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

Editor’s note: Career Choices features a psychiatry resident/fellow interviewing a psychiatrist about why he or she has chosen a specific career path. The goal is to inform trainees about the various psychiatric career options, and to give them a feel for the pros and cons of the various paths.

In this Career Choices, Saeed Ahmed, MD, Addiction Psychiatry Fellow at Boston University, talked with William Pirl, MD, MPH, FACLP, FAPOS. Dr. Pirl is Associate Professor, Psychiatry, Harvard Medical School. He joined Dana-Farber Cancer Institute in 2018 as Vice Chair for Psychosocial Oncology, Department of Psychosocial Oncology and Palliative Care. He is a past president of the American Psychosocial Oncology Society and North American Associate Editor for the journal Psycho-Oncology.

Dr. Ahmed: What made you choose the psychiatric oncology track, and how did your training lead you towards this path?

Dr. Pirl: I went to medical school thinking that I wanted to be a psychiatrist. However, I was really drawn to internal medicine, especially the process of sorting through medical differential diagnoses. I was deciding between applying for residency in medicine or psychiatry when I did an elective rotation in consultation-liaison (CL) psychiatry. Consultation-liaison psychiatry combined both medicine and psychiatry, which is exactly what I wanted to do. After residency, I wanted to do a CL fellowship outside of Boston, which is where I had done all of my medical education and training. One of my residency advisors suggested Memorial Sloan-Kettering Cancer Center, and I ended up going there. On the first day of fellowship, I realized that I’d only be working with cancer over that year, which I had not really thought about beforehand. Luckily, I loved it, and over the year I realized that the work had tremendous impact and meaning.

Dr. Ahmed: What are some of the pros and cons of working in psychiatric oncology?

Dr. Pirl: Things that I think are pros might be cons for some people. Consults in psychiatric oncology tend to be more relationship-based than they might be in other CL subspecialties. Oncology clinicians want to know who they are referring their patients to, and they are used to team-based care. If you like practicing as part of a multidisciplinary team, this is a pro.

Psychiatric oncology has more focus on existential issues, which interests me more than some other things in psychiatry. Bearing witness to so much tragedy can be a con at times, but psychiatrists who do this work learn ways to manage this within themselves. Psychiatric oncology also offers many experiences where you can see how much impact you make. It’s rewarding to see results and get positive feedback from patients and their families.

Continue to: Lastly, this is...

Lastly, this is a historic time in oncology. Over the last 15 years, things are happening that I never thought I would live to see. Some patients who 10 or 15 years ago would have had an expected survival of 6 to 9 months are now living years. We are now at a point where we might not actually know a patient’s prognosis, which introduces a whole other layer of uncertainty in cancer. Working as a psychiatrist during this time of rapidly evolving care is amazing. Cancer care will look very different over the next decade.

Dr. Ahmed: Based on your personal experience, what should one consider when choosing a psychiatric oncology program?

Dr. Pirl: I trained in a time before CL was a certified subspecialty of psychiatry. At that time, programs could focus solely on cancer, which cannot be done now. Trainees need to have broader training in certified fellowships. If someone knows that they are interested in psychiatric oncology, there are 2 programs that they should consider: the Dana-Farber Cancer Institute track of the Brigham and Women’s Hospital CL fellowship, and the Memorial Sloan-Kettering Cancer Center/New York Hospital CL fellowship. However, completing a CL fellowship will give someone the skills to do this work, even though they may not know all of the cancer content yet.

Dr. Ahmed: What are some of the career options and work settings in psychiatric oncology?

Dr. Pirl: There are many factors that make it difficult for psychiatrist to have a psychiatric oncology private practice. The amount of late cancellations and no-shows because of illness makes it hard to do this work without some institutional subsidy. Also, being able to communicate and work as a team with oncology providers is much easier if you are in the same place. Most psychiatrists who do psychiatric oncology work in a cancer center or hospital. Practice settings at those places include both inpatient and outpatient work. There is also a shortage of psychiatrists doing this work, which makes it easier to get a job and to advance into leadership roles.

Continue to: Dr. Ahmed...

Dr. Ahmed: What are some of the challenges in working in this field?

Dr. Pirl: One challenge is figuring out how to make sure you have income doing something that is not financially viable on its own. This is why most people work for cancer centers or hospitals and have some institutional subsidy for their work. Another challenge is access to care. There are not enough psychiatric resources for all the people with cancer who need them. Traditional referral-based models are getting harder and harder to manage. I think the emotional aspects of the work can also be challenging at times.

Dr. Ahmed: Where do you see the field going?

Dr. Pirl: Psychosocial care is now considered part of quality cancer care, and regulations require cancer centers to do certain aspects of it. This is leading to clinical growth and more integration into oncology. However, I am worried that we are not having enough psychiatry residents choose to do CL and/or psychiatric oncology. Some trainees are choosing to do a palliative care fellowship instead. When those trainees tell me why they want to do palliative care, I say that I do all of that and actually have much more time to do it because I am not managing constipation and vent settings. We need to do a better job of making trainees more aware of psychiatric oncology.

Dr. Ahmed: What advice do you have for those contemplating a career in psychiatric oncology?

Dr. Pirl: Please join the field. There is a shortage of psychiatrists who do this work, which is ironically one of the best and most meaningful jobs in psychiatry.

Editor’s note: Career Choices features a psychiatry resident/fellow interviewing a psychiatrist about why he or she has chosen a specific career path. The goal is to inform trainees about the various psychiatric career options, and to give them a feel for the pros and cons of the various paths.

In this Career Choices, Saeed Ahmed, MD, Addiction Psychiatry Fellow at Boston University, talked with William Pirl, MD, MPH, FACLP, FAPOS. Dr. Pirl is Associate Professor, Psychiatry, Harvard Medical School. He joined Dana-Farber Cancer Institute in 2018 as Vice Chair for Psychosocial Oncology, Department of Psychosocial Oncology and Palliative Care. He is a past president of the American Psychosocial Oncology Society and North American Associate Editor for the journal Psycho-Oncology.

Dr. Ahmed: What made you choose the psychiatric oncology track, and how did your training lead you towards this path?

Dr. Pirl: I went to medical school thinking that I wanted to be a psychiatrist. However, I was really drawn to internal medicine, especially the process of sorting through medical differential diagnoses. I was deciding between applying for residency in medicine or psychiatry when I did an elective rotation in consultation-liaison (CL) psychiatry. Consultation-liaison psychiatry combined both medicine and psychiatry, which is exactly what I wanted to do. After residency, I wanted to do a CL fellowship outside of Boston, which is where I had done all of my medical education and training. One of my residency advisors suggested Memorial Sloan-Kettering Cancer Center, and I ended up going there. On the first day of fellowship, I realized that I’d only be working with cancer over that year, which I had not really thought about beforehand. Luckily, I loved it, and over the year I realized that the work had tremendous impact and meaning.

Dr. Ahmed: What are some of the pros and cons of working in psychiatric oncology?

Dr. Pirl: Things that I think are pros might be cons for some people. Consults in psychiatric oncology tend to be more relationship-based than they might be in other CL subspecialties. Oncology clinicians want to know who they are referring their patients to, and they are used to team-based care. If you like practicing as part of a multidisciplinary team, this is a pro.

Psychiatric oncology has more focus on existential issues, which interests me more than some other things in psychiatry. Bearing witness to so much tragedy can be a con at times, but psychiatrists who do this work learn ways to manage this within themselves. Psychiatric oncology also offers many experiences where you can see how much impact you make. It’s rewarding to see results and get positive feedback from patients and their families.

Continue to: Lastly, this is...

Lastly, this is a historic time in oncology. Over the last 15 years, things are happening that I never thought I would live to see. Some patients who 10 or 15 years ago would have had an expected survival of 6 to 9 months are now living years. We are now at a point where we might not actually know a patient’s prognosis, which introduces a whole other layer of uncertainty in cancer. Working as a psychiatrist during this time of rapidly evolving care is amazing. Cancer care will look very different over the next decade.

Dr. Ahmed: Based on your personal experience, what should one consider when choosing a psychiatric oncology program?

Dr. Pirl: I trained in a time before CL was a certified subspecialty of psychiatry. At that time, programs could focus solely on cancer, which cannot be done now. Trainees need to have broader training in certified fellowships. If someone knows that they are interested in psychiatric oncology, there are 2 programs that they should consider: the Dana-Farber Cancer Institute track of the Brigham and Women’s Hospital CL fellowship, and the Memorial Sloan-Kettering Cancer Center/New York Hospital CL fellowship. However, completing a CL fellowship will give someone the skills to do this work, even though they may not know all of the cancer content yet.

Dr. Ahmed: What are some of the career options and work settings in psychiatric oncology?

Dr. Pirl: There are many factors that make it difficult for psychiatrist to have a psychiatric oncology private practice. The amount of late cancellations and no-shows because of illness makes it hard to do this work without some institutional subsidy. Also, being able to communicate and work as a team with oncology providers is much easier if you are in the same place. Most psychiatrists who do psychiatric oncology work in a cancer center or hospital. Practice settings at those places include both inpatient and outpatient work. There is also a shortage of psychiatrists doing this work, which makes it easier to get a job and to advance into leadership roles.

Continue to: Dr. Ahmed...

Dr. Ahmed: What are some of the challenges in working in this field?

Dr. Pirl: One challenge is figuring out how to make sure you have income doing something that is not financially viable on its own. This is why most people work for cancer centers or hospitals and have some institutional subsidy for their work. Another challenge is access to care. There are not enough psychiatric resources for all the people with cancer who need them. Traditional referral-based models are getting harder and harder to manage. I think the emotional aspects of the work can also be challenging at times.

Dr. Ahmed: Where do you see the field going?

Dr. Pirl: Psychosocial care is now considered part of quality cancer care, and regulations require cancer centers to do certain aspects of it. This is leading to clinical growth and more integration into oncology. However, I am worried that we are not having enough psychiatry residents choose to do CL and/or psychiatric oncology. Some trainees are choosing to do a palliative care fellowship instead. When those trainees tell me why they want to do palliative care, I say that I do all of that and actually have much more time to do it because I am not managing constipation and vent settings. We need to do a better job of making trainees more aware of psychiatric oncology.

