,14 The demonstration of increased global connectivity in the prefrontal cortex of patients with MDD, both during ketamine infusion and at 24 hours post-infusion, supports the clinical observations in clinics treating patients with K/ESK.

Opioid receptors and ketamine

During the past year, there has been significant discussion in psychiatry about the possible role of the mu opioid receptor and opioid system activation in ketamine’s RAAD effect. Remarkably, the literature supporting this hypothesis in humans is based on a single study by Williams et al.¹⁵ The authors’ claim: “We now present the first evidence in humans that opioid receptors are necessary for ketamine’s acute antidepressant effect.” In fact, in my opinion, this single study, which has not been replicated, is highly flawed. It included 30 adults with TRD, but only 12 of the 14 participants who qualified for the planned interim analysis completed the double-blind crossover. The population studied was quite treatment-refractory; the average duration of MDD was 24.1 years, the average age at onset was 17.3 years, and the duration of the current depressive episode at the time of the study was 8.6 years. Most significant to me was the reason the study was terminated: “At the interim analysis, given the finding that the combination of ketamine and naltrexone was not only ineffective but also noxious for many participants, we decided to stop enrolling patients in the study.” A distinct possibility is that the noxious adverse effects from the naltrexone impacted the participants’ experience in a negative manner, dampening down any antidepressant effect from ketamine.

In the August 2019 issue of Molecular Psychiatry, these same authors published a second article¹⁶ with conclusions based solely on “a secondary analysis of” the data from the same 12 participants in their first publication. Williams et al¹⁶ concluded that naltrexone also decreases the anti-suicidality effects of ketamine. Without any additional data or clinical research, these same authors extrapolated their hypothesized opioid receptor activity of ketamine to include it being responsible for ketamine’s established anti-suicidal effects.

Continue to: Mathew and Rivas-Grajales...

Mathew and Rivas-Grajales¹⁷ recently published a thoughtful critique and analysis of the study design and conclusions of the original Williams paper.¹⁵ They concluded that insufficient evidence exists to answer the question of how ketamine may interface with the opioid system, and they encourage further research into this important topic.

Two additional recent publications^18,19 reported that naltrexone pretreatment did not attenuate the antidepressant effects of ketamine in their participants. Additionally, a recent publication in the anesthesiology literature²⁰ concluded that esketamine reversed respiratory depression that was induced by remifentanil. From a clinical perspective, the most compelling argument against a direct mu opioid receptor mechanism for K/ESK is the lack of any craving, tolerance, or withdrawal in patients with TRD treated with K/ESK in numerous clinical publications comparing K/ESK with placebo. In the case of esketamine, during the 5 phase III clinical trials—including both short- and long-term studies—there was no signal for an opioid-like pharmacology. Significantly, both K/ESK are rapidly metabolized by the human body, and the typical dosing is 2 doses/week for the first month, then 1 dose/week for the next month, then 1 dose every week or less for the remainder of treatment.

Curiously, in the May 2019 issue of the American Journal of Psychiatry, Schatzberg²¹ (one of the co-authors of the prior 2 studies opining that ketamine has direct opioid system activation) wrote a “Reviews and Overviews” article in which he misrepresents the conclusions of an elegant study by Abdallah et al²² published in December 2018.

Abdallah et al²² added rapamycin, an immunosuppressant and a known inhibitor of mTOR, as a pretreatment to patients in a major depressive episode prior to infusion with IV ketamine. Their hypothesis was to see if the rapamycin decreased ketamine’s rapid antidepressant response—putatively by inhibiting the effect of mTOR. Rather than decreasing ketamine’s antidepressant effect, and in contrast to the placebo pretreatment group, at 2 weeks post IV ketamine infusion, patients treated with rapamycin-ketamine had a longer duration/greater improvement in their depressive symptoms compared with the patients receiving placebo-ketamine (improvement of 41% vs 13%, respectively, P = .04). Abdallah et al²² hypothesized that the pretreatment with rapamycin provides anti-inflammatory benefits to the synaptogenesis resulting from ketamine, which protects the newly formed synapses and prolongs ketamine’s antidepressant effect. Schatzberg²¹ came to a different conclusion than Abdallah et al,²² opining that because the rapamycin “failed to decrease ketamine response,” this result debunks the role of mTOR as a mediator in the antidepressant effect of ketamine through synaptogenesis.

Much more to learn

We still have a great deal to learn about the mechanism of action of K/ESK. However, clinics that are augmenting antidepressants with K/ESK in patients with TRD report significant and rapid symptom improvement in some patients (personal communications). We still do not understand the actual mechanisms of action of antidepressants and antipsychotics, but this does not curtail their use and clinical benefits to our patients. Ketamine has been extensively studied. In the current appropriate climate of concern about the pervasive and lethal opioid epidemic in the United States, we must remain on solid scientific ground before attributing an opioid mechanism to a novel treatment that has already benefitted many of our most depressed and refractory patients.

Continue to: Looking at the extensive...

Looking at the extensive published data over the past 20 years, a consistent model has emerged whereby glutamate agonism of the AMPA-glutamate receptor, both with and without antagonism of the NMDA-glutamate receptor, appears to set in motion a molecular cascade involving BDNF and VEGF, and ultimately increasing the activity of mTOR, with resulting synaptogenicity that increases global brain connectivity in the human prefrontal cortex. As we continue to understand the complexities and additional circuitries that are involved in the RAAD effect of K/ESK, the hope is that novel molecular targets for future drug development will emerge.

Bottom Line

Extensive published data over the past 20 years has produced a consistent model to explain the putative mechanisms of action for the rapid antidepressant effects of ketamine and esketamine. We must remain on solid scientific ground before attributing an opioid mechanism to a novel treatment that has already benefitted many of our patients with treatment-resistant depression.

Related Resources

• Mattingly GW, Anderson RH. Intranasal esketamine. Current Psychiatry. 2019;18(5):31-38.
• Thase M. Ketamine and esketamine for treating unipolar depression in adults: Administration, efficacy, and adverse effects. UpToDate. www.uptodate.com/contents/ketamine-and-esketamine-for-treating-unipolar-depression-in-adults-administration-efficacy-and-adverse-effects.

Drug Brand Names

Esketamine nasal spray • Spravato
Imipramine • Tofranil
Ketamine • Ketalar
Naltrexone • Vivitrol, ReVia
Rapamycin • Rapamune
Remifentanil • Ultiva

Since the FDA approved intranasal esketamine, there has understandably been significant dialogue, debate, and discussion about the possible mechanisms of action of its antidepressant effects. Ketamine, the racemate of esketamine and arketamine, has been used off-label since the late 1990s. The first study of IV ketamine’s rapid antidepressant activity was published in 2000.¹ In that study, 7 patients with major depressive disorder (MDD) were treated in a double-blind/placebo-controlled manner with IV ketamine or placebo. Researchers found a significant antidepressant effect within 72 hours with the administration of IV ketamine.

There is a tremendous number of publications related to ketamine, which creates a large reservoir of information to review in an attempt to piece together what we currently know about the mechanisms of action of ketamine/esketamine (K/ESK). A search of PubMed using the search word “ketamine” (October 8, 2019; www.ncbi.nlm.nih.gov/pubmed) produced a list of 4,869 articles just in the last 5 years; and the search words “ketamine and depression” produced a list of 1,221 publications over the same time period.

The FDA approval of intranasal esketamine in March 2019 was based on 5 phase III clinical studies (albeit not all were positive studies) and >9 years of intensive preclinical and clinical research on the efficacy and safety of intranasal esketamine in treatment-resistant depression (TRD). At the time the FDA approved it, esketamine had been studied in 1,700 patients with TRD, with 1-year safety data on approximately 800 patients. Despite this established data portfolio, critics of K/ESK continue to opine that we do not have enough long-term experience with these drugs, and some key opinion leaders continue to voice caution about the clinical use of K/ESK until we obtain more information and experience.

An article in the September 2019 issue Currrent Psychiatryby Epstein and Farrell² exemplifies my concern regarding the misrepresentation of significant details about what we know about the mechanism of action of K/ESK. Both K/ESK are certainly not “miracle cures,” and although I understand the use of this term in the article’s title, the continued use of this term to describe K/ESK in the article is detrimental. The authors caution about “miracle cures” ultimately proving to be harmful, and suggest that K/ESK could end up in the trash heap with Freud’s 1884 positive description of cocaine for depression and inducing insulin comas to treat patients with schizophrenia, a treatment used until 1960. These rogue treatments were used in the infancy of psychiatry, at a time when there was a paucity of treatments available in psychiatry, and only a primitive understanding of the brain.

Of greater concern to me is the authors’ simplistic and flawed description of the mechanism of action of ketamine. They state “based on available research, ketamine’s long-lasting effects seem to come from 2 mechanisms… activation of endogenous opioid receptors… [and] blockade of N-methyl-D-aspartate receptors.” In the spirit of scientific inquiry, I would like to explore the current evidence base of the putative mechanisms of action of K/ESK.

Ketamine: A plethora of studies

An impressive body of literature is attempting to piece together the complex and multidimensional neurophysiological mechanisms that result in ketamine’s rapid-acting antidepressant (RAAD) effect, which occurs as soon as 4 hours post-dose. A plethora of pre-clinical and clinical studies, including functional connectivity MRI scans in individuals with MDD, have provided a rough outline, albeit incomplete, of ketamine’s mechanisms of action. Ketamine was discovered in 1962 by chemist Calvin L. Stevens, who was experimenting with novel molecular structures to find a replacement for phencyclidine as a safer dissociative anesthetic. After successful experiments in human prisoners in 1964, ketamine was further studied and became FDA-approved in 1970 as a dissociative anesthetic. Lacking respiratory depression and hypotension, which were common adverse effects of other anesthetics, ketamine became commonly used on the battlefield in the Vietnam War, and continues to be used as a dissociative anesthetic.

Following the publication of the Berman article¹ in 2000 that demonstrated apparent RAAD activity of IV ketamine, interest in ketamine’s use for TRD—a huge unmet need in psychiatry—skyrocketed. Since the FDA approval of iproniazid (a monoamine oxidase inhibitor) as the first medication approved to treat major depression in 1958, and the FDA approval of imipramine in 1959, all subsequent FDA-approved antidepressants have shared iproniazid/imipramine’s properties of modulating the monoamines serotonin, dopamine, and norepinephrine. The infamous Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial concluded that only 37% of patients with a major depressive episode achieve remission with their first antidepressant trial, and only 49% respond (50% improvement in symptoms).³ Ketamine/esketamine offered a novel mechanism of action, presumed to be related to the glutamate system, that demonstrated a clinical improvement in depressive symptoms in as few as 4 hours, with benefits that lasted up to 1 week after a single dose.

Continue to: A model of how ketamine works

Numerous publications from preclinical and clinical research collectively have woven a putative model of how K/ESK may rapidly improve depression by ultimately increasing synaptogenesis in the human prefrontal cortex—a part of the brain known to atrophy in states of chronic stress and depression.⁴ What is well established is the noncompetitive antagonism of K/ESK at the N-methyl-D-aspartate (NMDA) glutamate receptor, but this pharmacodynamic property may or may not be responsible, or even required, for the ultimate antidepressant effect 4 hours after administration. It has been shown that unlike anesthetic doses of K/ESK that inhibit glutamate, subanesthetic doses activate neuronal glutamate transmission in the prefrontal cortex.⁵

A significant body of evidence supports agonism of the glutamate alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor as an important step in the cascade of events that ultimately increases levels of the mammalian target of rapamycin (mTOR), which unleashes protein synthesis in synapses facilitating synaptogenesis. Pretreatment with AMPA receptor antagonists blocks the downstream effect of synaptogenesis.^6,7 In support of this putative mechanism, hydroxynorketamine, a metabolite of racemic ketamine that has also demonstrated RAAD activity in a ketamine-like manner, is dependent upon AMPA glutamate receptor upregulation and activation, while not requiring activity at the NMDA-glutamate receptor.^8,9

A comprehensive model on the putative molecular cascade of events contributing to the antidepressant effect of ketamine has recently been published¹⁰ and mirrors the excellent previous review by Abdallah et al.¹¹ Hirota and Lambert¹⁰ propose that antagonism of interneuronal NMDA-glutamate receptors on GABAergic interneurons may result in a prefrontal cortex surge of glutamate, which increases agonism of the AMPA-glutamate receptor. This AMPA-glutamate receptor agonism has been shown to increase expression of brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF),¹² both of which converge on increasing levels of mTOR, and the subsequent activation of mTOR, which putatively plays a role in increased production of scaffolding proteins and increased synaptogenesis, especially in the prefrontal cortex. In support of this model, during infusion and at 24 hours after a single ketamine infusion in individuals with MDD, functional connectivity MRI demonstrated an increase in global brain connectivity in the prefrontal cortex.^13,14 The demonstration of increased global connectivity in the prefrontal cortex of patients with MDD, both during ketamine infusion and at 24 hours post-infusion, supports the clinical observations in clinics treating patients with K/ESK.