Dr. Ahmed: What advice do you have for those contemplating a career in psychiatric oncology?

Dr. Pirl: Please join the field. There is a shortage of psychiatrists who do this work, which is ironically one of the best and most meaningful jobs in psychiatry.

Editor’s note: Career Choices features a psychiatry resident/fellow interviewing a psychiatrist about why he or she has chosen a specific career path. The goal is to inform trainees about the various psychiatric career options, and to give them a feel for the pros and cons of the various paths.

In this Career Choices, Saeed Ahmed, MD, Addiction Psychiatry Fellow at Boston University, talked with William Pirl, MD, MPH, FACLP, FAPOS. Dr. Pirl is Associate Professor, Psychiatry, Harvard Medical School. He joined Dana-Farber Cancer Institute in 2018 as Vice Chair for Psychosocial Oncology, Department of Psychosocial Oncology and Palliative Care. He is a past president of the American Psychosocial Oncology Society and North American Associate Editor for the journal Psycho-Oncology.

Dr. Ahmed: What made you choose the psychiatric oncology track, and how did your training lead you towards this path?

Dr. Pirl: I went to medical school thinking that I wanted to be a psychiatrist. However, I was really drawn to internal medicine, especially the process of sorting through medical differential diagnoses. I was deciding between applying for residency in medicine or psychiatry when I did an elective rotation in consultation-liaison (CL) psychiatry. Consultation-liaison psychiatry combined both medicine and psychiatry, which is exactly what I wanted to do. After residency, I wanted to do a CL fellowship outside of Boston, which is where I had done all of my medical education and training. One of my residency advisors suggested Memorial Sloan-Kettering Cancer Center, and I ended up going there. On the first day of fellowship, I realized that I’d only be working with cancer over that year, which I had not really thought about beforehand. Luckily, I loved it, and over the year I realized that the work had tremendous impact and meaning.

Dr. Ahmed: What are some of the pros and cons of working in psychiatric oncology?

Dr. Pirl: Things that I think are pros might be cons for some people. Consults in psychiatric oncology tend to be more relationship-based than they might be in other CL subspecialties. Oncology clinicians want to know who they are referring their patients to, and they are used to team-based care. If you like practicing as part of a multidisciplinary team, this is a pro.

Psychiatric oncology has more focus on existential issues, which interests me more than some other things in psychiatry. Bearing witness to so much tragedy can be a con at times, but psychiatrists who do this work learn ways to manage this within themselves. Psychiatric oncology also offers many experiences where you can see how much impact you make. It’s rewarding to see results and get positive feedback from patients and their families.

Continue to: Lastly, this is...

Lastly, this is a historic time in oncology. Over the last 15 years, things are happening that I never thought I would live to see. Some patients who 10 or 15 years ago would have had an expected survival of 6 to 9 months are now living years. We are now at a point where we might not actually know a patient’s prognosis, which introduces a whole other layer of uncertainty in cancer. Working as a psychiatrist during this time of rapidly evolving care is amazing. Cancer care will look very different over the next decade.

Dr. Ahmed: Based on your personal experience, what should one consider when choosing a psychiatric oncology program?

Dr. Pirl: I trained in a time before CL was a certified subspecialty of psychiatry. At that time, programs could focus solely on cancer, which cannot be done now. Trainees need to have broader training in certified fellowships. If someone knows that they are interested in psychiatric oncology, there are 2 programs that they should consider: the Dana-Farber Cancer Institute track of the Brigham and Women’s Hospital CL fellowship, and the Memorial Sloan-Kettering Cancer Center/New York Hospital CL fellowship. However, completing a CL fellowship will give someone the skills to do this work, even though they may not know all of the cancer content yet.

Dr. Ahmed: What are some of the career options and work settings in psychiatric oncology?

Dr. Pirl: There are many factors that make it difficult for psychiatrist to have a psychiatric oncology private practice. The amount of late cancellations and no-shows because of illness makes it hard to do this work without some institutional subsidy. Also, being able to communicate and work as a team with oncology providers is much easier if you are in the same place. Most psychiatrists who do psychiatric oncology work in a cancer center or hospital. Practice settings at those places include both inpatient and outpatient work. There is also a shortage of psychiatrists doing this work, which makes it easier to get a job and to advance into leadership roles.

Continue to: Dr. Ahmed...

Dr. Ahmed: What are some of the challenges in working in this field?

Dr. Pirl: One challenge is figuring out how to make sure you have income doing something that is not financially viable on its own. This is why most people work for cancer centers or hospitals and have some institutional subsidy for their work. Another challenge is access to care. There are not enough psychiatric resources for all the people with cancer who need them. Traditional referral-based models are getting harder and harder to manage. I think the emotional aspects of the work can also be challenging at times.

Dr. Ahmed: Where do you see the field going?

Dr. Pirl: Psychosocial care is now considered part of quality cancer care, and regulations require cancer centers to do certain aspects of it. This is leading to clinical growth and more integration into oncology. However, I am worried that we are not having enough psychiatry residents choose to do CL and/or psychiatric oncology. Some trainees are choosing to do a palliative care fellowship instead. When those trainees tell me why they want to do palliative care, I say that I do all of that and actually have much more time to do it because I am not managing constipation and vent settings. We need to do a better job of making trainees more aware of psychiatric oncology.

Dr. Ahmed: What advice do you have for those contemplating a career in psychiatric oncology?

Dr. Pirl: Please join the field. There is a shortage of psychiatrists who do this work, which is ironically one of the best and most meaningful jobs in psychiatry.

In addition to offering an overall survival benefit for patients with MGMT-methylated glioblastoma, the combination of lomustine and temozolomide did not impair health-related quality of life (HRQOL) compared with temozolomide alone, investigators report.

Among 129 patients with newly-diagnosed glioblastoma with methylation of the MGMT promoter, there were no significant differences in any items on the European Organisation for Research and Treatment of Cancer (EORTC) quality of life questionnaire core-30 and the EORTC brain cancer module (BN20) between patients who received oral combined lomustine and temozolomide or temozolomide alone, reported Johannes Weller, MD, of University Hospital Bonn, Germany, and colleagues.

Although the combination was associated with slightly lower scores on the Mini-Mental State Exam (MMSE), the differences were not clinically significant, the investigators asserted.

“The absence of systematic and clinically relevant changes in HRQOL and neurocognitive function combined with the survival benefit of lomustine-temozolomide versus temozolomide alone suggests that a long-term net clinical benefit exists for patients with newly diagnosed glioblastoma with methylation of the MGMT promoter and supports the use of lomustine-temozolomide as a treatment option for these patients,” they wrote. The report is in The Lancet Oncology.

The investigators previously reported that median overall survival was improved from 31.4 months with temozolomide to 48.1 months with lomustine-temozolomide, translating into a hazard ratio (HR) for death with the combination of 0.60 (P = .0492).

In the current report, Dr. Weller and associates looked at the secondary endpoints of HRQOL as measured by the EORTC scales, and at neurocognitive function as assessed by the MMSE and a neurocognitive test battery (NOA-07) that include Trail Making Test A and B (TMT-A and B), working memory tests, and tests for word and semantic verbal fluency.

The modified intention-to-treat analysis included all patients who received at least one dose of study chemotherapy. The analysis included data on 63 patients randomly assigned to receive standard oral temozolomide, consisting of 75 mg/m² daily during radiotherapy plus six 4-week courses of temozolomide at doses ranging from 150 to 200 mg/m² on days 1-5, every 4 weeks; and 66 patients assigned to receive oral combined lomustine consisting of a 100 mg/m² dose on day 1, plus temozolomide 100 to 200 mg/m² on days 2-6 for six cycles of 6 weeks each.

After a median follow-up of 19.4 months for the HRQOL endpoint, there were no significant differences between the groups in decline from baselines in Karnofsky Performance Score, global health, physical functioning, cognitive functioning, social functioning, or communication deficit.

As noted before, however, there were small but significant differences between the groups favoring temozolomide on the MMSE, after a median follow-up for this measure of 15.3 months. The authors noted that the differences “were not significant when adjusted for multiple testing and were also not clinically relevant, because even over the time course of 4 years the differences between the groups would only add up to 1.76/30 points and clinically significant results would require a difference of more than 3/30 points.”

There were also no significant differences between the groups in any item of the neurocognitive test, they added.

The investigators acknowledged that the trial was limited by its relatively small size, and that after 3.5 years of follow-up about half of all the expected HRQOL forms were missing, which might lead to reporting bias.

“Overall, we conclude that the addition of lomustine to temozolomide in patients with newly diagnosed MGMT-methylated glioblastoma is associated with a clear long-term net clinical benefit and our data provide a good rationale for the trial regimen as a treatment option for these patients. Nevertheless, changes in HRQOL during the first year after beginning treatment needs further exploration in future studies,” Dr. Weller and colleagues wrote.

The German Federal Ministry of Education and Research funded the study. Dr. Weller reported having no conflict of interest. Several coauthors reported relationships with industry outside the submitted work.

SOURCE: Weller J et al. Lancet Oncol. Sept 2. doi: 10.1016/S1470-2045(19)30502-9.

In addition to offering an overall survival benefit for patients with MGMT-methylated glioblastoma, the combination of lomustine and temozolomide did not impair health-related quality of life (HRQOL) compared with temozolomide alone, investigators report.

Among 129 patients with newly-diagnosed glioblastoma with methylation of the MGMT promoter, there were no significant differences in any items on the European Organisation for Research and Treatment of Cancer (EORTC) quality of life questionnaire core-30 and the EORTC brain cancer module (BN20) between patients who received oral combined lomustine and temozolomide or temozolomide alone, reported Johannes Weller, MD, of University Hospital Bonn, Germany, and colleagues.

Although the combination was associated with slightly lower scores on the Mini-Mental State Exam (MMSE), the differences were not clinically significant, the investigators asserted.

“The absence of systematic and clinically relevant changes in HRQOL and neurocognitive function combined with the survival benefit of lomustine-temozolomide versus temozolomide alone suggests that a long-term net clinical benefit exists for patients with newly diagnosed glioblastoma with methylation of the MGMT promoter and supports the use of lomustine-temozolomide as a treatment option for these patients,” they wrote. The report is in The Lancet Oncology.

The investigators previously reported that median overall survival was improved from 31.4 months with temozolomide to 48.1 months with lomustine-temozolomide, translating into a hazard ratio (HR) for death with the combination of 0.60 (P = .0492).

In the current report, Dr. Weller and associates looked at the secondary endpoints of HRQOL as measured by the EORTC scales, and at neurocognitive function as assessed by the MMSE and a neurocognitive test battery (NOA-07) that include Trail Making Test A and B (TMT-A and B), working memory tests, and tests for word and semantic verbal fluency.

The modified intention-to-treat analysis included all patients who received at least one dose of study chemotherapy. The analysis included data on 63 patients randomly assigned to receive standard oral temozolomide, consisting of 75 mg/m² daily during radiotherapy plus six 4-week courses of temozolomide at doses ranging from 150 to 200 mg/m² on days 1-5, every 4 weeks; and 66 patients assigned to receive oral combined lomustine consisting of a 100 mg/m² dose on day 1, plus temozolomide 100 to 200 mg/m² on days 2-6 for six cycles of 6 weeks each.

After a median follow-up of 19.4 months for the HRQOL endpoint, there were no significant differences between the groups in decline from baselines in Karnofsky Performance Score, global health, physical functioning, cognitive functioning, social functioning, or communication deficit.

As noted before, however, there were small but significant differences between the groups favoring temozolomide on the MMSE, after a median follow-up for this measure of 15.3 months. The authors noted that the differences “were not significant when adjusted for multiple testing and were also not clinically relevant, because even over the time course of 4 years the differences between the groups would only add up to 1.76/30 points and clinically significant results would require a difference of more than 3/30 points.”

There were also no significant differences between the groups in any item of the neurocognitive test, they added.

The investigators acknowledged that the trial was limited by its relatively small size, and that after 3.5 years of follow-up about half of all the expected HRQOL forms were missing, which might lead to reporting bias.

“Overall, we conclude that the addition of lomustine to temozolomide in patients with newly diagnosed MGMT-methylated glioblastoma is associated with a clear long-term net clinical benefit and our data provide a good rationale for the trial regimen as a treatment option for these patients. Nevertheless, changes in HRQOL during the first year after beginning treatment needs further exploration in future studies,” Dr. Weller and colleagues wrote.

The German Federal Ministry of Education and Research funded the study. Dr. Weller reported having no conflict of interest. Several coauthors reported relationships with industry outside the submitted work.

SOURCE: Weller J et al. Lancet Oncol. Sept 2. doi: 10.1016/S1470-2045(19)30502-9.

In addition to offering an overall survival benefit for patients with MGMT-methylated glioblastoma, the combination of lomustine and temozolomide did not impair health-related quality of life (HRQOL) compared with temozolomide alone, investigators report.

Among 129 patients with newly-diagnosed glioblastoma with methylation of the MGMT promoter, there were no significant differences in any items on the European Organisation for Research and Treatment of Cancer (EORTC) quality of life questionnaire core-30 and the EORTC brain cancer module (BN20) between patients who received oral combined lomustine and temozolomide or temozolomide alone, reported Johannes Weller, MD, of University Hospital Bonn, Germany, and colleagues.

Although the combination was associated with slightly lower scores on the Mini-Mental State Exam (MMSE), the differences were not clinically significant, the investigators asserted.

“The absence of systematic and clinically relevant changes in HRQOL and neurocognitive function combined with the survival benefit of lomustine-temozolomide versus temozolomide alone suggests that a long-term net clinical benefit exists for patients with newly diagnosed glioblastoma with methylation of the MGMT promoter and supports the use of lomustine-temozolomide as a treatment option for these patients,” they wrote. The report is in The Lancet Oncology.

The investigators previously reported that median overall survival was improved from 31.4 months with temozolomide to 48.1 months with lomustine-temozolomide, translating into a hazard ratio (HR) for death with the combination of 0.60 (P = .0492).

In the current report, Dr. Weller and associates looked at the secondary endpoints of HRQOL as measured by the EORTC scales, and at neurocognitive function as assessed by the MMSE and a neurocognitive test battery (NOA-07) that include Trail Making Test A and B (TMT-A and B), working memory tests, and tests for word and semantic verbal fluency.

The modified intention-to-treat analysis included all patients who received at least one dose of study chemotherapy. The analysis included data on 63 patients randomly assigned to receive standard oral temozolomide, consisting of 75 mg/m² daily during radiotherapy plus six 4-week courses of temozolomide at doses ranging from 150 to 200 mg/m² on days 1-5, every 4 weeks; and 66 patients assigned to receive oral combined lomustine consisting of a 100 mg/m² dose on day 1, plus temozolomide 100 to 200 mg/m² on days 2-6 for six cycles of 6 weeks each.

After a median follow-up of 19.4 months for the HRQOL endpoint, there were no significant differences between the groups in decline from baselines in Karnofsky Performance Score, global health, physical functioning, cognitive functioning, social functioning, or communication deficit.

As noted before, however, there were small but significant differences between the groups favoring temozolomide on the MMSE, after a median follow-up for this measure of 15.3 months. The authors noted that the differences “were not significant when adjusted for multiple testing and were also not clinically relevant, because even over the time course of 4 years the differences between the groups would only add up to 1.76/30 points and clinically significant results would require a difference of more than 3/30 points.”

There were also no significant differences between the groups in any item of the neurocognitive test, they added.

The investigators acknowledged that the trial was limited by its relatively small size, and that after 3.5 years of follow-up about half of all the expected HRQOL forms were missing, which might lead to reporting bias.

“Overall, we conclude that the addition of lomustine to temozolomide in patients with newly diagnosed MGMT-methylated glioblastoma is associated with a clear long-term net clinical benefit and our data provide a good rationale for the trial regimen as a treatment option for these patients. Nevertheless, changes in HRQOL during the first year after beginning treatment needs further exploration in future studies,” Dr. Weller and colleagues wrote.

The German Federal Ministry of Education and Research funded the study. Dr. Weller reported having no conflict of interest. Several coauthors reported relationships with industry outside the submitted work.

SOURCE: Weller J et al. Lancet Oncol. Sept 2. doi: 10.1016/S1470-2045(19)30502-9.

Interleukin-17 and IL-23 inhibitors were safe and well-tolerated in most patients with psoriasis and psoriatic arthritis during treatment for up to 52 weeks, according to the results of a meta-analysis of 44 studies.

While associated with more adverse events than with placebo, IL-17 and IL-23 inhibitors are “generally well-tolerated and considered safe,” but the extent of adverse events and the existence of a possible drug class effect “have not been fully investigated,” wrote Nikolai D. Loft, MD, of the department of dermatology and allergy at Herlev and Gentofte Hospital in Hellerup, Denmark, and colleagues.

In a study published in the Journal of the European Academy of Dermatology and Venereology, the researchers identified phase 3 studies with data on adverse event reports in patients with psoriasis and psoriatic arthritis who were treated with either IL-17 inhibitors (brodalumab, ixekizumab, or secukinumab) or IL-23 inhibitors (guselkumab, risankizumab, or tildrakizumab).

Overall, across all treatments, the proportion of patients with reports of any adverse events ranged from 0.49 to 0.57 in short-term studies (12-16 weeks) and from 0.83 to 0.93 with long-term treatment (52 weeks). In a pooled analysis, the proportion of patients with any adverse events was 0.57, 0.52, 0.72, and 0.81, at 12, 16, 24, and 52 weeks, respectively.

The most common adverse events across all treatments were infections, nasopharyngitis, and headaches. Among those on ixekizumab, injection-site reactions was one of the most common adverse events reported, in nearly 16% of patients after 52 weeks of treatment, the authors noted.

Fewer adverse events were reported in patients on IL-23 inhibitors, compared with those on IL-17 inhibitors. The proportion of patients reporting serious adverse events was “low,” the researchers wrote. Patients on tildrakizumab had the lowest proportion of any adverse events overall, based on short-term data over 12-16 weeks.

No significant differences emerged in reported adverse events across IL-17 inhibitors after 52 weeks.

Other findings included a higher prevalence of Candida infections among those treated with IL-17 inhibitors after 12-16 weeks and 24 weeks, compared with those on placebo, but the infections, described as mild to moderate, did not result in drug discontinuation, the authors noted. The potential risk of inflammatory bowel disease (IBD) associated with IL-17 inhibitors has been raised as a concern, but in their analysis, “IBD was very rare and after 12 weeks no difference between active treatments and placebo was seen.”

The study findings were limited by several factors, including incomplete data for interdrug comparison, varying time points for safety measures, differences in dosing in clinical trials than the approved dosing, and lack of longer-term follow-up data for most of the treatments, the researchers noted. However, the analysis was strengthened by the inclusion of phase 3 studies with both short-and long-term data, and “overall, IL-17 and IL-23 inhibitors appear to be well-tolerated with good safety profiles.”

Dr. Loft disclosed serving as an honorary speaker for Eli Lilly; other coauthors disclosed relationships with multiple companies; two authors reported no conflicts of interest. There were no funding sources for the study listed.

SOURCE: Loft ND et al. J Eur Acad Dermatol Venereol 2019 Nov 13. doi: 10.1111/jdv.16073.

Interleukin-17 and IL-23 inhibitors were safe and well-tolerated in most patients with psoriasis and psoriatic arthritis during treatment for up to 52 weeks, according to the results of a meta-analysis of 44 studies.

While associated with more adverse events than with placebo, IL-17 and IL-23 inhibitors are “generally well-tolerated and considered safe,” but the extent of adverse events and the existence of a possible drug class effect “have not been fully investigated,” wrote Nikolai D. Loft, MD, of the department of dermatology and allergy at Herlev and Gentofte Hospital in Hellerup, Denmark, and colleagues.

In a study published in the Journal of the European Academy of Dermatology and Venereology, the researchers identified phase 3 studies with data on adverse event reports in patients with psoriasis and psoriatic arthritis who were treated with either IL-17 inhibitors (brodalumab, ixekizumab, or secukinumab) or IL-23 inhibitors (guselkumab, risankizumab, or tildrakizumab).

Overall, across all treatments, the proportion of patients with reports of any adverse events ranged from 0.49 to 0.57 in short-term studies (12-16 weeks) and from 0.83 to 0.93 with long-term treatment (52 weeks). In a pooled analysis, the proportion of patients with any adverse events was 0.57, 0.52, 0.72, and 0.81, at 12, 16, 24, and 52 weeks, respectively.