Opioid receptors and ketamine

During the past year, there has been significant discussion in psychiatry about the possible role of the mu opioid receptor and opioid system activation in ketamine’s RAAD effect. Remarkably, the literature supporting this hypothesis in humans is based on a single study by Williams et al.¹⁵ The authors’ claim: “We now present the first evidence in humans that opioid receptors are necessary for ketamine’s acute antidepressant effect.” In fact, in my opinion, this single study, which has not been replicated, is highly flawed. It included 30 adults with TRD, but only 12 of the 14 participants who qualified for the planned interim analysis completed the double-blind crossover. The population studied was quite treatment-refractory; the average duration of MDD was 24.1 years, the average age at onset was 17.3 years, and the duration of the current depressive episode at the time of the study was 8.6 years. Most significant to me was the reason the study was terminated: “At the interim analysis, given the finding that the combination of ketamine and naltrexone was not only ineffective but also noxious for many participants, we decided to stop enrolling patients in the study.” A distinct possibility is that the noxious adverse effects from the naltrexone impacted the participants’ experience in a negative manner, dampening down any antidepressant effect from ketamine.

In the August 2019 issue of Molecular Psychiatry, these same authors published a second article¹⁶ with conclusions based solely on “a secondary analysis of” the data from the same 12 participants in their first publication. Williams et al¹⁶ concluded that naltrexone also decreases the anti-suicidality effects of ketamine. Without any additional data or clinical research, these same authors extrapolated their hypothesized opioid receptor activity of ketamine to include it being responsible for ketamine’s established anti-suicidal effects.

Continue to: Mathew and Rivas-Grajales...

Mathew and Rivas-Grajales¹⁷ recently published a thoughtful critique and analysis of the study design and conclusions of the original Williams paper.¹⁵ They concluded that insufficient evidence exists to answer the question of how ketamine may interface with the opioid system, and they encourage further research into this important topic.

Two additional recent publications^18,19 reported that naltrexone pretreatment did not attenuate the antidepressant effects of ketamine in their participants. Additionally, a recent publication in the anesthesiology literature²⁰ concluded that esketamine reversed respiratory depression that was induced by remifentanil. From a clinical perspective, the most compelling argument against a direct mu opioid receptor mechanism for K/ESK is the lack of any craving, tolerance, or withdrawal in patients with TRD treated with K/ESK in numerous clinical publications comparing K/ESK with placebo. In the case of esketamine, during the 5 phase III clinical trials—including both short- and long-term studies—there was no signal for an opioid-like pharmacology. Significantly, both K/ESK are rapidly metabolized by the human body, and the typical dosing is 2 doses/week for the first month, then 1 dose/week for the next month, then 1 dose every week or less for the remainder of treatment.

Curiously, in the May 2019 issue of the American Journal of Psychiatry, Schatzberg²¹ (one of the co-authors of the prior 2 studies opining that ketamine has direct opioid system activation) wrote a “Reviews and Overviews” article in which he misrepresents the conclusions of an elegant study by Abdallah et al²² published in December 2018.

Abdallah et al²² added rapamycin, an immunosuppressant and a known inhibitor of mTOR, as a pretreatment to patients in a major depressive episode prior to infusion with IV ketamine. Their hypothesis was to see if the rapamycin decreased ketamine’s rapid antidepressant response—putatively by inhibiting the effect of mTOR. Rather than decreasing ketamine’s antidepressant effect, and in contrast to the placebo pretreatment group, at 2 weeks post IV ketamine infusion, patients treated with rapamycin-ketamine had a longer duration/greater improvement in their depressive symptoms compared with the patients receiving placebo-ketamine (improvement of 41% vs 13%, respectively, P = .04). Abdallah et al²² hypothesized that the pretreatment with rapamycin provides anti-inflammatory benefits to the synaptogenesis resulting from ketamine, which protects the newly formed synapses and prolongs ketamine’s antidepressant effect. Schatzberg²¹ came to a different conclusion than Abdallah et al,²² opining that because the rapamycin “failed to decrease ketamine response,” this result debunks the role of mTOR as a mediator in the antidepressant effect of ketamine through synaptogenesis.

Much more to learn

We still have a great deal to learn about the mechanism of action of K/ESK. However, clinics that are augmenting antidepressants with K/ESK in patients with TRD report significant and rapid symptom improvement in some patients (personal communications). We still do not understand the actual mechanisms of action of antidepressants and antipsychotics, but this does not curtail their use and clinical benefits to our patients. Ketamine has been extensively studied. In the current appropriate climate of concern about the pervasive and lethal opioid epidemic in the United States, we must remain on solid scientific ground before attributing an opioid mechanism to a novel treatment that has already benefitted many of our most depressed and refractory patients.

Continue to: Looking at the extensive...

Looking at the extensive published data over the past 20 years, a consistent model has emerged whereby glutamate agonism of the AMPA-glutamate receptor, both with and without antagonism of the NMDA-glutamate receptor, appears to set in motion a molecular cascade involving BDNF and VEGF, and ultimately increasing the activity of mTOR, with resulting synaptogenicity that increases global brain connectivity in the human prefrontal cortex. As we continue to understand the complexities and additional circuitries that are involved in the RAAD effect of K/ESK, the hope is that novel molecular targets for future drug development will emerge.

Bottom Line

Extensive published data over the past 20 years has produced a consistent model to explain the putative mechanisms of action for the rapid antidepressant effects of ketamine and esketamine. We must remain on solid scientific ground before attributing an opioid mechanism to a novel treatment that has already benefitted many of our patients with treatment-resistant depression.

Related Resources

• Mattingly GW, Anderson RH. Intranasal esketamine. Current Psychiatry. 2019;18(5):31-38.
• Thase M. Ketamine and esketamine for treating unipolar depression in adults: Administration, efficacy, and adverse effects. UpToDate. www.uptodate.com/contents/ketamine-and-esketamine-for-treating-unipolar-depression-in-adults-administration-efficacy-and-adverse-effects.

Drug Brand Names

Esketamine nasal spray • Spravato
Imipramine • Tofranil
Ketamine • Ketalar
Naltrexone • Vivitrol, ReVia
Rapamycin • Rapamune
Remifentanil • Ultiva

Rarely does someone come along who has new insight into behavior, someone who conceptualizes with such clarity that we wonder why we never saw it before.

Homer B. Martin, MD, was such a man. Over the course of 40 years’ psychodynamic psychotherapy work as a psychiatrist, he pieced together a concept of how we are emotionally conditioned in the first 3 years of life and how this conditioning affects us throughout our lives. Conditioning forces us to live on autopilot, creating inappropriate knee-jerk emotional responses to those closest to us.

Dr. Martin’s protégé, child and adolescent psychiatrist Christine B.L. Adams, MD, contributed her own 40 years of clinical practice as a psychodynamic psychotherapist to Dr. Martin’s new concept of emotional conditioning. Their findings are published in the award-winning book “Living on Automatic: How Emotional Conditioning Shapes our Lives and Relationships” (Praeger, 2018).

The authors aim to help both therapists and patients out of the quagmire of conflicted relationships and emotional illnesses that result from emotional conditioning. They propose a new understanding of personality development and subsequent relationship conflict, which incorporates work of Pavlov, Skinner, and Lorenz, along with techniques of Freud.

Dr. Martin and Dr. Adams discovered that we are conditioned into one of two roles – omnipotent and impotent. Those roles become the bedrock of our personalities. We display those roles in marriages, with our children, friends, and colleagues, without regard to gender.

Each role exists on a continuum, from mild to severe, determined by upbringing in the family. Once you acquire a role in childhood, the role is reinforced by both family and society at large – peers, teachers, and friends.

The authors unveil a new conceptualization of how the mind works for each role – thinking style, ways of elaborating emotions, attitudes, personal standards, value systems, reality testing mode, quality of thought, and mode of commitment.

The book has three sections. “Part One, Understanding Emotional Conditioning” describes the basic concepts, the effects of conditioning, and the two personality types. “Part Two, Relationship Struggles: Miscommunications and Marriages” examines marriage conflict, divorce, and living single. “Part Three, Solutions: Psychotherapy and Deconditioning” presents steps we can take to decondition ourselves, as well as the process of deconditioning psychotherapy.

To escape automatic living, Dr. Martin and Dr. Adams endorse the use of deconditioning psychotherapy, which helps people lessen their emotional conditioning. The cornerstone of deconditioning treatment is helping people turn off automatic responses through replacing emotional conditioning with thinking.

In undergoing deconditioning you discover how you were emotionally conditioned as a child and how you skew participation in your relationships. You learn to slow down and dissect the automatic responding that you and others do. You discover how to evaluate what the situation calls for with the involved people. Who needs what, how much, and from whom?

This book is written for both general readers and psychotherapists. Its novel approach for alleviating emotional illnesses in “ordinary” people is a welcome addition to the armamentarium of any therapist.

The book is extraordinarily well written. It offers valuable case vignettes, tables, and self-inquiry questions to assist in understanding the characteristics associated with each emotionally conditioned role. The authors also suggest reading materials and movies for viewing.

Dr. Martin and Dr. Adams have made the book very digestible, intriguing and practical. And it is a marvelous tribute to the value of a 30-year mentorship.

Judith R. Milner, MD, MEd, SpecEd, is a general, child, and adolescent psychiatrist in private practice in Everett, Wash. She has traveled with various groups over the years in an effort to alleviate some of the suffering caused by war and natural disaster. She has worked with Step Up Rwanda Women and Pygmy Survival Alliance, as well as on the Committee for Women at the American Psychiatric Association and the Consumer Issues Committee, the Committee on Diversity and Culture, and the Membership Committee for the American Academy of Child and Adolescent Psychiatry.

Rarely does someone come along who has new insight into behavior, someone who conceptualizes with such clarity that we wonder why we never saw it before.

Homer B. Martin, MD, was such a man. Over the course of 40 years’ psychodynamic psychotherapy work as a psychiatrist, he pieced together a concept of how we are emotionally conditioned in the first 3 years of life and how this conditioning affects us throughout our lives. Conditioning forces us to live on autopilot, creating inappropriate knee-jerk emotional responses to those closest to us.

Dr. Martin’s protégé, child and adolescent psychiatrist Christine B.L. Adams, MD, contributed her own 40 years of clinical practice as a psychodynamic psychotherapist to Dr. Martin’s new concept of emotional conditioning. Their findings are published in the award-winning book “Living on Automatic: How Emotional Conditioning Shapes our Lives and Relationships” (Praeger, 2018).

The authors aim to help both therapists and patients out of the quagmire of conflicted relationships and emotional illnesses that result from emotional conditioning. They propose a new understanding of personality development and subsequent relationship conflict, which incorporates work of Pavlov, Skinner, and Lorenz, along with techniques of Freud.

Dr. Martin and Dr. Adams discovered that we are conditioned into one of two roles – omnipotent and impotent. Those roles become the bedrock of our personalities. We display those roles in marriages, with our children, friends, and colleagues, without regard to gender.

Each role exists on a continuum, from mild to severe, determined by upbringing in the family. Once you acquire a role in childhood, the role is reinforced by both family and society at large – peers, teachers, and friends.

The authors unveil a new conceptualization of how the mind works for each role – thinking style, ways of elaborating emotions, attitudes, personal standards, value systems, reality testing mode, quality of thought, and mode of commitment.

The book has three sections. “Part One, Understanding Emotional Conditioning” describes the basic concepts, the effects of conditioning, and the two personality types. “Part Two, Relationship Struggles: Miscommunications and Marriages” examines marriage conflict, divorce, and living single. “Part Three, Solutions: Psychotherapy and Deconditioning” presents steps we can take to decondition ourselves, as well as the process of deconditioning psychotherapy.

To escape automatic living, Dr. Martin and Dr. Adams endorse the use of deconditioning psychotherapy, which helps people lessen their emotional conditioning. The cornerstone of deconditioning treatment is helping people turn off automatic responses through replacing emotional conditioning with thinking.

In undergoing deconditioning you discover how you were emotionally conditioned as a child and how you skew participation in your relationships. You learn to slow down and dissect the automatic responding that you and others do. You discover how to evaluate what the situation calls for with the involved people. Who needs what, how much, and from whom?

This book is written for both general readers and psychotherapists. Its novel approach for alleviating emotional illnesses in “ordinary” people is a welcome addition to the armamentarium of any therapist.

The book is extraordinarily well written. It offers valuable case vignettes, tables, and self-inquiry questions to assist in understanding the characteristics associated with each emotionally conditioned role. The authors also suggest reading materials and movies for viewing.

Dr. Martin and Dr. Adams have made the book very digestible, intriguing and practical. And it is a marvelous tribute to the value of a 30-year mentorship.

Judith R. Milner, MD, MEd, SpecEd, is a general, child, and adolescent psychiatrist in private practice in Everett, Wash. She has traveled with various groups over the years in an effort to alleviate some of the suffering caused by war and natural disaster. She has worked with Step Up Rwanda Women and Pygmy Survival Alliance, as well as on the Committee for Women at the American Psychiatric Association and the Consumer Issues Committee, the Committee on Diversity and Culture, and the Membership Committee for the American Academy of Child and Adolescent Psychiatry.

Rarely does someone come along who has new insight into behavior, someone who conceptualizes with such clarity that we wonder why we never saw it before.

Homer B. Martin, MD, was such a man. Over the course of 40 years’ psychodynamic psychotherapy work as a psychiatrist, he pieced together a concept of how we are emotionally conditioned in the first 3 years of life and how this conditioning affects us throughout our lives. Conditioning forces us to live on autopilot, creating inappropriate knee-jerk emotional responses to those closest to us.