The most common adverse events across all treatments were infections, nasopharyngitis, and headaches. Among those on ixekizumab, injection-site reactions was one of the most common adverse events reported, in nearly 16% of patients after 52 weeks of treatment, the authors noted.

Fewer adverse events were reported in patients on IL-23 inhibitors, compared with those on IL-17 inhibitors. The proportion of patients reporting serious adverse events was “low,” the researchers wrote. Patients on tildrakizumab had the lowest proportion of any adverse events overall, based on short-term data over 12-16 weeks.

No significant differences emerged in reported adverse events across IL-17 inhibitors after 52 weeks.

Other findings included a higher prevalence of Candida infections among those treated with IL-17 inhibitors after 12-16 weeks and 24 weeks, compared with those on placebo, but the infections, described as mild to moderate, did not result in drug discontinuation, the authors noted. The potential risk of inflammatory bowel disease (IBD) associated with IL-17 inhibitors has been raised as a concern, but in their analysis, “IBD was very rare and after 12 weeks no difference between active treatments and placebo was seen.”

The study findings were limited by several factors, including incomplete data for interdrug comparison, varying time points for safety measures, differences in dosing in clinical trials than the approved dosing, and lack of longer-term follow-up data for most of the treatments, the researchers noted. However, the analysis was strengthened by the inclusion of phase 3 studies with both short-and long-term data, and “overall, IL-17 and IL-23 inhibitors appear to be well-tolerated with good safety profiles.”

Dr. Loft disclosed serving as an honorary speaker for Eli Lilly; other coauthors disclosed relationships with multiple companies; two authors reported no conflicts of interest. There were no funding sources for the study listed.

SOURCE: Loft ND et al. J Eur Acad Dermatol Venereol 2019 Nov 13. doi: 10.1111/jdv.16073.

Interleukin-17 and IL-23 inhibitors were safe and well-tolerated in most patients with psoriasis and psoriatic arthritis during treatment for up to 52 weeks, according to the results of a meta-analysis of 44 studies.

While associated with more adverse events than with placebo, IL-17 and IL-23 inhibitors are “generally well-tolerated and considered safe,” but the extent of adverse events and the existence of a possible drug class effect “have not been fully investigated,” wrote Nikolai D. Loft, MD, of the department of dermatology and allergy at Herlev and Gentofte Hospital in Hellerup, Denmark, and colleagues.

In a study published in the Journal of the European Academy of Dermatology and Venereology, the researchers identified phase 3 studies with data on adverse event reports in patients with psoriasis and psoriatic arthritis who were treated with either IL-17 inhibitors (brodalumab, ixekizumab, or secukinumab) or IL-23 inhibitors (guselkumab, risankizumab, or tildrakizumab).

Overall, across all treatments, the proportion of patients with reports of any adverse events ranged from 0.49 to 0.57 in short-term studies (12-16 weeks) and from 0.83 to 0.93 with long-term treatment (52 weeks). In a pooled analysis, the proportion of patients with any adverse events was 0.57, 0.52, 0.72, and 0.81, at 12, 16, 24, and 52 weeks, respectively.

The most common adverse events across all treatments were infections, nasopharyngitis, and headaches. Among those on ixekizumab, injection-site reactions was one of the most common adverse events reported, in nearly 16% of patients after 52 weeks of treatment, the authors noted.

Fewer adverse events were reported in patients on IL-23 inhibitors, compared with those on IL-17 inhibitors. The proportion of patients reporting serious adverse events was “low,” the researchers wrote. Patients on tildrakizumab had the lowest proportion of any adverse events overall, based on short-term data over 12-16 weeks.

No significant differences emerged in reported adverse events across IL-17 inhibitors after 52 weeks.

Other findings included a higher prevalence of Candida infections among those treated with IL-17 inhibitors after 12-16 weeks and 24 weeks, compared with those on placebo, but the infections, described as mild to moderate, did not result in drug discontinuation, the authors noted. The potential risk of inflammatory bowel disease (IBD) associated with IL-17 inhibitors has been raised as a concern, but in their analysis, “IBD was very rare and after 12 weeks no difference between active treatments and placebo was seen.”

The study findings were limited by several factors, including incomplete data for interdrug comparison, varying time points for safety measures, differences in dosing in clinical trials than the approved dosing, and lack of longer-term follow-up data for most of the treatments, the researchers noted. However, the analysis was strengthened by the inclusion of phase 3 studies with both short-and long-term data, and “overall, IL-17 and IL-23 inhibitors appear to be well-tolerated with good safety profiles.”

Dr. Loft disclosed serving as an honorary speaker for Eli Lilly; other coauthors disclosed relationships with multiple companies; two authors reported no conflicts of interest. There were no funding sources for the study listed.

SOURCE: Loft ND et al. J Eur Acad Dermatol Venereol 2019 Nov 13. doi: 10.1111/jdv.16073.

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.

The bonding process between individuals is essential to human life as we know it. The depth and strength of emotional bonds that we develop with other individuals are among the cardinal aspects of being human.

The strengths of the bonds that we form with others often are the most enduring aspects of our lives and can stretch back in time to include family members and friends who are no longer alive. The brain processes and neurochemicals involved in the bonding process are related to psychological processes using Bayesian theory. Abnormalities in attachment are described in terms of abnormal predictive models.

John Bowlby MD, and colleagues developed a psychological theory of early childhood attachment that shows the impact of different childhood experiences.¹ Over many decades, they conducted painstaking observations, trials, and retrials that elucidated specific types of attachment that reflect the child’s internal representations of the parent.

Dr. Bowlby described the mental representations of attachment as “the internal working models of expectations” about the maternal-child relationship. This internal model guides the child’s behaviors, attitudes, and expectations, and is constantly being revised and expanded as the child matures in order to adapt to increasingly complex relationships. More current research has shown that adults who have experienced extreme early childhood adversity develop odd or deficient descriptions of primary attachment relationships, now refined into a low-coherence CC category.² These children experience attachments that are characterized by feelings of emptiness, inconsistency, and fragmentation.

Object relations theory was created by Heinz Kohut, MD, to explain our internal models of others in psychoanalytic language.^{3 Dr.} Kohut expands the concept of transference describing three new transferential relationships: mirroring, idealized, and twinship transferences. A mirroring transference describes the psychological mechanism whereby “the other” serves as a mirror that reflects back to the person a sense of self-worth and value. A mirroring transference uses the affirming and positive responses of others so that a person then can see positive traits within themselves. The idealizing transference refers to a person’s need for “another” who will make them feel calm and comfortable. The other is idealized as somebody who is calm and soothing when the person cannot provide that on their own. The twinship/alter ego transference occurs when a person feels a sense of likeness with “an other.” These advances in psychoanalytic theory advance our understanding of how we internalize aspects of other people and use these internalizations in our own development.

The neuroscience of attachment was revealed in the study of the children abandoned in Romanian orphanages before the 1989 revolution. These children were placed in orphanages that lacked adequate staff, and they were subjected to profound psychosocial neglect. In the Bucharest Early Intervention Project, the effects of neglect were seen in children aged less than 30-96 months, in EEG data.⁴ Abnormalities were found in two aberrantly connected brain networks: a hyperconnected parieto-occipital network and a hypoconnected network between left temporal and distributed bilateral regions. This study provides the first evidence of the adverse effects of early psychosocial neglect on the wiring of the developing brain.

Neurochemistry has suggested the impact of oxytocin on the promotion of attachment. Oxytocin has been called the “cuddle hormone,” as it is stimulated in mothers to promote bonding with their infant. Many studies have examined the introduction of intranasal oxytocin increases bonding and trust with others, but recent meta-analyses challenge those findings.^5,6 Nevertheless, the process of bonding and attachment is thought to engage the mesocorticolimbic, nigrostriatal dopaminergic, and oxytocinergic systems. Tops and colleagues proposed that oxytocin facilitates a shift from ventral striatal “novelty processing” toward dorsal striatal “familiarity processing.”⁷ This shift to familiarity is thought to create secure internal working models. In addition, brain activity in specific regions, such as the right caudate, is correlated with romantic love.⁸ In summary, specific pathways and neurotransmitters underlie the emotional process of bonding and attachment.

However, it is Karl Friston, MD, who suggests a model of brain functioning that describes how we actually process our experiences of the world.⁹ Dr. Friston uses Bayesian modeling to describe how we interact and understand our world, describing the way we process information. Dr. Friston states that the process of inference that we use to discern our world is a process that uses Bayes’ theorem to update the probability for a specific hypothesis about our world. As more evidence or information becomes available, we update our internal models of the world. Predictive modeling is the term used in Bayesian terms to describe this process of continuous revision of our internal model of the world. Any new sensory input is compared to our current internal model, and if they do not match, our internal model of the world is updated and revised. Dr. Friston states: “As surprise is resolved, Bayesian model evidence is increased. This means that every living organism behaves as if it is a little statistician, analyzing its sensory data in exactly the same way that scientists evaluate the evidence for their hypotheses about how experimental data were caused. In this view, minimizing surprise is, literally, the search for evidence for one’s own existence.” This process of predictive modeling also can be applied to our internal models of other people, meaning that our internal model of another person is an iterative process that changes as the other person changes.

When our experience of the world and others fall into predictive patterns, we expect the “usual” responses from our world and from the people in it. This predictive processing makes it easier for us to understand our world, so that we do not have to continually analyze and reanalyze each event as a new experience. For example, a young child examines the waves as they crash on the shore. For a while, he will watch the waves but soon begins to recognize that there is a predictable pattern. With each ocean he visits, he will examine wave action and soon develop an internal model of what happens when the water reaches the shore. Similarly, when a young child has a secure and loving parent, he will expect security and love in his future relationships. On the other hand, the child who has been subjected to abuse and neglect has an internal working model of the other as nonreciprocal and perhaps irrelevant to their well-being. They will, therefore, have extreme difficulty in understanding the purpose or value of relationships. Their predictive model of the other reflects a lack of input in the case of neglect, or perverted input in the case of abuse. Their internal predictive model will require a great deal of therapeutic healthy inputs to be able to evolve to allow a healthy relationship with the other. This is the work of therapy.