Dr. Martin’s protégé, child and adolescent psychiatrist Christine B.L. Adams, MD, contributed her own 40 years of clinical practice as a psychodynamic psychotherapist to Dr. Martin’s new concept of emotional conditioning. Their findings are published in the award-winning book “Living on Automatic: How Emotional Conditioning Shapes our Lives and Relationships” (Praeger, 2018).

The authors aim to help both therapists and patients out of the quagmire of conflicted relationships and emotional illnesses that result from emotional conditioning. They propose a new understanding of personality development and subsequent relationship conflict, which incorporates work of Pavlov, Skinner, and Lorenz, along with techniques of Freud.

Dr. Martin and Dr. Adams discovered that we are conditioned into one of two roles – omnipotent and impotent. Those roles become the bedrock of our personalities. We display those roles in marriages, with our children, friends, and colleagues, without regard to gender.

Each role exists on a continuum, from mild to severe, determined by upbringing in the family. Once you acquire a role in childhood, the role is reinforced by both family and society at large – peers, teachers, and friends.

The authors unveil a new conceptualization of how the mind works for each role – thinking style, ways of elaborating emotions, attitudes, personal standards, value systems, reality testing mode, quality of thought, and mode of commitment.

The book has three sections. “Part One, Understanding Emotional Conditioning” describes the basic concepts, the effects of conditioning, and the two personality types. “Part Two, Relationship Struggles: Miscommunications and Marriages” examines marriage conflict, divorce, and living single. “Part Three, Solutions: Psychotherapy and Deconditioning” presents steps we can take to decondition ourselves, as well as the process of deconditioning psychotherapy.

To escape automatic living, Dr. Martin and Dr. Adams endorse the use of deconditioning psychotherapy, which helps people lessen their emotional conditioning. The cornerstone of deconditioning treatment is helping people turn off automatic responses through replacing emotional conditioning with thinking.

In undergoing deconditioning you discover how you were emotionally conditioned as a child and how you skew participation in your relationships. You learn to slow down and dissect the automatic responding that you and others do. You discover how to evaluate what the situation calls for with the involved people. Who needs what, how much, and from whom?

This book is written for both general readers and psychotherapists. Its novel approach for alleviating emotional illnesses in “ordinary” people is a welcome addition to the armamentarium of any therapist.

The book is extraordinarily well written. It offers valuable case vignettes, tables, and self-inquiry questions to assist in understanding the characteristics associated with each emotionally conditioned role. The authors also suggest reading materials and movies for viewing.

Dr. Martin and Dr. Adams have made the book very digestible, intriguing and practical. And it is a marvelous tribute to the value of a 30-year mentorship.

Judith R. Milner, MD, MEd, SpecEd, is a general, child, and adolescent psychiatrist in private practice in Everett, Wash. She has traveled with various groups over the years in an effort to alleviate some of the suffering caused by war and natural disaster. She has worked with Step Up Rwanda Women and Pygmy Survival Alliance, as well as on the Committee for Women at the American Psychiatric Association and the Consumer Issues Committee, the Committee on Diversity and Culture, and the Membership Committee for the American Academy of Child and Adolescent Psychiatry.

In this edition of “How I Will Treat My Next Patient,” I highlight two presentations from the recent San Antonio Breast Cancer Symposium (SABCS) that will likely change practice for some breast cancer patients – even before the ball drops in Times Square on New Year’s Eve.

Residual cancer burden

Researchers reported a multi-institutional analysis of individual patient-level data on 5,160 patients who had received neoadjuvant chemotherapy (NAC) for localized breast cancer at 11 different centers. They found that residual cancer burden (RCB) was significantly associated with event-free (EFS) and distant recurrence-free survival. The value of calculating RCB was seen across all breast cancer tumor phenotypes (SABCS 2019, Abstract GS5-01).

RCB is calculated by analyzing the residual disease after NAC for the primary tumor bed, the number of positive axillary nodes, and the size of largest node metastasis. It is graded from RCB-0 (pCR) to RCB-III (extensive residual disease).

Both EFS and distant recurrence-free survival were strongly associated with RCB for the overall population and for each breast cancer subtype. For hormone receptor–positive/HER2-negative disease there was a slight hiccup in that RCB-0 was associated with a 10-year EFS of 81%, but EFS was 86% for RCB-I. Fortunately, the prognostic reliability of RCB was clear for RCB-II (69%) and RCB-III (52%). The presenter, W. Fraser Symmans, MD, commented that RCB is most prognostic when higher levels of residual disease are present. RCB remained prognostic in multivariate models adjusting for age, grade, and clinical T and N stage at diagnosis.

How these results influence practice

After neoadjuvant chemotherapy in patients with localized breast cancer, we struggle when patients ask: “So, doctor, how am I likely to do?” We piece together a complicated – and inconsistent – answer, based on breast cancer subtype, original stage of disease, whether pCR was attained, and other factors.

For patients with triple-negative breast cancer, we have the option of adding capecitabine and/or participation in ongoing clinical trials, for patients with residual disease after NAC. Among the HER2-positive patients, we have data from the KATHERINE, ExtaNET, and APHINITY trials that provide options for additional treatment in those patients, as well. For patients with potentially hormonally responsive, HER2-negative disease, we can emphasize the importance of postoperative adjuvant endocrine therapy, the mandate for continued adherence to oral therapy, and the lower likelihood of (and prognostic value of) pCR in that breast cancer subtype.

Where we previously had a complicated, nuanced discussion, we now have data from a multi-institutional, meticulous analysis to guide further treatment, candidacy for clinical trials, and our expectations of what would be meaningful results from additional therapy. This meets my definition of “practice-changing” research.
 

APHINITY follow-up

APHINITY was a randomized, multicenter, double-blind, placebo-controlled trial that previously demonstrated that pertuzumab added to standard chemotherapy plus 1 year of trastuzumab in operable HER2-positive breast cancer was associated with modest, but statistically significant, improvement in invasive disease–free survival (IDFS), compared with placebo and chemotherapy plus trastuzumab (hazard ratio, 0.81; P = .04). When the initial results – with a median follow-up of 45.4 months – were published, the authors promised an update at 6 years. Martine Piccart, MD, PhD, provided that update at the 2019 SABCS (Abstract GS1-04).

In the updated analysis, overall survival was 94.8% among patients on the pertuzumab arm and 93.9% among patients taking placebo (HR, 0.85). IDFS rates were 90.6% versus 87.8% in the intent-to-treat population. The investigator commented that this difference was caused mainly by a reduction in distant and loco-regional recurrences.

Central nervous system metastases, contralateral invasive breast cancers, and death without a prior event were no different between the two treatment groups.

Improvement in IDFS (the primary endpoint) from pertuzumab was most impressive in the node-positive cohort, 87.9% versus 83.4% for placebo (HR, 0.72). There was no benefit in the node-negative population (95.0% vs. 94.9%; HR, 1.02).

In contrast to the 3-year analysis, the benefits in IDFS were seen regardless of hormone receptor status. Additionally, no new safety concerns emerged. The rate of severe cardiac events was below 1% in both groups.

How these results influence practice

“Patience is a virtue” appeared for the first time in the English language around 1360, in William Langland’s poem “Piers Plowman.” They are true words, indeed.

When the initial results of APHINITY were published in 2017, they led to the approval of pertuzumab as an addition to chemotherapy plus trastuzumab for high-risk, early, HER2-positive breast cancer patients. Still, the difference in IDFS curves was visually unimpressive (absolute difference 1.7% in the intent-to-treat and 3.2% in the node-positive patients) and pertuzumab was associated with more grade 3 toxicities (primarily diarrhea) and treatment discontinuations.

An optimist would have observed that the IDFS curves in 2017 did not start to diverge until 24 months and would have noted that the divergence increased with time. That virtuously patient person would have expected that the second interim analysis would show larger absolute benefits, and that the hormone receptor–positive patients (64% of the total) would not yet have relapsed by the first interim analysis and that pertuzumab’s benefit in that group would emerge late.

That appears to be what is happening. It provides hope that an overall survival benefit will become more evident with time. If the target P value for an overall survival difference (.0012) is met by the time of the third interim analysis, our patience (and the FDA’s decision to grant approval for pertuzumab for this indication) will have been amply rewarded. For selected HER2-posiitve patients with high RCB, especially those who tolerated neoadjuvant trastuzumab plus pertuzumab regimens, postoperative adjuvant pertuzumab may be an appealing option.

Dr. Lyss has been a community-based medical oncologist and clinical researcher for more than 35 years, practicing in St. Louis. His clinical and research interests are in the prevention, diagnosis, and treatment of breast and lung cancers and in expanding access to clinical trials to medically underserved populations.

In this edition of “How I Will Treat My Next Patient,” I highlight two presentations from the recent San Antonio Breast Cancer Symposium (SABCS) that will likely change practice for some breast cancer patients – even before the ball drops in Times Square on New Year’s Eve.

Residual cancer burden

Researchers reported a multi-institutional analysis of individual patient-level data on 5,160 patients who had received neoadjuvant chemotherapy (NAC) for localized breast cancer at 11 different centers. They found that residual cancer burden (RCB) was significantly associated with event-free (EFS) and distant recurrence-free survival. The value of calculating RCB was seen across all breast cancer tumor phenotypes (SABCS 2019, Abstract GS5-01).

RCB is calculated by analyzing the residual disease after NAC for the primary tumor bed, the number of positive axillary nodes, and the size of largest node metastasis. It is graded from RCB-0 (pCR) to RCB-III (extensive residual disease).

Both EFS and distant recurrence-free survival were strongly associated with RCB for the overall population and for each breast cancer subtype. For hormone receptor–positive/HER2-negative disease there was a slight hiccup in that RCB-0 was associated with a 10-year EFS of 81%, but EFS was 86% for RCB-I. Fortunately, the prognostic reliability of RCB was clear for RCB-II (69%) and RCB-III (52%). The presenter, W. Fraser Symmans, MD, commented that RCB is most prognostic when higher levels of residual disease are present. RCB remained prognostic in multivariate models adjusting for age, grade, and clinical T and N stage at diagnosis.

How these results influence practice

After neoadjuvant chemotherapy in patients with localized breast cancer, we struggle when patients ask: “So, doctor, how am I likely to do?” We piece together a complicated – and inconsistent – answer, based on breast cancer subtype, original stage of disease, whether pCR was attained, and other factors.

For patients with triple-negative breast cancer, we have the option of adding capecitabine and/or participation in ongoing clinical trials, for patients with residual disease after NAC. Among the HER2-positive patients, we have data from the KATHERINE, ExtaNET, and APHINITY trials that provide options for additional treatment in those patients, as well. For patients with potentially hormonally responsive, HER2-negative disease, we can emphasize the importance of postoperative adjuvant endocrine therapy, the mandate for continued adherence to oral therapy, and the lower likelihood of (and prognostic value of) pCR in that breast cancer subtype.

Where we previously had a complicated, nuanced discussion, we now have data from a multi-institutional, meticulous analysis to guide further treatment, candidacy for clinical trials, and our expectations of what would be meaningful results from additional therapy. This meets my definition of “practice-changing” research.
 

APHINITY follow-up

APHINITY was a randomized, multicenter, double-blind, placebo-controlled trial that previously demonstrated that pertuzumab added to standard chemotherapy plus 1 year of trastuzumab in operable HER2-positive breast cancer was associated with modest, but statistically significant, improvement in invasive disease–free survival (IDFS), compared with placebo and chemotherapy plus trastuzumab (hazard ratio, 0.81; P = .04). When the initial results – with a median follow-up of 45.4 months – were published, the authors promised an update at 6 years. Martine Piccart, MD, PhD, provided that update at the 2019 SABCS (Abstract GS1-04).

In the updated analysis, overall survival was 94.8% among patients on the pertuzumab arm and 93.9% among patients taking placebo (HR, 0.85). IDFS rates were 90.6% versus 87.8% in the intent-to-treat population. The investigator commented that this difference was caused mainly by a reduction in distant and loco-regional recurrences.

Central nervous system metastases, contralateral invasive breast cancers, and death without a prior event were no different between the two treatment groups.

Improvement in IDFS (the primary endpoint) from pertuzumab was most impressive in the node-positive cohort, 87.9% versus 83.4% for placebo (HR, 0.72). There was no benefit in the node-negative population (95.0% vs. 94.9%; HR, 1.02).

In contrast to the 3-year analysis, the benefits in IDFS were seen regardless of hormone receptor status. Additionally, no new safety concerns emerged. The rate of severe cardiac events was below 1% in both groups.

How these results influence practice

“Patience is a virtue” appeared for the first time in the English language around 1360, in William Langland’s poem “Piers Plowman.” They are true words, indeed.

When the initial results of APHINITY were published in 2017, they led to the approval of pertuzumab as an addition to chemotherapy plus trastuzumab for high-risk, early, HER2-positive breast cancer patients. Still, the difference in IDFS curves was visually unimpressive (absolute difference 1.7% in the intent-to-treat and 3.2% in the node-positive patients) and pertuzumab was associated with more grade 3 toxicities (primarily diarrhea) and treatment discontinuations.

An optimist would have observed that the IDFS curves in 2017 did not start to diverge until 24 months and would have noted that the divergence increased with time. That virtuously patient person would have expected that the second interim analysis would show larger absolute benefits, and that the hormone receptor–positive patients (64% of the total) would not yet have relapsed by the first interim analysis and that pertuzumab’s benefit in that group would emerge late.

That appears to be what is happening. It provides hope that an overall survival benefit will become more evident with time. If the target P value for an overall survival difference (.0012) is met by the time of the third interim analysis, our patience (and the FDA’s decision to grant approval for pertuzumab for this indication) will have been amply rewarded. For selected HER2-posiitve patients with high RCB, especially those who tolerated neoadjuvant trastuzumab plus pertuzumab regimens, postoperative adjuvant pertuzumab may be an appealing option.

Dr. Lyss has been a community-based medical oncologist and clinical researcher for more than 35 years, practicing in St. Louis. His clinical and research interests are in the prevention, diagnosis, and treatment of breast and lung cancers and in expanding access to clinical trials to medically underserved populations.

In this edition of “How I Will Treat My Next Patient,” I highlight two presentations from the recent San Antonio Breast Cancer Symposium (SABCS) that will likely change practice for some breast cancer patients – even before the ball drops in Times Square on New Year’s Eve.

Residual cancer burden

Researchers reported a multi-institutional analysis of individual patient-level data on 5,160 patients who had received neoadjuvant chemotherapy (NAC) for localized breast cancer at 11 different centers. They found that residual cancer burden (RCB) was significantly associated with event-free (EFS) and distant recurrence-free survival. The value of calculating RCB was seen across all breast cancer tumor phenotypes (SABCS 2019, Abstract GS5-01).

RCB is calculated by analyzing the residual disease after NAC for the primary tumor bed, the number of positive axillary nodes, and the size of largest node metastasis. It is graded from RCB-0 (pCR) to RCB-III (extensive residual disease).

Both EFS and distant recurrence-free survival were strongly associated with RCB for the overall population and for each breast cancer subtype. For hormone receptor–positive/HER2-negative disease there was a slight hiccup in that RCB-0 was associated with a 10-year EFS of 81%, but EFS was 86% for RCB-I. Fortunately, the prognostic reliability of RCB was clear for RCB-II (69%) and RCB-III (52%). The presenter, W. Fraser Symmans, MD, commented that RCB is most prognostic when higher levels of residual disease are present. RCB remained prognostic in multivariate models adjusting for age, grade, and clinical T and N stage at diagnosis.

How these results influence practice

After neoadjuvant chemotherapy in patients with localized breast cancer, we struggle when patients ask: “So, doctor, how am I likely to do?” We piece together a complicated – and inconsistent – answer, based on breast cancer subtype, original stage of disease, whether pCR was attained, and other factors.

For patients with triple-negative breast cancer, we have the option of adding capecitabine and/or participation in ongoing clinical trials, for patients with residual disease after NAC. Among the HER2-positive patients, we have data from the KATHERINE, ExtaNET, and APHINITY trials that provide options for additional treatment in those patients, as well. For patients with potentially hormonally responsive, HER2-negative disease, we can emphasize the importance of postoperative adjuvant endocrine therapy, the mandate for continued adherence to oral therapy, and the lower likelihood of (and prognostic value of) pCR in that breast cancer subtype.

Where we previously had a complicated, nuanced discussion, we now have data from a multi-institutional, meticulous analysis to guide further treatment, candidacy for clinical trials, and our expectations of what would be meaningful results from additional therapy. This meets my definition of “practice-changing” research.
 

APHINITY follow-up

APHINITY was a randomized, multicenter, double-blind, placebo-controlled trial that previously demonstrated that pertuzumab added to standard chemotherapy plus 1 year of trastuzumab in operable HER2-positive breast cancer was associated with modest, but statistically significant, improvement in invasive disease–free survival (IDFS), compared with placebo and chemotherapy plus trastuzumab (hazard ratio, 0.81; P = .04). When the initial results – with a median follow-up of 45.4 months – were published, the authors promised an update at 6 years. Martine Piccart, MD, PhD, provided that update at the 2019 SABCS (Abstract GS1-04).

In the updated analysis, overall survival was 94.8% among patients on the pertuzumab arm and 93.9% among patients taking placebo (HR, 0.85). IDFS rates were 90.6% versus 87.8% in the intent-to-treat population. The investigator commented that this difference was caused mainly by a reduction in distant and loco-regional recurrences.

Central nervous system metastases, contralateral invasive breast cancers, and death without a prior event were no different between the two treatment groups.

Improvement in IDFS (the primary endpoint) from pertuzumab was most impressive in the node-positive cohort, 87.9% versus 83.4% for placebo (HR, 0.72). There was no benefit in the node-negative population (95.0% vs. 94.9%; HR, 1.02).

In contrast to the 3-year analysis, the benefits in IDFS were seen regardless of hormone receptor status. Additionally, no new safety concerns emerged. The rate of severe cardiac events was below 1% in both groups.

How these results influence practice

“Patience is a virtue” appeared for the first time in the English language around 1360, in William Langland’s poem “Piers Plowman.” They are true words, indeed.

When the initial results of APHINITY were published in 2017, they led to the approval of pertuzumab as an addition to chemotherapy plus trastuzumab for high-risk, early, HER2-positive breast cancer patients. Still, the difference in IDFS curves was visually unimpressive (absolute difference 1.7% in the intent-to-treat and 3.2% in the node-positive patients) and pertuzumab was associated with more grade 3 toxicities (primarily diarrhea) and treatment discontinuations.

An optimist would have observed that the IDFS curves in 2017 did not start to diverge until 24 months and would have noted that the divergence increased with time. That virtuously patient person would have expected that the second interim analysis would show larger absolute benefits, and that the hormone receptor–positive patients (64% of the total) would not yet have relapsed by the first interim analysis and that pertuzumab’s benefit in that group would emerge late.

That appears to be what is happening. It provides hope that an overall survival benefit will become more evident with time. If the target P value for an overall survival difference (.0012) is met by the time of the third interim analysis, our patience (and the FDA’s decision to grant approval for pertuzumab for this indication) will have been amply rewarded. For selected HER2-posiitve patients with high RCB, especially those who tolerated neoadjuvant trastuzumab plus pertuzumab regimens, postoperative adjuvant pertuzumab may be an appealing option.

Dr. Lyss has been a community-based medical oncologist and clinical researcher for more than 35 years, practicing in St. Louis. His clinical and research interests are in the prevention, diagnosis, and treatment of breast and lung cancers and in expanding access to clinical trials to medically underserved populations.

Editor's note: This article was originally published in the January/February 2003 issue of Clinician News. It placed first in the journal's Most Unusual Patient Contest.

Late one morning, a woman and her 13-year-old daughter came into our office. “Mrs. Smith” reported that “Lisa” had a retained tampon. Lisa looked scared as her mother did all of the talking.

One of the male doctors saw Lisa first. After about 10 minutes, he emerged from the examination room looking perplexed. He said he wasn’t sure what was going on. He asked me to go in and try to get Lisa to allow a more thorough pelvic examination.

My exam of Lisa proved only slightly easier. I was able to visualize something curved and firm that sounded like plastic when touched with the ring forceps. I could pull the object as far as the vaginal introitus, but it would always slide back. “This is no tampon,” I repeated several times. Each time I pulled down, Lisa became more agitated. After several tries, I gave Lisa a rest and left the room to consult with a doctor.

The doctor suggested a trip to same-day surgery for evaluation under anesthesia but decided to give it one more try before heading for the operating room.

Continue to: Together, we entered the exam room...

Together, we entered the exam room. “Well, we’ve had some true confessions,” Mrs. Smith said dryly. “Lisa has a Christmas bell in her vagina—obviously the work of a curious 13-year-old!”

The doctor and I were taken by surprise, but we proceeded with the challenge of the day. Thinking we were dealing with a standard Christmas bell, we attempted to break the suction of the bell on Lisa’s cervix. This proved to be more difficult than we anticipated. After getting a closer look at the bell, we realized that it was a “jingle” bell rather than a standard bell shape.

The crosshair opening of the jingle bell had slipped over Lisa’s cervix. The cervix had become edematous and necrotic. The doctor gave one final pull, and the bell—with cervical tissue inside—flew out.

We needed pliers to open the bell so we could send a tissue sample to the pathology department for evaluation. Lisa received high-dose antibiotics and after several follow-up visits, she was declared healed.

This patient encounter, which also falls under the categories of unbelievable, unconventional, and amazing, was definitely unforgettable to me.

Editor's note: This article was originally published in the January/February 2003 issue of Clinician News. It placed first in the journal's Most Unusual Patient Contest.

Late one morning, a woman and her 13-year-old daughter came into our office. “Mrs. Smith” reported that “Lisa” had a retained tampon. Lisa looked scared as her mother did all of the talking.

One of the male doctors saw Lisa first. After about 10 minutes, he emerged from the examination room looking perplexed. He said he wasn’t sure what was going on. He asked me to go in and try to get Lisa to allow a more thorough pelvic examination.

My exam of Lisa proved only slightly easier. I was able to visualize something curved and firm that sounded like plastic when touched with the ring forceps. I could pull the object as far as the vaginal introitus, but it would always slide back. “This is no tampon,” I repeated several times. Each time I pulled down, Lisa became more agitated. After several tries, I gave Lisa a rest and left the room to consult with a doctor.

The doctor suggested a trip to same-day surgery for evaluation under anesthesia but decided to give it one more try before heading for the operating room.

Continue to: Together, we entered the exam room...

Together, we entered the exam room. “Well, we’ve had some true confessions,” Mrs. Smith said dryly. “Lisa has a Christmas bell in her vagina—obviously the work of a curious 13-year-old!”

The doctor and I were taken by surprise, but we proceeded with the challenge of the day. Thinking we were dealing with a standard Christmas bell, we attempted to break the suction of the bell on Lisa’s cervix. This proved to be more difficult than we anticipated. After getting a closer look at the bell, we realized that it was a “jingle” bell rather than a standard bell shape.

The crosshair opening of the jingle bell had slipped over Lisa’s cervix. The cervix had become edematous and necrotic. The doctor gave one final pull, and the bell—with cervical tissue inside—flew out.

We needed pliers to open the bell so we could send a tissue sample to the pathology department for evaluation. Lisa received high-dose antibiotics and after several follow-up visits, she was declared healed.

This patient encounter, which also falls under the categories of unbelievable, unconventional, and amazing, was definitely unforgettable to me.

Editor's note: This article was originally published in the January/February 2003 issue of Clinician News. It placed first in the journal's Most Unusual Patient Contest.

Late one morning, a woman and her 13-year-old daughter came into our office. “Mrs. Smith” reported that “Lisa” had a retained tampon. Lisa looked scared as her mother did all of the talking.

One of the male doctors saw Lisa first. After about 10 minutes, he emerged from the examination room looking perplexed. He said he wasn’t sure what was going on. He asked me to go in and try to get Lisa to allow a more thorough pelvic examination.

My exam of Lisa proved only slightly easier. I was able to visualize something curved and firm that sounded like plastic when touched with the ring forceps. I could pull the object as far as the vaginal introitus, but it would always slide back. “This is no tampon,” I repeated several times. Each time I pulled down, Lisa became more agitated. After several tries, I gave Lisa a rest and left the room to consult with a doctor.

The doctor suggested a trip to same-day surgery for evaluation under anesthesia but decided to give it one more try before heading for the operating room.

Continue to: Together, we entered the exam room...

Together, we entered the exam room. “Well, we’ve had some true confessions,” Mrs. Smith said dryly. “Lisa has a Christmas bell in her vagina—obviously the work of a curious 13-year-old!”

The doctor and I were taken by surprise, but we proceeded with the challenge of the day. Thinking we were dealing with a standard Christmas bell, we attempted to break the suction of the bell on Lisa’s cervix. This proved to be more difficult than we anticipated. After getting a closer look at the bell, we realized that it was a “jingle” bell rather than a standard bell shape.

The crosshair opening of the jingle bell had slipped over Lisa’s cervix. The cervix had become edematous and necrotic. The doctor gave one final pull, and the bell—with cervical tissue inside—flew out.

We needed pliers to open the bell so we could send a tissue sample to the pathology department for evaluation. Lisa received high-dose antibiotics and after several follow-up visits, she was declared healed.

This patient encounter, which also falls under the categories of unbelievable, unconventional, and amazing, was definitely unforgettable to me.

In this edition of “How I Will Treat My Next Patient,” I highlight two recent studies that reinforce prior diagnostic and treatment preferences among many oncologists and will certainly influence the discussions we all will have with our patients in the coming weeks and months.

Rituximab maintenance in follicular lymphoma

The largest trial addressing the role of maintenance CD20-targeted antibody therapy was the Primary Rituximab and Maintenance (PRIMA) phase 3, intergroup study in 1,018 advanced follicular lymphoma patients with an initial response to induction chemoimmunotherapy. The induction regimen could be either of three commonly used regimens plus rituximab. Importantly, none of the induction regimens included bendamustine.

Patients were randomized to 2 years of rituximab maintenance or observation. Prior interim analyses at 3 and 6 years showed improvements for the rituximab maintenance patients in progression-free survival and other secondary endpoints, but no improvement in overall survival. Emmanuel Bachy, MD, PhD, and colleagues published the final survival data after 9 years of follow-up, including a final safety analysis (J Clin Oncol. 2019 Nov 1;37[31]:2815-24).