When thinking about relationships, predictive processing makes clinical sense. In a committed partnership, each partner has a predictive model of their partner’s response to events/speech utterances/emotional displays. The prediction of the partner’s response is based on prior experience. This predictive model reduces the need to repeatedly reinterpret the partner’s actions. The partner is understood through an internal predictive model. When one partner changes their behavior, the other partner experiences the world/environment as disrupted or different. The couple, through an iterative process, can incorporate change and grow together. If the patient has an internalized model of a loving relationship, then they are more likely to find a partner who resonates with this internalized model. Using predictive modeling, we can understand how two people with their own internal models of each other interact. As one person approaches the other person, each internal model of the other person finds a “fit” with the behaviors of the other person. When a child with emotional deprivation approaches the other, the child perceives the other person in a way that fits with their prior experience of deprivation. It is an easy fit that requires little internal work, and the patient falls into a familiar relational pattern. This model of predictive processing explains why people repeatedly fall into similar familiar relationships: They recognize the relationship patterns. There is less predictive processing required, less emotional and cognitive work, and therefore less adjustment.

Psychotherapy helps patients by improving their understanding of the link between prior and current experience. Each piece of behavior is analyzed and compared with the patient’s internal model of the event. What neuroscience now provides is a deeper scientific understanding of this process. A neuroscience-based visualization of our internal models of other people can help us better describe the iterative process that occurs in therapeutic progress.

In summary, the processes of attachment and bonding occur through oxytocin-mediated caudate–dorsal striatum pathways. Bayesian predictive modeling describes the processes by which our internal models of others are shaped and refined, and underscores the work of our psychotherapies. Neuroscience is beginning to delineate the “where” and “how” of attachment and bonding, thus advancing our understanding of the attachment process and giving us a new language to describe the work of psychotherapy.
 

References

1. Bowlby J. “A Secure Base: Parent-Child Attachment and Healthy Human Development.” New York: Basic Books, 1988.

2. Speranza AM et al. Attach Hum Dev. 2017 Dec;19(6):613-34.

3. Kohut H. “How Does Analysis Cure?” Chicago: University of Chicago Press, 1984.

4. Stamoulis C et al. J Neurophysiol. 2017 Oct 1;118(4):2275-88.

5. Leng G and Ludwig M.Biol Psychiatry. 2016 Feb 1;79(3):243-50.

6. Leppanen J et al. Neurosci Biobehav Rev. 2017 Jul;78:125-44.

7. Tops M et al. Pharmacol Biochem Behav. 2014 Apr;119:39-48.

8. Acevedo BP et al. Soc Cogn Affect Neurosci. 2012 Feb;7(2):145-59.

9. Friston K. Entropy (Basel). 2012 Nov;14(11):2100-21.

The bonding process between individuals is essential to human life as we know it. The depth and strength of emotional bonds that we develop with other individuals are among the cardinal aspects of being human.

The strengths of the bonds that we form with others often are the most enduring aspects of our lives and can stretch back in time to include family members and friends who are no longer alive. The brain processes and neurochemicals involved in the bonding process are related to psychological processes using Bayesian theory. Abnormalities in attachment are described in terms of abnormal predictive models.

John Bowlby MD, and colleagues developed a psychological theory of early childhood attachment that shows the impact of different childhood experiences.¹ Over many decades, they conducted painstaking observations, trials, and retrials that elucidated specific types of attachment that reflect the child’s internal representations of the parent.

Dr. Bowlby described the mental representations of attachment as “the internal working models of expectations” about the maternal-child relationship. This internal model guides the child’s behaviors, attitudes, and expectations, and is constantly being revised and expanded as the child matures in order to adapt to increasingly complex relationships. More current research has shown that adults who have experienced extreme early childhood adversity develop odd or deficient descriptions of primary attachment relationships, now refined into a low-coherence CC category.² These children experience attachments that are characterized by feelings of emptiness, inconsistency, and fragmentation.

Object relations theory was created by Heinz Kohut, MD, to explain our internal models of others in psychoanalytic language.^{3 Dr.} Kohut expands the concept of transference describing three new transferential relationships: mirroring, idealized, and twinship transferences. A mirroring transference describes the psychological mechanism whereby “the other” serves as a mirror that reflects back to the person a sense of self-worth and value. A mirroring transference uses the affirming and positive responses of others so that a person then can see positive traits within themselves. The idealizing transference refers to a person’s need for “another” who will make them feel calm and comfortable. The other is idealized as somebody who is calm and soothing when the person cannot provide that on their own. The twinship/alter ego transference occurs when a person feels a sense of likeness with “an other.” These advances in psychoanalytic theory advance our understanding of how we internalize aspects of other people and use these internalizations in our own development.

The neuroscience of attachment was revealed in the study of the children abandoned in Romanian orphanages before the 1989 revolution. These children were placed in orphanages that lacked adequate staff, and they were subjected to profound psychosocial neglect. In the Bucharest Early Intervention Project, the effects of neglect were seen in children aged less than 30-96 months, in EEG data.⁴ Abnormalities were found in two aberrantly connected brain networks: a hyperconnected parieto-occipital network and a hypoconnected network between left temporal and distributed bilateral regions. This study provides the first evidence of the adverse effects of early psychosocial neglect on the wiring of the developing brain.

Neurochemistry has suggested the impact of oxytocin on the promotion of attachment. Oxytocin has been called the “cuddle hormone,” as it is stimulated in mothers to promote bonding with their infant. Many studies have examined the introduction of intranasal oxytocin increases bonding and trust with others, but recent meta-analyses challenge those findings.^5,6 Nevertheless, the process of bonding and attachment is thought to engage the mesocorticolimbic, nigrostriatal dopaminergic, and oxytocinergic systems. Tops and colleagues proposed that oxytocin facilitates a shift from ventral striatal “novelty processing” toward dorsal striatal “familiarity processing.”⁷ This shift to familiarity is thought to create secure internal working models. In addition, brain activity in specific regions, such as the right caudate, is correlated with romantic love.⁸ In summary, specific pathways and neurotransmitters underlie the emotional process of bonding and attachment.

However, it is Karl Friston, MD, who suggests a model of brain functioning that describes how we actually process our experiences of the world.⁹ Dr. Friston uses Bayesian modeling to describe how we interact and understand our world, describing the way we process information. Dr. Friston states that the process of inference that we use to discern our world is a process that uses Bayes’ theorem to update the probability for a specific hypothesis about our world. As more evidence or information becomes available, we update our internal models of the world. Predictive modeling is the term used in Bayesian terms to describe this process of continuous revision of our internal model of the world. Any new sensory input is compared to our current internal model, and if they do not match, our internal model of the world is updated and revised. Dr. Friston states: “As surprise is resolved, Bayesian model evidence is increased. This means that every living organism behaves as if it is a little statistician, analyzing its sensory data in exactly the same way that scientists evaluate the evidence for their hypotheses about how experimental data were caused. In this view, minimizing surprise is, literally, the search for evidence for one’s own existence.” This process of predictive modeling also can be applied to our internal models of other people, meaning that our internal model of another person is an iterative process that changes as the other person changes.

When our experience of the world and others fall into predictive patterns, we expect the “usual” responses from our world and from the people in it. This predictive processing makes it easier for us to understand our world, so that we do not have to continually analyze and reanalyze each event as a new experience. For example, a young child examines the waves as they crash on the shore. For a while, he will watch the waves but soon begins to recognize that there is a predictable pattern. With each ocean he visits, he will examine wave action and soon develop an internal model of what happens when the water reaches the shore. Similarly, when a young child has a secure and loving parent, he will expect security and love in his future relationships. On the other hand, the child who has been subjected to abuse and neglect has an internal working model of the other as nonreciprocal and perhaps irrelevant to their well-being. They will, therefore, have extreme difficulty in understanding the purpose or value of relationships. Their predictive model of the other reflects a lack of input in the case of neglect, or perverted input in the case of abuse. Their internal predictive model will require a great deal of therapeutic healthy inputs to be able to evolve to allow a healthy relationship with the other. This is the work of therapy.

When thinking about relationships, predictive processing makes clinical sense. In a committed partnership, each partner has a predictive model of their partner’s response to events/speech utterances/emotional displays. The prediction of the partner’s response is based on prior experience. This predictive model reduces the need to repeatedly reinterpret the partner’s actions. The partner is understood through an internal predictive model. When one partner changes their behavior, the other partner experiences the world/environment as disrupted or different. The couple, through an iterative process, can incorporate change and grow together. If the patient has an internalized model of a loving relationship, then they are more likely to find a partner who resonates with this internalized model. Using predictive modeling, we can understand how two people with their own internal models of each other interact. As one person approaches the other person, each internal model of the other person finds a “fit” with the behaviors of the other person. When a child with emotional deprivation approaches the other, the child perceives the other person in a way that fits with their prior experience of deprivation. It is an easy fit that requires little internal work, and the patient falls into a familiar relational pattern. This model of predictive processing explains why people repeatedly fall into similar familiar relationships: They recognize the relationship patterns. There is less predictive processing required, less emotional and cognitive work, and therefore less adjustment.

Psychotherapy helps patients by improving their understanding of the link between prior and current experience. Each piece of behavior is analyzed and compared with the patient’s internal model of the event. What neuroscience now provides is a deeper scientific understanding of this process. A neuroscience-based visualization of our internal models of other people can help us better describe the iterative process that occurs in therapeutic progress.

In summary, the processes of attachment and bonding occur through oxytocin-mediated caudate–dorsal striatum pathways. Bayesian predictive modeling describes the processes by which our internal models of others are shaped and refined, and underscores the work of our psychotherapies. Neuroscience is beginning to delineate the “where” and “how” of attachment and bonding, thus advancing our understanding of the attachment process and giving us a new language to describe the work of psychotherapy.
 