Among the 607 patients consenting to extended follow-up, median progression-free survival was 10.5 years with rituximab maintenance, compared with 4.1 years for observation (hazard ratio, 0.61; P less than .001). There were more patients with progression-free survival at 3 years, complete response or unconfirmed complete response at 2 years, longer time to next antilymphoma treatment, and later time to next chemotherapy. But the 10-year overall survival was similar in the two groups, as were the quality of life ratings.

In all, 503 patients experienced disease progression. Overall survival after progression was shorter in the rituximab maintenance arm versus the observation arm. Among the approximately 4% of patients experiencing transformation from follicular lymphoma to a more aggressive histology, there was no difference observed in time to transformation. Results were independent of the induction regimen received, response to induction, Follicular Lymphoma International Prognostic Index score, and other clinical factors.

In the safety analysis, there were more grade 3-4 adverse events among the rituximab maintenance patients – primarily cytopenia and infections – more serious adverse events, and more adverse events overall. Fatal adverse events were low in both groups (1.6 vs. 0.6%).
 

How these results influence practice

Many years ago, a senior mentor of mine taught that “progression-free survival is an important endpoint since the quality of life for patients is generally superior before relapse than afterwards.”

With that mantra playing in my mind and with the reality that discussions about relapse and subsequent treatment are never easy, the results of PRIMA seem straightforward: Rituximab maintenance is beneficial, despite the absence of an overall survival benefit, in a disease with multiple options for subsequent therapy and a long natural history. In this 9-year, final analysis of PRIMA, rituximab maintenance seems to have achieved its goals of deepening responses with low (but not inconsequential) toxicity and delaying substantially those difficult conversations with patients about how to proceed after relapse.

The influence of the final analysis of PRIMA, however, may be more complicated that it would initially seem. Bendamustine-containing regimens were not employed, are commonly used now, and some studies with bendamustine have suggested higher nonrelapse mortality with rituximab maintenance.

Low-grade adverse events take on greater importance for patients on long-term therapy than they do for patients receiving abbreviated treatment, and with noncurative treatment, the higher adverse event profile with 2 years of rituximab maintenance needs to be taken seriously. Induction and maintenance regimens involving rituximab alone, lenalidomide, or obinutuzumab may be preferred for some patients. For all of those reasons, the discussion about rituximab with advanced follicular lymphoma patients remains a long one, demanding detailed descriptions of risks, benefits, limitations of the data, and multiple modern day alternatives to the treatments employed in PRIMA.
 

Supplemental MRI for dense breast tissue

In the DENSE trial, investigators assigned 40,373 women with extremely dense breast tissue and negative results on screening mammography to be offered either supplemental MRI or mammography screening every other year only. The women were 50-75 years old and were enrolled in the Dutch population-based digital mammography screening program. The primary outcome was the difference in the number of cancers that developed in the 2-year interval between mammograms (N Engl J Med 2019;381:2091-102).

The interval cancer rate was 2.5 per 1,000 screenings among 4,783 women in the “MRI-invitation” group (41% of whom did not actually agree to have an MRI), and 5 per 1,000 in the 32,312 women in the “mammography-only” group, a difference of 2.5 per 1,000 screenings (P less than .001).

Of the 20 interval cancers diagnosed in the MRI-invitation group, 4 were diagnosed in the 59% of women who had undergone MRI (0.8 per 1,000 screenings). The remaining 16 were diagnosed in those who had declined an MRI (4.9 per 1,000 screenings) – virtually identical to the rate of interval cancers in the group that was not invited to have an MRI. This speaks against nonrandom allocation of patients between the mammography-only and the supplemental MRI groups.

Although supplemental MRI was associated with a cancer-detection rate of 16.5 per 1,000 screenings, there was a false positive rate of 8.0% (79.8 per 1,000 screenings). Of the women who underwent a breast biopsy after MRI, 73.7% did not have cancer. Among the women who had MRI-detected cancers, in general, the malignancies diagnosed were smaller, more likely node negative, better differentiated, and more often hormone receptor–positive, compared with those in the mammography-only group.

At the next screening mammogram, the cancer detection rate was lower in the MRI-screened group (2 per 1,000 screenings) than in the MRI–“offered but declined” (7.1 per 1,000 screenings) or mammogram-only groups (6 per 1,000 screenings).
 

How these results influence practice

American physicians are obligated to inform women with dense breast tissue about the limitations (for them) of conventional mammography, an unquantified, but elevated, risk of breast cancer in women with dense breast tissue, and the fact that there are no universally accepted recommended subsequent steps those women should take.

One side benefit of the requirement to disclose information about breast density, however, is that disclosure can prompt discussions about breast cancer risk reduction – an important discussion with multiple possible health-maintaining interventions.

The DENSE trial is very important news, with potential for even more value in future years. It is finite (2 years of study, with only one MRI scan mandated), narrow (Vopara or BI-RADs breast density grade 4 only), and oligo-institutional (eight participating centers in the Netherlands). Still, it provides randomized, rigorously gathered and analyzed data where there were previously none. Importantly, it answers the question, “So what can I do now, doctor?”

I have some concerns about whether we, as a medical community, have the discipline to restrict application of supplemental MRI screening beyond the population that was studied in the Netherlands. Will we be able to restrain ourselves from ordering MRI scans in women with heterogeneously dense – but not extremely dense – breasts? Will we truly manage patients whose MRI scans had BI-RADs readings of less than 4 in the rigorous, but conservative, fashion employed in the trial? Would we miss fewer significant cancers and subject fewer patients to potential expense and harm with annual mammography, instead of the biennial screening performed in the Netherlands? Does tomo-synthesis improve the interpretation of screening mammograms so much that the interval cancer rate is a lot closer to the rate obtained with supplemental MRI scans? Is the expense of MRI scanning, with the resultant subsequent tests and procedures, justified by the reduction in detecting relatively favorable breast cancers that may not materially impact overall survival?

The DENSE study promises to be a “gift that keeps on giving” as the investigators continue to assess a number of factors including: the value of ongoing supplemental MRI scans (compared with the one-time-only screening reported here); whether there will be a reduction in the advanced cancers and subsequent mortality benefit; the extent of over diagnosis, costs, and impact on quality-of-life; and the applicability of artificial intelligence techniques to reduce false positive MRI results.

While the study may not be practice changing in the United States at the present time, it may be just that as subsequent analyses emerge.
 

Dr. Lyss has been a community-based medical oncologist and clinical researcher for more than 35 years, practicing in St. Louis. His clinical and research interests are in the prevention, diagnosis, and treatment of breast and lung cancers and in expanding access to clinical trials to medically underserved populations.

In this edition of “How I Will Treat My Next Patient,” I highlight two recent studies that reinforce prior diagnostic and treatment preferences among many oncologists and will certainly influence the discussions we all will have with our patients in the coming weeks and months.

Rituximab maintenance in follicular lymphoma

The largest trial addressing the role of maintenance CD20-targeted antibody therapy was the Primary Rituximab and Maintenance (PRIMA) phase 3, intergroup study in 1,018 advanced follicular lymphoma patients with an initial response to induction chemoimmunotherapy. The induction regimen could be either of three commonly used regimens plus rituximab. Importantly, none of the induction regimens included bendamustine.

Patients were randomized to 2 years of rituximab maintenance or observation. Prior interim analyses at 3 and 6 years showed improvements for the rituximab maintenance patients in progression-free survival and other secondary endpoints, but no improvement in overall survival. Emmanuel Bachy, MD, PhD, and colleagues published the final survival data after 9 years of follow-up, including a final safety analysis (J Clin Oncol. 2019 Nov 1;37[31]:2815-24).

Among the 607 patients consenting to extended follow-up, median progression-free survival was 10.5 years with rituximab maintenance, compared with 4.1 years for observation (hazard ratio, 0.61; P less than .001). There were more patients with progression-free survival at 3 years, complete response or unconfirmed complete response at 2 years, longer time to next antilymphoma treatment, and later time to next chemotherapy. But the 10-year overall survival was similar in the two groups, as were the quality of life ratings.

In all, 503 patients experienced disease progression. Overall survival after progression was shorter in the rituximab maintenance arm versus the observation arm. Among the approximately 4% of patients experiencing transformation from follicular lymphoma to a more aggressive histology, there was no difference observed in time to transformation. Results were independent of the induction regimen received, response to induction, Follicular Lymphoma International Prognostic Index score, and other clinical factors.

In the safety analysis, there were more grade 3-4 adverse events among the rituximab maintenance patients – primarily cytopenia and infections – more serious adverse events, and more adverse events overall. Fatal adverse events were low in both groups (1.6 vs. 0.6%).
 

How these results influence practice

Many years ago, a senior mentor of mine taught that “progression-free survival is an important endpoint since the quality of life for patients is generally superior before relapse than afterwards.”

With that mantra playing in my mind and with the reality that discussions about relapse and subsequent treatment are never easy, the results of PRIMA seem straightforward: Rituximab maintenance is beneficial, despite the absence of an overall survival benefit, in a disease with multiple options for subsequent therapy and a long natural history. In this 9-year, final analysis of PRIMA, rituximab maintenance seems to have achieved its goals of deepening responses with low (but not inconsequential) toxicity and delaying substantially those difficult conversations with patients about how to proceed after relapse.

The influence of the final analysis of PRIMA, however, may be more complicated that it would initially seem. Bendamustine-containing regimens were not employed, are commonly used now, and some studies with bendamustine have suggested higher nonrelapse mortality with rituximab maintenance.

Low-grade adverse events take on greater importance for patients on long-term therapy than they do for patients receiving abbreviated treatment, and with noncurative treatment, the higher adverse event profile with 2 years of rituximab maintenance needs to be taken seriously. Induction and maintenance regimens involving rituximab alone, lenalidomide, or obinutuzumab may be preferred for some patients. For all of those reasons, the discussion about rituximab with advanced follicular lymphoma patients remains a long one, demanding detailed descriptions of risks, benefits, limitations of the data, and multiple modern day alternatives to the treatments employed in PRIMA.
 

Supplemental MRI for dense breast tissue

In the DENSE trial, investigators assigned 40,373 women with extremely dense breast tissue and negative results on screening mammography to be offered either supplemental MRI or mammography screening every other year only. The women were 50-75 years old and were enrolled in the Dutch population-based digital mammography screening program. The primary outcome was the difference in the number of cancers that developed in the 2-year interval between mammograms (N Engl J Med 2019;381:2091-102).

The interval cancer rate was 2.5 per 1,000 screenings among 4,783 women in the “MRI-invitation” group (41% of whom did not actually agree to have an MRI), and 5 per 1,000 in the 32,312 women in the “mammography-only” group, a difference of 2.5 per 1,000 screenings (P less than .001).

Of the 20 interval cancers diagnosed in the MRI-invitation group, 4 were diagnosed in the 59% of women who had undergone MRI (0.8 per 1,000 screenings). The remaining 16 were diagnosed in those who had declined an MRI (4.9 per 1,000 screenings) – virtually identical to the rate of interval cancers in the group that was not invited to have an MRI. This speaks against nonrandom allocation of patients between the mammography-only and the supplemental MRI groups.

Although supplemental MRI was associated with a cancer-detection rate of 16.5 per 1,000 screenings, there was a false positive rate of 8.0% (79.8 per 1,000 screenings). Of the women who underwent a breast biopsy after MRI, 73.7% did not have cancer. Among the women who had MRI-detected cancers, in general, the malignancies diagnosed were smaller, more likely node negative, better differentiated, and more often hormone receptor–positive, compared with those in the mammography-only group.

At the next screening mammogram, the cancer detection rate was lower in the MRI-screened group (2 per 1,000 screenings) than in the MRI–“offered but declined” (7.1 per 1,000 screenings) or mammogram-only groups (6 per 1,000 screenings).
 

How these results influence practice

American physicians are obligated to inform women with dense breast tissue about the limitations (for them) of conventional mammography, an unquantified, but elevated, risk of breast cancer in women with dense breast tissue, and the fact that there are no universally accepted recommended subsequent steps those women should take.

One side benefit of the requirement to disclose information about breast density, however, is that disclosure can prompt discussions about breast cancer risk reduction – an important discussion with multiple possible health-maintaining interventions.

The DENSE trial is very important news, with potential for even more value in future years. It is finite (2 years of study, with only one MRI scan mandated), narrow (Vopara or BI-RADs breast density grade 4 only), and oligo-institutional (eight participating centers in the Netherlands). Still, it provides randomized, rigorously gathered and analyzed data where there were previously none. Importantly, it answers the question, “So what can I do now, doctor?”

I have some concerns about whether we, as a medical community, have the discipline to restrict application of supplemental MRI screening beyond the population that was studied in the Netherlands. Will we be able to restrain ourselves from ordering MRI scans in women with heterogeneously dense – but not extremely dense – breasts? Will we truly manage patients whose MRI scans had BI-RADs readings of less than 4 in the rigorous, but conservative, fashion employed in the trial? Would we miss fewer significant cancers and subject fewer patients to potential expense and harm with annual mammography, instead of the biennial screening performed in the Netherlands? Does tomo-synthesis improve the interpretation of screening mammograms so much that the interval cancer rate is a lot closer to the rate obtained with supplemental MRI scans? Is the expense of MRI scanning, with the resultant subsequent tests and procedures, justified by the reduction in detecting relatively favorable breast cancers that may not materially impact overall survival?

The DENSE study promises to be a “gift that keeps on giving” as the investigators continue to assess a number of factors including: the value of ongoing supplemental MRI scans (compared with the one-time-only screening reported here); whether there will be a reduction in the advanced cancers and subsequent mortality benefit; the extent of over diagnosis, costs, and impact on quality-of-life; and the applicability of artificial intelligence techniques to reduce false positive MRI results.

While the study may not be practice changing in the United States at the present time, it may be just that as subsequent analyses emerge.
 

Dr. Lyss has been a community-based medical oncologist and clinical researcher for more than 35 years, practicing in St. Louis. His clinical and research interests are in the prevention, diagnosis, and treatment of breast and lung cancers and in expanding access to clinical trials to medically underserved populations.

In this edition of “How I Will Treat My Next Patient,” I highlight two recent studies that reinforce prior diagnostic and treatment preferences among many oncologists and will certainly influence the discussions we all will have with our patients in the coming weeks and months.

Rituximab maintenance in follicular lymphoma

The largest trial addressing the role of maintenance CD20-targeted antibody therapy was the Primary Rituximab and Maintenance (PRIMA) phase 3, intergroup study in 1,018 advanced follicular lymphoma patients with an initial response to induction chemoimmunotherapy. The induction regimen could be either of three commonly used regimens plus rituximab. Importantly, none of the induction regimens included bendamustine.

Patients were randomized to 2 years of rituximab maintenance or observation. Prior interim analyses at 3 and 6 years showed improvements for the rituximab maintenance patients in progression-free survival and other secondary endpoints, but no improvement in overall survival. Emmanuel Bachy, MD, PhD, and colleagues published the final survival data after 9 years of follow-up, including a final safety analysis (J Clin Oncol. 2019 Nov 1;37[31]:2815-24).

Among the 607 patients consenting to extended follow-up, median progression-free survival was 10.5 years with rituximab maintenance, compared with 4.1 years for observation (hazard ratio, 0.61; P less than .001). There were more patients with progression-free survival at 3 years, complete response or unconfirmed complete response at 2 years, longer time to next antilymphoma treatment, and later time to next chemotherapy. But the 10-year overall survival was similar in the two groups, as were the quality of life ratings.

In all, 503 patients experienced disease progression. Overall survival after progression was shorter in the rituximab maintenance arm versus the observation arm. Among the approximately 4% of patients experiencing transformation from follicular lymphoma to a more aggressive histology, there was no difference observed in time to transformation. Results were independent of the induction regimen received, response to induction, Follicular Lymphoma International Prognostic Index score, and other clinical factors.

In the safety analysis, there were more grade 3-4 adverse events among the rituximab maintenance patients – primarily cytopenia and infections – more serious adverse events, and more adverse events overall. Fatal adverse events were low in both groups (1.6 vs. 0.6%).
 

How these results influence practice

Many years ago, a senior mentor of mine taught that “progression-free survival is an important endpoint since the quality of life for patients is generally superior before relapse than afterwards.”

With that mantra playing in my mind and with the reality that discussions about relapse and subsequent treatment are never easy, the results of PRIMA seem straightforward: Rituximab maintenance is beneficial, despite the absence of an overall survival benefit, in a disease with multiple options for subsequent therapy and a long natural history. In this 9-year, final analysis of PRIMA, rituximab maintenance seems to have achieved its goals of deepening responses with low (but not inconsequential) toxicity and delaying substantially those difficult conversations with patients about how to proceed after relapse.

The influence of the final analysis of PRIMA, however, may be more complicated that it would initially seem. Bendamustine-containing regimens were not employed, are commonly used now, and some studies with bendamustine have suggested higher nonrelapse mortality with rituximab maintenance.

Low-grade adverse events take on greater importance for patients on long-term therapy than they do for patients receiving abbreviated treatment, and with noncurative treatment, the higher adverse event profile with 2 years of rituximab maintenance needs to be taken seriously. Induction and maintenance regimens involving rituximab alone, lenalidomide, or obinutuzumab may be preferred for some patients. For all of those reasons, the discussion about rituximab with advanced follicular lymphoma patients remains a long one, demanding detailed descriptions of risks, benefits, limitations of the data, and multiple modern day alternatives to the treatments employed in PRIMA.
 

Supplemental MRI for dense breast tissue

In the DENSE trial, investigators assigned 40,373 women with extremely dense breast tissue and negative results on screening mammography to be offered either supplemental MRI or mammography screening every other year only. The women were 50-75 years old and were enrolled in the Dutch population-based digital mammography screening program. The primary outcome was the difference in the number of cancers that developed in the 2-year interval between mammograms (N Engl J Med 2019;381:2091-102).

The interval cancer rate was 2.5 per 1,000 screenings among 4,783 women in the “MRI-invitation” group (41% of whom did not actually agree to have an MRI), and 5 per 1,000 in the 32,312 women in the “mammography-only” group, a difference of 2.5 per 1,000 screenings (P less than .001).

Of the 20 interval cancers diagnosed in the MRI-invitation group, 4 were diagnosed in the 59% of women who had undergone MRI (0.8 per 1,000 screenings). The remaining 16 were diagnosed in those who had declined an MRI (4.9 per 1,000 screenings) – virtually identical to the rate of interval cancers in the group that was not invited to have an MRI. This speaks against nonrandom allocation of patients between the mammography-only and the supplemental MRI groups.

Although supplemental MRI was associated with a cancer-detection rate of 16.5 per 1,000 screenings, there was a false positive rate of 8.0% (79.8 per 1,000 screenings). Of the women who underwent a breast biopsy after MRI, 73.7% did not have cancer. Among the women who had MRI-detected cancers, in general, the malignancies diagnosed were smaller, more likely node negative, better differentiated, and more often hormone receptor–positive, compared with those in the mammography-only group.

At the next screening mammogram, the cancer detection rate was lower in the MRI-screened group (2 per 1,000 screenings) than in the MRI–“offered but declined” (7.1 per 1,000 screenings) or mammogram-only groups (6 per 1,000 screenings).
 

How these results influence practice

American physicians are obligated to inform women with dense breast tissue about the limitations (for them) of conventional mammography, an unquantified, but elevated, risk of breast cancer in women with dense breast tissue, and the fact that there are no universally accepted recommended subsequent steps those women should take.

One side benefit of the requirement to disclose information about breast density, however, is that disclosure can prompt discussions about breast cancer risk reduction – an important discussion with multiple possible health-maintaining interventions.

The DENSE trial is very important news, with potential for even more value in future years. It is finite (2 years of study, with only one MRI scan mandated), narrow (Vopara or BI-RADs breast density grade 4 only), and oligo-institutional (eight participating centers in the Netherlands). Still, it provides randomized, rigorously gathered and analyzed data where there were previously none. Importantly, it answers the question, “So what can I do now, doctor?”

I have some concerns about whether we, as a medical community, have the discipline to restrict application of supplemental MRI screening beyond the population that was studied in the Netherlands. Will we be able to restrain ourselves from ordering MRI scans in women with heterogeneously dense – but not extremely dense – breasts? Will we truly manage patients whose MRI scans had BI-RADs readings of less than 4 in the rigorous, but conservative, fashion employed in the trial? Would we miss fewer significant cancers and subject fewer patients to potential expense and harm with annual mammography, instead of the biennial screening performed in the Netherlands? Does tomo-synthesis improve the interpretation of screening mammograms so much that the interval cancer rate is a lot closer to the rate obtained with supplemental MRI scans? Is the expense of MRI scanning, with the resultant subsequent tests and procedures, justified by the reduction in detecting relatively favorable breast cancers that may not materially impact overall survival?

The DENSE study promises to be a “gift that keeps on giving” as the investigators continue to assess a number of factors including: the value of ongoing supplemental MRI scans (compared with the one-time-only screening reported here); whether there will be a reduction in the advanced cancers and subsequent mortality benefit; the extent of over diagnosis, costs, and impact on quality-of-life; and the applicability of artificial intelligence techniques to reduce false positive MRI results.

While the study may not be practice changing in the United States at the present time, it may be just that as subsequent analyses emerge.
 

Dr. Lyss has been a community-based medical oncologist and clinical researcher for more than 35 years, practicing in St. Louis. His clinical and research interests are in the prevention, diagnosis, and treatment of breast and lung cancers and in expanding access to clinical trials to medically underserved populations.

I practice in Seattle, where many of my patients are interested in natural treatment options. I am always puzzled that so many people assume that natural treatment options would be safer than prescription medications. Tsunamis, wildfires, flooding, and earthquakes are all natural and are deadly. There are certainly many natural poisons. There are a number of natural treatments that are very helpful, and recommending them are an important part of my practice. I want to share a few with you.

A useful vein pursuit?

Case: A 60-year-old woman presents to clinic with increasing pain in her left leg. She had a deep vein thrombosis in her left leg 2 years ago, which involved a large portion of her superficial femoral vein. She has noticed edema over the past few weeks, and pain has been more severe over the past 3 months. On exam, varicosities on left lower extremity with grade 2+ edema. Duplex of the lower extremity does not show deep vein thrombosis, but does show a great deal of venous valvular incompetence. She has tried compression stockings for the past 2 weeks. What is the best treatment option?

A) Turmeric

B) Amitriptyline

C) Vitamin B12

D) Horse chestnut

The treatment option with positive data for this problem is horse chestnut. What is horse chestnut? Horse chestnut is a kind of tree, and the seed extract contains aescin which is believed to be the active ingredient. Diehm et al. studied horse chestnut seed extract (HCSE), compared with compression stockings and placebo for edema from chronic venous insufficiency in a study of 240 patients.¹ Lower-leg volume decreased by 43 mL with HCSE, 46 mL with compression stockings, and increased by 9 mL with placebo (P less than .005 for HCSE and P less than .002 for compression). In a Cochrane review, HCSE was considered efficacious and safe for the short-term therapy for chronic venous insufficiency.² Studies have shown both an improvement in pain as well as swelling in patients with chronic venous insufficiency.

The question of UTIs

Probably the most popular natural treatment for prevention and treatment of urinary tract infections (UTIs) in women is cranberry juice (or cranberry extract). Unfortunately, there is little evidence that this treatment is helpful. In a Cochrane analysis, the conclusion was, based on current evidence, cranberry juice cannot currently be recommended for the prevention of UTIs.³ A natural product that appears to be more promising is the sugar D-mannose. Kranjčec et al. studied 308 women with acute UTI who had a history of recurrent UTI.⁴ All the women were treated for their symptomatic infection with ciprofloxacin (500 mg twice daily for 1 week). The women were allocated equally to three groups for 6 months: D-mannose 2 g daily, nitrofurantoin 50 mg daily, or no prophylaxis. About 60% of the women who received no prophylaxis had a UTI during the study period, compared with 20% in the nitrofurantoin group and 15% in the D-mannose group. The relative risk for D-mannose, compared with no prophylaxis, was 0.24 and for nitrofurantoin was 0.34 (P less than .0001), compared with no prophylaxis.

Made for migraines?

Migraine prophylaxis is challenging because all medications that are commonly used have side effects that often limit patient adherence. Tricyclic antidepressants (dry mouth, dizziness and weight gain), beta-blockers (fatigue, decreased exercise tolerance), valproate (weight gain and fatigue), and topiramate (parasthesias and mental slowing) all have troubling side effects. Riboflavin is a vitamin with evidence of effectiveness for migraine prophylaxis. It is extremely well tolerated. In a recent study in children with migraines, Talebian et al. studied 90 children with migraines who were randomized to three groups (200 mg of riboflavin a day, 100 mg of riboflavin a day, or placebo) after observation during a 1-month baseline period.⁵ There was a significant reduction in migraine frequency and duration in patients receiving 200 mg of riboflavin daily, compared with placebo. Rahimdel et al. published an interesting study comparing high-dose riboflavin with valproate for migraine prophylaxis. A total of 90 patients were randomized to receive 400 mg of riboflavin or 500 mg of valproate over a 12-month study.⁶ Both treatments resulted in marked reduction in frequency, duration, and severity of migraines (not statistically significantly different from each other). The reduction in migraine frequency for the riboflavin group was from 9.2 headache days per month to 2.4. The American Academy of Neurology rates the level of evidence for riboflavin as B.

Pearl

Horse chestnut, D-mannose, and riboflavin are safe alternative therapies that can be helpful for several common problems we see frequently in primary care.

References

1. Diehm C et al. Lancet. 1996;347(8997):292-4.

2. Pittler MH, Ernst E. Cochrane Database Syst Rev. 2012 Nov 14;11:CD003230.

3. Jepson RG et al. Cochrane Database Syst Rev. 2012;10:CD001321.

4. Kranjčec B et al. World J Urol. 2014 Feb;32(1):79-84.

5. Talebian A et al. Electron Physician. Feb 25;10(2):6279-85.

6. Rahimdel A et al. Electron Physician. 2015 Oct 19;7(6):1344-8.

Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and he serves as third-year medical student clerkship director at the University of Washington. Contact Dr. Paauw at [email protected].