References

1. Bowlby J. “A Secure Base: Parent-Child Attachment and Healthy Human Development.” New York: Basic Books, 1988.

2. Speranza AM et al. Attach Hum Dev. 2017 Dec;19(6):613-34.

3. Kohut H. “How Does Analysis Cure?” Chicago: University of Chicago Press, 1984.

4. Stamoulis C et al. J Neurophysiol. 2017 Oct 1;118(4):2275-88.

5. Leng G and Ludwig M.Biol Psychiatry. 2016 Feb 1;79(3):243-50.

6. Leppanen J et al. Neurosci Biobehav Rev. 2017 Jul;78:125-44.

7. Tops M et al. Pharmacol Biochem Behav. 2014 Apr;119:39-48.

8. Acevedo BP et al. Soc Cogn Affect Neurosci. 2012 Feb;7(2):145-59.

9. Friston K. Entropy (Basel). 2012 Nov;14(11):2100-21.

The bonding process between individuals is essential to human life as we know it. The depth and strength of emotional bonds that we develop with other individuals are among the cardinal aspects of being human.

The strengths of the bonds that we form with others often are the most enduring aspects of our lives and can stretch back in time to include family members and friends who are no longer alive. The brain processes and neurochemicals involved in the bonding process are related to psychological processes using Bayesian theory. Abnormalities in attachment are described in terms of abnormal predictive models.

John Bowlby MD, and colleagues developed a psychological theory of early childhood attachment that shows the impact of different childhood experiences.¹ Over many decades, they conducted painstaking observations, trials, and retrials that elucidated specific types of attachment that reflect the child’s internal representations of the parent.

Dr. Bowlby described the mental representations of attachment as “the internal working models of expectations” about the maternal-child relationship. This internal model guides the child’s behaviors, attitudes, and expectations, and is constantly being revised and expanded as the child matures in order to adapt to increasingly complex relationships. More current research has shown that adults who have experienced extreme early childhood adversity develop odd or deficient descriptions of primary attachment relationships, now refined into a low-coherence CC category.² These children experience attachments that are characterized by feelings of emptiness, inconsistency, and fragmentation.

Object relations theory was created by Heinz Kohut, MD, to explain our internal models of others in psychoanalytic language.^{3 Dr.} Kohut expands the concept of transference describing three new transferential relationships: mirroring, idealized, and twinship transferences. A mirroring transference describes the psychological mechanism whereby “the other” serves as a mirror that reflects back to the person a sense of self-worth and value. A mirroring transference uses the affirming and positive responses of others so that a person then can see positive traits within themselves. The idealizing transference refers to a person’s need for “another” who will make them feel calm and comfortable. The other is idealized as somebody who is calm and soothing when the person cannot provide that on their own. The twinship/alter ego transference occurs when a person feels a sense of likeness with “an other.” These advances in psychoanalytic theory advance our understanding of how we internalize aspects of other people and use these internalizations in our own development.

The neuroscience of attachment was revealed in the study of the children abandoned in Romanian orphanages before the 1989 revolution. These children were placed in orphanages that lacked adequate staff, and they were subjected to profound psychosocial neglect. In the Bucharest Early Intervention Project, the effects of neglect were seen in children aged less than 30-96 months, in EEG data.⁴ Abnormalities were found in two aberrantly connected brain networks: a hyperconnected parieto-occipital network and a hypoconnected network between left temporal and distributed bilateral regions. This study provides the first evidence of the adverse effects of early psychosocial neglect on the wiring of the developing brain.

Neurochemistry has suggested the impact of oxytocin on the promotion of attachment. Oxytocin has been called the “cuddle hormone,” as it is stimulated in mothers to promote bonding with their infant. Many studies have examined the introduction of intranasal oxytocin increases bonding and trust with others, but recent meta-analyses challenge those findings.^5,6 Nevertheless, the process of bonding and attachment is thought to engage the mesocorticolimbic, nigrostriatal dopaminergic, and oxytocinergic systems. Tops and colleagues proposed that oxytocin facilitates a shift from ventral striatal “novelty processing” toward dorsal striatal “familiarity processing.”⁷ This shift to familiarity is thought to create secure internal working models. In addition, brain activity in specific regions, such as the right caudate, is correlated with romantic love.⁸ In summary, specific pathways and neurotransmitters underlie the emotional process of bonding and attachment.

However, it is Karl Friston, MD, who suggests a model of brain functioning that describes how we actually process our experiences of the world.⁹ Dr. Friston uses Bayesian modeling to describe how we interact and understand our world, describing the way we process information. Dr. Friston states that the process of inference that we use to discern our world is a process that uses Bayes’ theorem to update the probability for a specific hypothesis about our world. As more evidence or information becomes available, we update our internal models of the world. Predictive modeling is the term used in Bayesian terms to describe this process of continuous revision of our internal model of the world. Any new sensory input is compared to our current internal model, and if they do not match, our internal model of the world is updated and revised. Dr. Friston states: “As surprise is resolved, Bayesian model evidence is increased. This means that every living organism behaves as if it is a little statistician, analyzing its sensory data in exactly the same way that scientists evaluate the evidence for their hypotheses about how experimental data were caused. In this view, minimizing surprise is, literally, the search for evidence for one’s own existence.” This process of predictive modeling also can be applied to our internal models of other people, meaning that our internal model of another person is an iterative process that changes as the other person changes.

When our experience of the world and others fall into predictive patterns, we expect the “usual” responses from our world and from the people in it. This predictive processing makes it easier for us to understand our world, so that we do not have to continually analyze and reanalyze each event as a new experience. For example, a young child examines the waves as they crash on the shore. For a while, he will watch the waves but soon begins to recognize that there is a predictable pattern. With each ocean he visits, he will examine wave action and soon develop an internal model of what happens when the water reaches the shore. Similarly, when a young child has a secure and loving parent, he will expect security and love in his future relationships. On the other hand, the child who has been subjected to abuse and neglect has an internal working model of the other as nonreciprocal and perhaps irrelevant to their well-being. They will, therefore, have extreme difficulty in understanding the purpose or value of relationships. Their predictive model of the other reflects a lack of input in the case of neglect, or perverted input in the case of abuse. Their internal predictive model will require a great deal of therapeutic healthy inputs to be able to evolve to allow a healthy relationship with the other. This is the work of therapy.

When thinking about relationships, predictive processing makes clinical sense. In a committed partnership, each partner has a predictive model of their partner’s response to events/speech utterances/emotional displays. The prediction of the partner’s response is based on prior experience. This predictive model reduces the need to repeatedly reinterpret the partner’s actions. The partner is understood through an internal predictive model. When one partner changes their behavior, the other partner experiences the world/environment as disrupted or different. The couple, through an iterative process, can incorporate change and grow together. If the patient has an internalized model of a loving relationship, then they are more likely to find a partner who resonates with this internalized model. Using predictive modeling, we can understand how two people with their own internal models of each other interact. As one person approaches the other person, each internal model of the other person finds a “fit” with the behaviors of the other person. When a child with emotional deprivation approaches the other, the child perceives the other person in a way that fits with their prior experience of deprivation. It is an easy fit that requires little internal work, and the patient falls into a familiar relational pattern. This model of predictive processing explains why people repeatedly fall into similar familiar relationships: They recognize the relationship patterns. There is less predictive processing required, less emotional and cognitive work, and therefore less adjustment.

Psychotherapy helps patients by improving their understanding of the link between prior and current experience. Each piece of behavior is analyzed and compared with the patient’s internal model of the event. What neuroscience now provides is a deeper scientific understanding of this process. A neuroscience-based visualization of our internal models of other people can help us better describe the iterative process that occurs in therapeutic progress.

In summary, the processes of attachment and bonding occur through oxytocin-mediated caudate–dorsal striatum pathways. Bayesian predictive modeling describes the processes by which our internal models of others are shaped and refined, and underscores the work of our psychotherapies. Neuroscience is beginning to delineate the “where” and “how” of attachment and bonding, thus advancing our understanding of the attachment process and giving us a new language to describe the work of psychotherapy.
 

References

1. Bowlby J. “A Secure Base: Parent-Child Attachment and Healthy Human Development.” New York: Basic Books, 1988.

2. Speranza AM et al. Attach Hum Dev. 2017 Dec;19(6):613-34.

3. Kohut H. “How Does Analysis Cure?” Chicago: University of Chicago Press, 1984.

4. Stamoulis C et al. J Neurophysiol. 2017 Oct 1;118(4):2275-88.

5. Leng G and Ludwig M.Biol Psychiatry. 2016 Feb 1;79(3):243-50.

6. Leppanen J et al. Neurosci Biobehav Rev. 2017 Jul;78:125-44.

7. Tops M et al. Pharmacol Biochem Behav. 2014 Apr;119:39-48.

8. Acevedo BP et al. Soc Cogn Affect Neurosci. 2012 Feb;7(2):145-59.

9. Friston K. Entropy (Basel). 2012 Nov;14(11):2100-21.

Our understanding of pain mechanisms continues to evolve and, accordingly, so do our treatment strategies. The fundamental differences between acute and chronic pain were only recently recognized; this lack of recognition led to the application of acute pain treatments to chronic pain, contributing to the opioid epidemic in the United States.

With the diminishing emphasis on opioid medications, researchers are exploring other pharmacologic modalities for treating pain. Many nonopioid psychiatric medications are used off-label for the treatment of pain. Psychiatric medications play a larger role in the management of pain as pain becomes more chronic (Table 1¹). For simplicity, acute pain may be seen as nociception colored by emotions, and chronic pain as emotions colored by nociception. Protracted pain connects those extremes with a diminishing role of nociception and an increasing role of emotion,¹ which may increase the potential role of psychiatric medications, including antipsychotics.

In this article, I discuss the potential role of dopamine in the perception of pain, and review the potential use of first- and second-generation antipsychotics for treating various pain syndromes.

Role of dopamine in pain

There is increasing interest in exploring antipsychotics to treat chronic pain² because dopamine dysfunction is part of pathological pain perception. Excess dopamine is associated with headaches (dopamine hypersensitivity hypothesis^3,4) and dopamine dysfunction is a part of posttraumatic stress disorder (PTSD),⁵ dissociation,⁶ paranoia,⁷ and catastrophizing.⁸ Somatic psychosis, like any psychosis, can be based on dopamine pathology. Dopaminergic neurons affect nociceptive function in the spinal dorsal horn,⁹ and dopamine receptors are altered in atypical facial pain,¹⁰ burning mouth syndrome,¹¹ and fibromyalgia.¹²

In normal circumstances, dopamine is fundamentally a protective neurotransmitter. In acute pain, dopamine is powerfully released, making the pain bearable. A patient may describe acute pain as seeming “like it was not happening to me” or “it was like a dream”; both are examples of dopamine-caused dissociation and a possible prediction of subsequent chronification. In chronic pain, pathological mechanisms settle in and take root; therefore, keeping protective dopamine levels high becomes a priority. This is especially common in patients who have experienced abuse or PTSD. The only natural way to keep dopamine up for prolonged periods of time is to decrease pain and stress thresholds. Both phenomena are readily observed in patients with pain. In extreme cases, self-mutilation and involvement in conflicts become pathologically gratifying.

The dopaminergic system is essential for pain control with a tissue injury.¹³ It becomes pathologically stimulated and increasingly dysfunctional as algopathy (a pathological pain perception) develops. At the same time, a flood or drought of any neurotransmitter is equally bad and may produce similar clinical pictures. Both a lack of and excess of dopamine are associated with pain.¹⁴ This is why opposite treatments may be beneficial in different patients with chronic pain. As an example, the use of stimulants¹⁵ and bupropion¹⁶ has been reported in the treatment of abdominal pain. And, reversely, antipsychotics, especially first-generation agents, may be associated with chronic (tardive) pain, including orofacial and genital pain.¹⁷

First-generation antipsychotics

First-generation antipsychotics (FGAs) have been used to treat various nonpsychiatric conditions (Table 2). Although they are powerful D2 receptor inhibitors, FGAs lack the intrinsic ability to counteract the unwanted adverse effects of strong inhibition. As a result, movement disorders and prolactinemia are commonly induced by FGAs. The most dangerous consequence of treatment with these agents is neuroleptic malignant syndrome (NMS).

Continue to: Haloperidol

Haloperidol is prescribed widely by nonpsychiatrists, primarily to treat agitation. Intravenous haloperidol has been used for the abortive treatment of headaches.¹⁸ Paradoxically, IV haloperidol is less likely to induce extrapyramidal symptoms (EPS) than the oral formulation because of a more pronounced anticholinergic action in IV use. Haloperidol can help relieve gastroparesis and nausea, especially in IV administration,¹⁹ but prolonged oral administration is associated with unwanted movement problems and should be avoided.²⁰

Chlorpromazine is more anticholinergic than haloperidol. It can be used in the abortive treatment of headaches (preferably via IV and IM administration), nausea, hiccups, porphyria, and serotonin syndrome, but it is very sedating and frequently produces hypotension, dangerous QT prolongation, and sensations of thought-blocking.²¹

Pimozide is reported to help with skin picking, trichotillomania, and somatic hallucinations.²²

Droperidol, promethazine, and prochlorperazine are used off-label to treat nausea and headaches. Primary care clinicians may not be aware that these commonly used medications are antipsychotics. Similar to other FGAs, these 3 agents may produce NMS and tardive dyskinesia (TD). The same applies to the prokinetic drug metoclopramide.

Second-generation antipsychotics

Second-generation antipsychotics (SGAs) work with various serotonin receptors, offsetting and enhancing the antipsychotic function of dopamine blockade. This diminishes but does not eliminate EPS and the risk of TD. Fortunately, the risk of NMS is lower with SGAs than with FGAs. Many SGAs are FDA-approved for treating schizophrenia and other psychiatric disorders, and some have relevance for pain management (Table 3). Many SGAs help with depressive symptoms and are powerful mood stabilizers. As such, they may diminish central over-firing of dopaminergic and serotonergic neurons involved in the pain cascade, which in turn decreases pain transmission and perception. The downside is that in general, SGAs increase the risk of diabetes and hyperlipidemia.

Continue to: Risperidone

Risperidone was the second FDA-approved SGA. Pain practitioners primarily prescribe it for treatmeant-resistant headaches, but patients with fibromyalgia and those with phantom and thalamic pain also may respond. Because risperidone’s properties are similar to that of many FGAs, it may potently cause EPS, TD, and prolactinemia. Neuroleptic malignant syndrome also has been reported.²³

Ziprasidone is frequently overlooked by clinicians who treat pain. Although ziprasidone may be sedating, it is powerful as both a preventive and abortive (in an IM formulation) agent for treatment-resistant headaches. This might be attributed to its effects on the 5HT9 receptor. It is approved for treating bipolar depression and has been prescribed to effectively treat anxiety. For patients receiving ziprasidone, QT prolongation needs to be monitored closely.²⁴

Olanzapine was modeled after clozapine and is effective as a mood stabilizer and an antianxiety, antipsychotic, and sleep-promoting medication. It has a useful “mellowing” effect and helps with central pain syndrome management. Patients with fibromyalgia respond well; in some cases, patients with phantom and thalamic pain also respond. Among SGAs prescribed to treat chronic pain, olanzapine has the most published studies. However, the downside is the risk of severe weight gain and diabetes. Usually, if a patient is already overweight, they gain less, but these patients typically are concerned about any additional weight gain.²⁵

Aripiprazole is a partial dopamine agonist. It increases dopamine function in the prefrontal cortex, and by doing so it possibly improves cognition, mental acuity, goal-oriented activity, and attention. At the same time, it decreases dopamine activity in the basal ganglia and limbic system, improving catastrophizing, paranoia, abnormal pain perception, and multiple homeostasis functions. This combination of effects can be invaluable for some patients, but depending on individual susceptibility, aripiprazole might be too activating (causing agitation and akathisia) or too sedating.²⁶

Brexpiprazole is a relative of aripiprazole, but for some patients it is better tolerated, and compliance with this medication usually is good. It partially antagonizes the D2 and 5HT1A receptors while antagonizing the 5HT2A receptors (which decreases the dopamine release in the striatum) and mimics the mechanism of action of an antidepressant. Through alpha-1-adrenergic receptor antagonism, it reduces EPS. All these effects are also part of the mechanisms of action of quetiapine, clozapine, and iloperidone, but brexpiprazole is considered to be the most alpha-1 antagonistic, which is a mechanism of action of other potential pain-controlling medications such as clonidine and tizanidine. In patients with pain who have an overactive noradrenergic system, this property may be beneficial. Its major problem stems from cytochrome P450 2D6 (CYP2D6) enzyme-dependent metabolism, which causes an approximately 5-fold increase in brexpiprazole blood level in poor CYP2D6 metabolizers. Therefore, combining brexpiprazole with CYP2D6 inhibitors such as fluoxetine, paroxetine, and duloxetine would be unwise. Aripiprazole and brexpiprazole are less associated with diabetes and sexual adverse effects than many other SGAs.²⁷

Continue to: Asenapine

Asenapine is an underutilized antipsychotic. Its mechanism of action spans multiple receptors and is less specific in individual receptor activity than other dopamine blockers. It is administered under the tongue due to poor absorption when swallowed, and its molecule has an anesthetic property that causes mouth and tongue numbness/paresthesia. This function may help patients with orofacial pain. Significant somnolence and weight gain (although less than with olanzapine) limit its use. Some patients cannot tolerate the taste.²⁸

Quetiapine is prescribed rather frequently due to its significant antianxiety effect. It is also reported to be beneficial in pain control.²⁹ Weight gain may be severe. In doses smaller than typically administered to patients with bipolar disorder or schizophrenia, quetiapine is widely prescribed off-label for sleep. In lower doses, it acts primarily as an antihistamine (hence the sedation), but at an increased dose it activates the adrenergic system, which offsets sedation. Quetiapine antagonizes H1 histamine and 5HT2C receptors, which may explain its associated sedation and weight gain. Constipation is common. Due to its relatively low risk for EPS, quetiapine is safer to prescribe in patients with Parkinson’s disease. It can cause withdrawal if abruptly discontinued, so it needs to be tapered. Quetiapine has become a commodity in the prison population because of its ability to diminish anxiety symptoms.³⁰ There are also reports that quetiapine may be associated with pain induction. This is consistent with the above-mentioned phenomenon that pain is associated with both the lack and excess of dopaminergic function.³¹ Pain perception is reported to be diminished in patients with schizophrenia,³² and quetiapine may increase pain just by improving cognition.

Cariprazine is typically well tolerated because of its benign metabolic profile. It does not increase the QT interval and is not sedating. Cariprazine is a D2 and D3 partial receptor agonist. This allows the medication to inhibit overstimulated dopamine receptors (a desirable effect in pain management) and induces them when the endogenous dopamine level is low (helping with cognition, volition, and attention). Pro-cognitive effects are always beneficial for patients with pain. Cariprazine produces less EPS due to more ventral striatum vs dorsal striatum activity. Mood improvement caused by this medication is attributed to its 5HT2A, 5HT2B, and 5HT2C inverse agonism, which modulates the serotonergic system. Cariprazine will likely have a positive future in pain management because it has shown efficacy in the chronic stress model.³³

A complex condition

No single medication or group of medications may be exclusively relied on for treating patients with chronic pain. Identifying alternatives to opioids for treating pain brings more attention to centrally-acting medications that may aid in the stabilization of the nervous system, which can decrease pathological pain perception and help patients cope with chronic painful conditions.

Bottom Line

Antipsychotics may be a valuable asset in the treatment of chronic pain, offering a potential alternative to prescribing opioids for pain. More research is needed to identify specific ways of using dopamine blockade or dopamine enhancement to help patients with chronic pain.

Continue to: Related Resource

• Tripathi A. Antipsychotics for migraines, cluster headaches, and nausea. Current Psychiatry. 2013;12(2):E1-E4.

Drug Brand Names

Aripiprazole • Abilify
Asenapine • Saphris
Brexpiprazole • Rexulti
Bupropion • Wellbutrin, Zyban
Cariprazine • Vraylar
Chlorpromazine • Thorazine
Clonidine • Catapres
Clozapine • Clozaril
Droperidol • Inapsine
Duloxetine • Cymbalta
Fluoxetine • Prozac
Haloperidol • Haldol
Iloperidone • Fanapt
Metoclopramide • Reglan
Olanzapine • Zyprexa
Paroxetine • Paxil
Pimozide • Orap
Prochlorperazine • Compazine
Promethazine • Phenergan
Quetiapine • Seroquel
Risperidone • Risperdal
Tizanidine • Zanaflex
Ziprasidone • Geodon

Our understanding of pain mechanisms continues to evolve and, accordingly, so do our treatment strategies. The fundamental differences between acute and chronic pain were only recently recognized; this lack of recognition led to the application of acute pain treatments to chronic pain, contributing to the opioid epidemic in the United States.