I practice in Seattle, where many of my patients are interested in natural treatment options. I am always puzzled that so many people assume that natural treatment options would be safer than prescription medications. Tsunamis, wildfires, flooding, and earthquakes are all natural and are deadly. There are certainly many natural poisons. There are a number of natural treatments that are very helpful, and recommending them are an important part of my practice. I want to share a few with you.

A useful vein pursuit?

Case: A 60-year-old woman presents to clinic with increasing pain in her left leg. She had a deep vein thrombosis in her left leg 2 years ago, which involved a large portion of her superficial femoral vein. She has noticed edema over the past few weeks, and pain has been more severe over the past 3 months. On exam, varicosities on left lower extremity with grade 2+ edema. Duplex of the lower extremity does not show deep vein thrombosis, but does show a great deal of venous valvular incompetence. She has tried compression stockings for the past 2 weeks. What is the best treatment option?

A) Turmeric

B) Amitriptyline

C) Vitamin B12

D) Horse chestnut

The treatment option with positive data for this problem is horse chestnut. What is horse chestnut? Horse chestnut is a kind of tree, and the seed extract contains aescin which is believed to be the active ingredient. Diehm et al. studied horse chestnut seed extract (HCSE), compared with compression stockings and placebo for edema from chronic venous insufficiency in a study of 240 patients.¹ Lower-leg volume decreased by 43 mL with HCSE, 46 mL with compression stockings, and increased by 9 mL with placebo (P less than .005 for HCSE and P less than .002 for compression). In a Cochrane review, HCSE was considered efficacious and safe for the short-term therapy for chronic venous insufficiency.² Studies have shown both an improvement in pain as well as swelling in patients with chronic venous insufficiency.

The question of UTIs

Probably the most popular natural treatment for prevention and treatment of urinary tract infections (UTIs) in women is cranberry juice (or cranberry extract). Unfortunately, there is little evidence that this treatment is helpful. In a Cochrane analysis, the conclusion was, based on current evidence, cranberry juice cannot currently be recommended for the prevention of UTIs.³ A natural product that appears to be more promising is the sugar D-mannose. Kranjčec et al. studied 308 women with acute UTI who had a history of recurrent UTI.⁴ All the women were treated for their symptomatic infection with ciprofloxacin (500 mg twice daily for 1 week). The women were allocated equally to three groups for 6 months: D-mannose 2 g daily, nitrofurantoin 50 mg daily, or no prophylaxis. About 60% of the women who received no prophylaxis had a UTI during the study period, compared with 20% in the nitrofurantoin group and 15% in the D-mannose group. The relative risk for D-mannose, compared with no prophylaxis, was 0.24 and for nitrofurantoin was 0.34 (P less than .0001), compared with no prophylaxis.

Made for migraines?

Migraine prophylaxis is challenging because all medications that are commonly used have side effects that often limit patient adherence. Tricyclic antidepressants (dry mouth, dizziness and weight gain), beta-blockers (fatigue, decreased exercise tolerance), valproate (weight gain and fatigue), and topiramate (parasthesias and mental slowing) all have troubling side effects. Riboflavin is a vitamin with evidence of effectiveness for migraine prophylaxis. It is extremely well tolerated. In a recent study in children with migraines, Talebian et al. studied 90 children with migraines who were randomized to three groups (200 mg of riboflavin a day, 100 mg of riboflavin a day, or placebo) after observation during a 1-month baseline period.⁵ There was a significant reduction in migraine frequency and duration in patients receiving 200 mg of riboflavin daily, compared with placebo. Rahimdel et al. published an interesting study comparing high-dose riboflavin with valproate for migraine prophylaxis. A total of 90 patients were randomized to receive 400 mg of riboflavin or 500 mg of valproate over a 12-month study.⁶ Both treatments resulted in marked reduction in frequency, duration, and severity of migraines (not statistically significantly different from each other). The reduction in migraine frequency for the riboflavin group was from 9.2 headache days per month to 2.4. The American Academy of Neurology rates the level of evidence for riboflavin as B.

Pearl

Horse chestnut, D-mannose, and riboflavin are safe alternative therapies that can be helpful for several common problems we see frequently in primary care.

References

1. Diehm C et al. Lancet. 1996;347(8997):292-4.

2. Pittler MH, Ernst E. Cochrane Database Syst Rev. 2012 Nov 14;11:CD003230.

3. Jepson RG et al. Cochrane Database Syst Rev. 2012;10:CD001321.

4. Kranjčec B et al. World J Urol. 2014 Feb;32(1):79-84.

5. Talebian A et al. Electron Physician. Feb 25;10(2):6279-85.

6. Rahimdel A et al. Electron Physician. 2015 Oct 19;7(6):1344-8.

Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and he serves as third-year medical student clerkship director at the University of Washington. Contact Dr. Paauw at [email protected].

I practice in Seattle, where many of my patients are interested in natural treatment options. I am always puzzled that so many people assume that natural treatment options would be safer than prescription medications. Tsunamis, wildfires, flooding, and earthquakes are all natural and are deadly. There are certainly many natural poisons. There are a number of natural treatments that are very helpful, and recommending them are an important part of my practice. I want to share a few with you.

A useful vein pursuit?

Case: A 60-year-old woman presents to clinic with increasing pain in her left leg. She had a deep vein thrombosis in her left leg 2 years ago, which involved a large portion of her superficial femoral vein. She has noticed edema over the past few weeks, and pain has been more severe over the past 3 months. On exam, varicosities on left lower extremity with grade 2+ edema. Duplex of the lower extremity does not show deep vein thrombosis, but does show a great deal of venous valvular incompetence. She has tried compression stockings for the past 2 weeks. What is the best treatment option?

A) Turmeric

B) Amitriptyline

C) Vitamin B12

D) Horse chestnut

The treatment option with positive data for this problem is horse chestnut. What is horse chestnut? Horse chestnut is a kind of tree, and the seed extract contains aescin which is believed to be the active ingredient. Diehm et al. studied horse chestnut seed extract (HCSE), compared with compression stockings and placebo for edema from chronic venous insufficiency in a study of 240 patients.¹ Lower-leg volume decreased by 43 mL with HCSE, 46 mL with compression stockings, and increased by 9 mL with placebo (P less than .005 for HCSE and P less than .002 for compression). In a Cochrane review, HCSE was considered efficacious and safe for the short-term therapy for chronic venous insufficiency.² Studies have shown both an improvement in pain as well as swelling in patients with chronic venous insufficiency.

The question of UTIs

Probably the most popular natural treatment for prevention and treatment of urinary tract infections (UTIs) in women is cranberry juice (or cranberry extract). Unfortunately, there is little evidence that this treatment is helpful. In a Cochrane analysis, the conclusion was, based on current evidence, cranberry juice cannot currently be recommended for the prevention of UTIs.³ A natural product that appears to be more promising is the sugar D-mannose. Kranjčec et al. studied 308 women with acute UTI who had a history of recurrent UTI.⁴ All the women were treated for their symptomatic infection with ciprofloxacin (500 mg twice daily for 1 week). The women were allocated equally to three groups for 6 months: D-mannose 2 g daily, nitrofurantoin 50 mg daily, or no prophylaxis. About 60% of the women who received no prophylaxis had a UTI during the study period, compared with 20% in the nitrofurantoin group and 15% in the D-mannose group. The relative risk for D-mannose, compared with no prophylaxis, was 0.24 and for nitrofurantoin was 0.34 (P less than .0001), compared with no prophylaxis.

Made for migraines?

Migraine prophylaxis is challenging because all medications that are commonly used have side effects that often limit patient adherence. Tricyclic antidepressants (dry mouth, dizziness and weight gain), beta-blockers (fatigue, decreased exercise tolerance), valproate (weight gain and fatigue), and topiramate (parasthesias and mental slowing) all have troubling side effects. Riboflavin is a vitamin with evidence of effectiveness for migraine prophylaxis. It is extremely well tolerated. In a recent study in children with migraines, Talebian et al. studied 90 children with migraines who were randomized to three groups (200 mg of riboflavin a day, 100 mg of riboflavin a day, or placebo) after observation during a 1-month baseline period.⁵ There was a significant reduction in migraine frequency and duration in patients receiving 200 mg of riboflavin daily, compared with placebo. Rahimdel et al. published an interesting study comparing high-dose riboflavin with valproate for migraine prophylaxis. A total of 90 patients were randomized to receive 400 mg of riboflavin or 500 mg of valproate over a 12-month study.⁶ Both treatments resulted in marked reduction in frequency, duration, and severity of migraines (not statistically significantly different from each other). The reduction in migraine frequency for the riboflavin group was from 9.2 headache days per month to 2.4. The American Academy of Neurology rates the level of evidence for riboflavin as B.

Pearl

Horse chestnut, D-mannose, and riboflavin are safe alternative therapies that can be helpful for several common problems we see frequently in primary care.

References

1. Diehm C et al. Lancet. 1996;347(8997):292-4.

2. Pittler MH, Ernst E. Cochrane Database Syst Rev. 2012 Nov 14;11:CD003230.

3. Jepson RG et al. Cochrane Database Syst Rev. 2012;10:CD001321.

4. Kranjčec B et al. World J Urol. 2014 Feb;32(1):79-84.

5. Talebian A et al. Electron Physician. Feb 25;10(2):6279-85.

6. Rahimdel A et al. Electron Physician. 2015 Oct 19;7(6):1344-8.

Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and he serves as third-year medical student clerkship director at the University of Washington. Contact Dr. Paauw at [email protected].

The first time I was sure I was witnessing someone vaping occurred when I saw an alarming cloud of smoke billowing from driver’s side window of the car in front of me. My initial concern was that vehicle was on fire. But none of the other drivers around me seemed concerned and as I pulled up next to the car I could see the driver ostentatiously inhaling deeply in preparation for releasing another monstrous cloud of vapor.

However, you probably have learned, as have I, that most vaping is done furtively. In fact, the pocketability of vaping devices is part of their appeal to teenagers. Hiding a lit cigarette in one’s pocket is something even the most risk-loving adolescent usually won’t attempt. I suspect that regardless of what is in the vapor, the high one can get by putting one over on the school administration by vaping in the school restroom or in the middle of history class is a temptation that many teenagers can’t resist.

Listening to educators, substance abuse counselors, and police officers who have first hand knowledge, it’s clear that vaping is an activity that’s very difficult to detect and police. Where there’s smoke there’s fire, but if it’s just a vapor it is easy to hide.

Part of the problem seems to be that vaping was flying under the radar and expanding rapidly long before educators, parents, and I fear physicians woke up to the severity and magnitude of the problem. And now everybody is playing catchup.

Of course the initial, and as yet unconfirmed, notion that e-cigarettes might provide a viable strategy for tobacco withdrawal has added confusion to the mix. It turns out that vaping can provide many orders of magnitude more nicotine in a small volume than cigarettes, which creates an outsized addiction potential for those more vulnerable users – even with a very short history of use. My experts tell me that this level of addiction has forced them to consider strategies and dosages far beyond those they are accustomed to using with patients whose addiction stems from standard cigarette use.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Email him at [email protected].

The first time I was sure I was witnessing someone vaping occurred when I saw an alarming cloud of smoke billowing from driver’s side window of the car in front of me. My initial concern was that vehicle was on fire. But none of the other drivers around me seemed concerned and as I pulled up next to the car I could see the driver ostentatiously inhaling deeply in preparation for releasing another monstrous cloud of vapor.

However, you probably have learned, as have I, that most vaping is done furtively. In fact, the pocketability of vaping devices is part of their appeal to teenagers. Hiding a lit cigarette in one’s pocket is something even the most risk-loving adolescent usually won’t attempt. I suspect that regardless of what is in the vapor, the high one can get by putting one over on the school administration by vaping in the school restroom or in the middle of history class is a temptation that many teenagers can’t resist.

Listening to educators, substance abuse counselors, and police officers who have first hand knowledge, it’s clear that vaping is an activity that’s very difficult to detect and police. Where there’s smoke there’s fire, but if it’s just a vapor it is easy to hide.

Part of the problem seems to be that vaping was flying under the radar and expanding rapidly long before educators, parents, and I fear physicians woke up to the severity and magnitude of the problem. And now everybody is playing catchup.

Of course the initial, and as yet unconfirmed, notion that e-cigarettes might provide a viable strategy for tobacco withdrawal has added confusion to the mix. It turns out that vaping can provide many orders of magnitude more nicotine in a small volume than cigarettes, which creates an outsized addiction potential for those more vulnerable users – even with a very short history of use. My experts tell me that this level of addiction has forced them to consider strategies and dosages far beyond those they are accustomed to using with patients whose addiction stems from standard cigarette use.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Email him at [email protected].

The first time I was sure I was witnessing someone vaping occurred when I saw an alarming cloud of smoke billowing from driver’s side window of the car in front of me. My initial concern was that vehicle was on fire. But none of the other drivers around me seemed concerned and as I pulled up next to the car I could see the driver ostentatiously inhaling deeply in preparation for releasing another monstrous cloud of vapor.

However, you probably have learned, as have I, that most vaping is done furtively. In fact, the pocketability of vaping devices is part of their appeal to teenagers. Hiding a lit cigarette in one’s pocket is something even the most risk-loving adolescent usually won’t attempt. I suspect that regardless of what is in the vapor, the high one can get by putting one over on the school administration by vaping in the school restroom or in the middle of history class is a temptation that many teenagers can’t resist.

Listening to educators, substance abuse counselors, and police officers who have first hand knowledge, it’s clear that vaping is an activity that’s very difficult to detect and police. Where there’s smoke there’s fire, but if it’s just a vapor it is easy to hide.

Part of the problem seems to be that vaping was flying under the radar and expanding rapidly long before educators, parents, and I fear physicians woke up to the severity and magnitude of the problem. And now everybody is playing catchup.

Of course the initial, and as yet unconfirmed, notion that e-cigarettes might provide a viable strategy for tobacco withdrawal has added confusion to the mix. It turns out that vaping can provide many orders of magnitude more nicotine in a small volume than cigarettes, which creates an outsized addiction potential for those more vulnerable users – even with a very short history of use. My experts tell me that this level of addiction has forced them to consider strategies and dosages far beyond those they are accustomed to using with patients whose addiction stems from standard cigarette use.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Email him at [email protected].

In North America, breakfast is the most personal of all the traditional daily meals and usually the one at which people show the least amount of day-to-day variation.

FluxFactory/E+

For example, since retiring from active practice I eat three scrambled eggs and bowl of fresh fruit every morning (yes, I have my lipid screen done annually and it’s fine). When I was a child there were stretches measuring in years during which I would eat the same cold cereal and drink a glass of orange juice. As an adolescent trying to bulk up for football, there was a breakfast-in-a-glass that I drank along with the cereal every morning. There was the frozen waffle decade.

When I was a busy general pediatrician, the meals were short on preparation and equally short on variety. But I always had something to eat before heading out for the day. That’s what my folks did, and that’s the pattern my wife and I programmed into our children. I think my dietary history is not unique. Most people don’t have time for a complex breakfast, and in many cases, they aren’t feeling terribly adventuresome when it comes to food at 6 or 7 in the morning. Breakfast is more of a habit than an event to satisfy one’s hunger. Several generations ago, breakfast was a big deal. Men (and occasionally women) were headed out for a day of demanding physical labor and stoking the furnace at the beginning of the day made sense. In farm families, breakfast was a major meal after the morning chores were completed. Those Norman Rockwellesque days are behind us, and breakfast has receded into a minor nutritional role.

For many adults, it’s just something to chew on with a cup of a stimulant liquid. In some families, breakfast has disappeared completely. For as long as there have been dietitians and nutritionists, we have been told that breakfast can be the most important meal of the day. And for a child, the failure to eat breakfast could jeopardize his or her ability to perform in school. I guess at face value this dictum makes sense, but I’ve never been terribly impressed with the evidence supporting it. A recent study from England has gotten me thinking about the whole issue of breakfast and school performance again (“associations between habitual school-day breakfast consumption frequency and academic performance in British adolescents.” Front Public Health. 2019 Nov 20. doi. 10.3389/fpubh.2019.00283). A trio of researchers at the Human Appetite Research Unit of the School of Psychology, University of Leeds (England), found that in the study group of nearly 300 adolescents aged 16-18 years, the students who frequently skipped breakfast performed more poorly on a battery of standardized national tests. Well, I guess we have to chalk another one up for the dietitians and nutritionists. But let’s think this through again. The authors observe in the discussion of their results that “breakfast quality was not considered in the analysis and therefore conclusions regarding what aspects of breakfast are correlated with academic performance cannot be drawn.”

Maybe it’s not the food consumed at breakfast but merely taking part in the event itself that is associated with better school performance. Could it be that families who don’t give breakfast a priority also don’t prioritize school work? Maybe teenagers with poor sleep hygiene who are habitually difficult to awaken in the morning don’t have time to eat breakfast. It is likely their sleep deprivation is more of a factor in their school performance than the small nutritional deficit that they have incurred by not eating breakfast. The study that might answer these questions hasn’t been done yet. And maybe it doesn’t need to be done. We don’t need to be asking children what they have for breakfast. But we should be entering into a dialogue that begins with “Why don’t you have breakfast?” The answers may lead into a productive discussion with the family about more important contributors to poor school performance.
 

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Email him at [email protected].

In North America, breakfast is the most personal of all the traditional daily meals and usually the one at which people show the least amount of day-to-day variation.

FluxFactory/E+

For example, since retiring from active practice I eat three scrambled eggs and bowl of fresh fruit every morning (yes, I have my lipid screen done annually and it’s fine). When I was a child there were stretches measuring in years during which I would eat the same cold cereal and drink a glass of orange juice. As an adolescent trying to bulk up for football, there was a breakfast-in-a-glass that I drank along with the cereal every morning. There was the frozen waffle decade.

When I was a busy general pediatrician, the meals were short on preparation and equally short on variety. But I always had something to eat before heading out for the day. That’s what my folks did, and that’s the pattern my wife and I programmed into our children. I think my dietary history is not unique. Most people don’t have time for a complex breakfast, and in many cases, they aren’t feeling terribly adventuresome when it comes to food at 6 or 7 in the morning. Breakfast is more of a habit than an event to satisfy one’s hunger. Several generations ago, breakfast was a big deal. Men (and occasionally women) were headed out for a day of demanding physical labor and stoking the furnace at the beginning of the day made sense. In farm families, breakfast was a major meal after the morning chores were completed. Those Norman Rockwellesque days are behind us, and breakfast has receded into a minor nutritional role.

For many adults, it’s just something to chew on with a cup of a stimulant liquid. In some families, breakfast has disappeared completely. For as long as there have been dietitians and nutritionists, we have been told that breakfast can be the most important meal of the day. And for a child, the failure to eat breakfast could jeopardize his or her ability to perform in school. I guess at face value this dictum makes sense, but I’ve never been terribly impressed with the evidence supporting it. A recent study from England has gotten me thinking about the whole issue of breakfast and school performance again (“associations between habitual school-day breakfast consumption frequency and academic performance in British adolescents.” Front Public Health. 2019 Nov 20. doi. 10.3389/fpubh.2019.00283). A trio of researchers at the Human Appetite Research Unit of the School of Psychology, University of Leeds (England), found that in the study group of nearly 300 adolescents aged 16-18 years, the students who frequently skipped breakfast performed more poorly on a battery of standardized national tests. Well, I guess we have to chalk another one up for the dietitians and nutritionists. But let’s think this through again. The authors observe in the discussion of their results that “breakfast quality was not considered in the analysis and therefore conclusions regarding what aspects of breakfast are correlated with academic performance cannot be drawn.”

Maybe it’s not the food consumed at breakfast but merely taking part in the event itself that is associated with better school performance. Could it be that families who don’t give breakfast a priority also don’t prioritize school work? Maybe teenagers with poor sleep hygiene who are habitually difficult to awaken in the morning don’t have time to eat breakfast. It is likely their sleep deprivation is more of a factor in their school performance than the small nutritional deficit that they have incurred by not eating breakfast. The study that might answer these questions hasn’t been done yet. And maybe it doesn’t need to be done. We don’t need to be asking children what they have for breakfast. But we should be entering into a dialogue that begins with “Why don’t you have breakfast?” The answers may lead into a productive discussion with the family about more important contributors to poor school performance.
 

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Email him at [email protected].

In North America, breakfast is the most personal of all the traditional daily meals and usually the one at which people show the least amount of day-to-day variation.

FluxFactory/E+

For example, since retiring from active practice I eat three scrambled eggs and bowl of fresh fruit every morning (yes, I have my lipid screen done annually and it’s fine). When I was a child there were stretches measuring in years during which I would eat the same cold cereal and drink a glass of orange juice. As an adolescent trying to bulk up for football, there was a breakfast-in-a-glass that I drank along with the cereal every morning. There was the frozen waffle decade.

When I was a busy general pediatrician, the meals were short on preparation and equally short on variety. But I always had something to eat before heading out for the day. That’s what my folks did, and that’s the pattern my wife and I programmed into our children. I think my dietary history is not unique. Most people don’t have time for a complex breakfast, and in many cases, they aren’t feeling terribly adventuresome when it comes to food at 6 or 7 in the morning. Breakfast is more of a habit than an event to satisfy one’s hunger. Several generations ago, breakfast was a big deal. Men (and occasionally women) were headed out for a day of demanding physical labor and stoking the furnace at the beginning of the day made sense. In farm families, breakfast was a major meal after the morning chores were completed. Those Norman Rockwellesque days are behind us, and breakfast has receded into a minor nutritional role.

For many adults, it’s just something to chew on with a cup of a stimulant liquid. In some families, breakfast has disappeared completely. For as long as there have been dietitians and nutritionists, we have been told that breakfast can be the most important meal of the day. And for a child, the failure to eat breakfast could jeopardize his or her ability to perform in school. I guess at face value this dictum makes sense, but I’ve never been terribly impressed with the evidence supporting it. A recent study from England has gotten me thinking about the whole issue of breakfast and school performance again (“associations between habitual school-day breakfast consumption frequency and academic performance in British adolescents.” Front Public Health. 2019 Nov 20. doi. 10.3389/fpubh.2019.00283). A trio of researchers at the Human Appetite Research Unit of the School of Psychology, University of Leeds (England), found that in the study group of nearly 300 adolescents aged 16-18 years, the students who frequently skipped breakfast performed more poorly on a battery of standardized national tests. Well, I guess we have to chalk another one up for the dietitians and nutritionists. But let’s think this through again. The authors observe in the discussion of their results that “breakfast quality was not considered in the analysis and therefore conclusions regarding what aspects of breakfast are correlated with academic performance cannot be drawn.”

Maybe it’s not the food consumed at breakfast but merely taking part in the event itself that is associated with better school performance. Could it be that families who don’t give breakfast a priority also don’t prioritize school work? Maybe teenagers with poor sleep hygiene who are habitually difficult to awaken in the morning don’t have time to eat breakfast. It is likely their sleep deprivation is more of a factor in their school performance than the small nutritional deficit that they have incurred by not eating breakfast. The study that might answer these questions hasn’t been done yet. And maybe it doesn’t need to be done. We don’t need to be asking children what they have for breakfast. But we should be entering into a dialogue that begins with “Why don’t you have breakfast?” The answers may lead into a productive discussion with the family about more important contributors to poor school performance.
 

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Email him at [email protected].

Several studies published over the last few years have shown declining rates of diagnosis and treatment of osteoporosis in older adults. In part, this may be due to declining ability to diagnose osteoporosis because declining reimbursement for dual x-ray absorptiometry has made it less available to patients and doctors. The study by Curtis et al. from the annual meeting of the American College of Rheumatology confirms prior findings and confirmation is important in driving the message home.

More research is needed to understand the reasons why patients and health care providers are not diagnosing osteoporosis, given that we can easily do so, and not treating osteoporosis or accepting recommended treatments for osteoporosis, given that we have many effective treatments that reduce the risk of fractures, many of them very inexpensive.

The vast majority of Medicare patients have major risk factors for falls, and falls are the most important risk factor for osteoporotic fractures. It is important to be proactive, to ask about drugs and diseases than increase falls, to educate patients about how to prevent falls, and to initiate treatments that strengthen bones so that they are less likely to break as a consequence of falling.

Dr. Shane is an endocrinologist, professor of medicine, and vice chair of medicine for clinical and epidemiological research at Columbia University in New York. She had no conflicts to disclose.

Several studies published over the last few years have shown declining rates of diagnosis and treatment of osteoporosis in older adults. In part, this may be due to declining ability to diagnose osteoporosis because declining reimbursement for dual x-ray absorptiometry has made it less available to patients and doctors. The study by Curtis et al. from the annual meeting of the American College of Rheumatology confirms prior findings and confirmation is important in driving the message home.

More research is needed to understand the reasons why patients and health care providers are not diagnosing osteoporosis, given that we can easily do so, and not treating osteoporosis or accepting recommended treatments for osteoporosis, given that we have many effective treatments that reduce the risk of fractures, many of them very inexpensive.

The vast majority of Medicare patients have major risk factors for falls, and falls are the most important risk factor for osteoporotic fractures. It is important to be proactive, to ask about drugs and diseases than increase falls, to educate patients about how to prevent falls, and to initiate treatments that strengthen bones so that they are less likely to break as a consequence of falling.

Dr. Shane is an endocrinologist, professor of medicine, and vice chair of medicine for clinical and epidemiological research at Columbia University in New York. She had no conflicts to disclose.

Several studies published over the last few years have shown declining rates of diagnosis and treatment of osteoporosis in older adults. In part, this may be due to declining ability to diagnose osteoporosis because declining reimbursement for dual x-ray absorptiometry has made it less available to patients and doctors. The study by Curtis et al. from the annual meeting of the American College of Rheumatology confirms prior findings and confirmation is important in driving the message home.

More research is needed to understand the reasons why patients and health care providers are not diagnosing osteoporosis, given that we can easily do so, and not treating osteoporosis or accepting recommended treatments for osteoporosis, given that we have many effective treatments that reduce the risk of fractures, many of them very inexpensive.

The vast majority of Medicare patients have major risk factors for falls, and falls are the most important risk factor for osteoporotic fractures. It is important to be proactive, to ask about drugs and diseases than increase falls, to educate patients about how to prevent falls, and to initiate treatments that strengthen bones so that they are less likely to break as a consequence of falling.

Dr. Shane is an endocrinologist, professor of medicine, and vice chair of medicine for clinical and epidemiological research at Columbia University in New York. She had no conflicts to disclose.