With the diminishing emphasis on opioid medications, researchers are exploring other pharmacologic modalities for treating pain. Many nonopioid psychiatric medications are used off-label for the treatment of pain. Psychiatric medications play a larger role in the management of pain as pain becomes more chronic (Table 1¹). For simplicity, acute pain may be seen as nociception colored by emotions, and chronic pain as emotions colored by nociception. Protracted pain connects those extremes with a diminishing role of nociception and an increasing role of emotion,¹ which may increase the potential role of psychiatric medications, including antipsychotics.

In this article, I discuss the potential role of dopamine in the perception of pain, and review the potential use of first- and second-generation antipsychotics for treating various pain syndromes.

Role of dopamine in pain

There is increasing interest in exploring antipsychotics to treat chronic pain² because dopamine dysfunction is part of pathological pain perception. Excess dopamine is associated with headaches (dopamine hypersensitivity hypothesis^3,4) and dopamine dysfunction is a part of posttraumatic stress disorder (PTSD),⁵ dissociation,⁶ paranoia,⁷ and catastrophizing.⁸ Somatic psychosis, like any psychosis, can be based on dopamine pathology. Dopaminergic neurons affect nociceptive function in the spinal dorsal horn,⁹ and dopamine receptors are altered in atypical facial pain,¹⁰ burning mouth syndrome,¹¹ and fibromyalgia.¹²

In normal circumstances, dopamine is fundamentally a protective neurotransmitter. In acute pain, dopamine is powerfully released, making the pain bearable. A patient may describe acute pain as seeming “like it was not happening to me” or “it was like a dream”; both are examples of dopamine-caused dissociation and a possible prediction of subsequent chronification. In chronic pain, pathological mechanisms settle in and take root; therefore, keeping protective dopamine levels high becomes a priority. This is especially common in patients who have experienced abuse or PTSD. The only natural way to keep dopamine up for prolonged periods of time is to decrease pain and stress thresholds. Both phenomena are readily observed in patients with pain. In extreme cases, self-mutilation and involvement in conflicts become pathologically gratifying.

The dopaminergic system is essential for pain control with a tissue injury.¹³ It becomes pathologically stimulated and increasingly dysfunctional as algopathy (a pathological pain perception) develops. At the same time, a flood or drought of any neurotransmitter is equally bad and may produce similar clinical pictures. Both a lack of and excess of dopamine are associated with pain.¹⁴ This is why opposite treatments may be beneficial in different patients with chronic pain. As an example, the use of stimulants¹⁵ and bupropion¹⁶ has been reported in the treatment of abdominal pain. And, reversely, antipsychotics, especially first-generation agents, may be associated with chronic (tardive) pain, including orofacial and genital pain.¹⁷

First-generation antipsychotics

First-generation antipsychotics (FGAs) have been used to treat various nonpsychiatric conditions (Table 2). Although they are powerful D2 receptor inhibitors, FGAs lack the intrinsic ability to counteract the unwanted adverse effects of strong inhibition. As a result, movement disorders and prolactinemia are commonly induced by FGAs. The most dangerous consequence of treatment with these agents is neuroleptic malignant syndrome (NMS).

Continue to: Haloperidol

Haloperidol is prescribed widely by nonpsychiatrists, primarily to treat agitation. Intravenous haloperidol has been used for the abortive treatment of headaches.¹⁸ Paradoxically, IV haloperidol is less likely to induce extrapyramidal symptoms (EPS) than the oral formulation because of a more pronounced anticholinergic action in IV use. Haloperidol can help relieve gastroparesis and nausea, especially in IV administration,¹⁹ but prolonged oral administration is associated with unwanted movement problems and should be avoided.²⁰

Chlorpromazine is more anticholinergic than haloperidol. It can be used in the abortive treatment of headaches (preferably via IV and IM administration), nausea, hiccups, porphyria, and serotonin syndrome, but it is very sedating and frequently produces hypotension, dangerous QT prolongation, and sensations of thought-blocking.²¹

Pimozide is reported to help with skin picking, trichotillomania, and somatic hallucinations.²²

Droperidol, promethazine, and prochlorperazine are used off-label to treat nausea and headaches. Primary care clinicians may not be aware that these commonly used medications are antipsychotics. Similar to other FGAs, these 3 agents may produce NMS and tardive dyskinesia (TD). The same applies to the prokinetic drug metoclopramide.

Second-generation antipsychotics

Second-generation antipsychotics (SGAs) work with various serotonin receptors, offsetting and enhancing the antipsychotic function of dopamine blockade. This diminishes but does not eliminate EPS and the risk of TD. Fortunately, the risk of NMS is lower with SGAs than with FGAs. Many SGAs are FDA-approved for treating schizophrenia and other psychiatric disorders, and some have relevance for pain management (Table 3). Many SGAs help with depressive symptoms and are powerful mood stabilizers. As such, they may diminish central over-firing of dopaminergic and serotonergic neurons involved in the pain cascade, which in turn decreases pain transmission and perception. The downside is that in general, SGAs increase the risk of diabetes and hyperlipidemia.

Continue to: Risperidone

Risperidone was the second FDA-approved SGA. Pain practitioners primarily prescribe it for treatmeant-resistant headaches, but patients with fibromyalgia and those with phantom and thalamic pain also may respond. Because risperidone’s properties are similar to that of many FGAs, it may potently cause EPS, TD, and prolactinemia. Neuroleptic malignant syndrome also has been reported.²³

Ziprasidone is frequently overlooked by clinicians who treat pain. Although ziprasidone may be sedating, it is powerful as both a preventive and abortive (in an IM formulation) agent for treatment-resistant headaches. This might be attributed to its effects on the 5HT9 receptor. It is approved for treating bipolar depression and has been prescribed to effectively treat anxiety. For patients receiving ziprasidone, QT prolongation needs to be monitored closely.²⁴

Olanzapine was modeled after clozapine and is effective as a mood stabilizer and an antianxiety, antipsychotic, and sleep-promoting medication. It has a useful “mellowing” effect and helps with central pain syndrome management. Patients with fibromyalgia respond well; in some cases, patients with phantom and thalamic pain also respond. Among SGAs prescribed to treat chronic pain, olanzapine has the most published studies. However, the downside is the risk of severe weight gain and diabetes. Usually, if a patient is already overweight, they gain less, but these patients typically are concerned about any additional weight gain.²⁵

Aripiprazole is a partial dopamine agonist. It increases dopamine function in the prefrontal cortex, and by doing so it possibly improves cognition, mental acuity, goal-oriented activity, and attention. At the same time, it decreases dopamine activity in the basal ganglia and limbic system, improving catastrophizing, paranoia, abnormal pain perception, and multiple homeostasis functions. This combination of effects can be invaluable for some patients, but depending on individual susceptibility, aripiprazole might be too activating (causing agitation and akathisia) or too sedating.²⁶

Brexpiprazole is a relative of aripiprazole, but for some patients it is better tolerated, and compliance with this medication usually is good. It partially antagonizes the D2 and 5HT1A receptors while antagonizing the 5HT2A receptors (which decreases the dopamine release in the striatum) and mimics the mechanism of action of an antidepressant. Through alpha-1-adrenergic receptor antagonism, it reduces EPS. All these effects are also part of the mechanisms of action of quetiapine, clozapine, and iloperidone, but brexpiprazole is considered to be the most alpha-1 antagonistic, which is a mechanism of action of other potential pain-controlling medications such as clonidine and tizanidine. In patients with pain who have an overactive noradrenergic system, this property may be beneficial. Its major problem stems from cytochrome P450 2D6 (CYP2D6) enzyme-dependent metabolism, which causes an approximately 5-fold increase in brexpiprazole blood level in poor CYP2D6 metabolizers. Therefore, combining brexpiprazole with CYP2D6 inhibitors such as fluoxetine, paroxetine, and duloxetine would be unwise. Aripiprazole and brexpiprazole are less associated with diabetes and sexual adverse effects than many other SGAs.²⁷

Continue to: Asenapine

Asenapine is an underutilized antipsychotic. Its mechanism of action spans multiple receptors and is less specific in individual receptor activity than other dopamine blockers. It is administered under the tongue due to poor absorption when swallowed, and its molecule has an anesthetic property that causes mouth and tongue numbness/paresthesia. This function may help patients with orofacial pain. Significant somnolence and weight gain (although less than with olanzapine) limit its use. Some patients cannot tolerate the taste.²⁸

Quetiapine is prescribed rather frequently due to its significant antianxiety effect. It is also reported to be beneficial in pain control.²⁹ Weight gain may be severe. In doses smaller than typically administered to patients with bipolar disorder or schizophrenia, quetiapine is widely prescribed off-label for sleep. In lower doses, it acts primarily as an antihistamine (hence the sedation), but at an increased dose it activates the adrenergic system, which offsets sedation. Quetiapine antagonizes H1 histamine and 5HT2C receptors, which may explain its associated sedation and weight gain. Constipation is common. Due to its relatively low risk for EPS, quetiapine is safer to prescribe in patients with Parkinson’s disease. It can cause withdrawal if abruptly discontinued, so it needs to be tapered. Quetiapine has become a commodity in the prison population because of its ability to diminish anxiety symptoms.³⁰ There are also reports that quetiapine may be associated with pain induction. This is consistent with the above-mentioned phenomenon that pain is associated with both the lack and excess of dopaminergic function.³¹ Pain perception is reported to be diminished in patients with schizophrenia,³² and quetiapine may increase pain just by improving cognition.

Cariprazine is typically well tolerated because of its benign metabolic profile. It does not increase the QT interval and is not sedating. Cariprazine is a D2 and D3 partial receptor agonist. This allows the medication to inhibit overstimulated dopamine receptors (a desirable effect in pain management) and induces them when the endogenous dopamine level is low (helping with cognition, volition, and attention). Pro-cognitive effects are always beneficial for patients with pain. Cariprazine produces less EPS due to more ventral striatum vs dorsal striatum activity. Mood improvement caused by this medication is attributed to its 5HT2A, 5HT2B, and 5HT2C inverse agonism, which modulates the serotonergic system. Cariprazine will likely have a positive future in pain management because it has shown efficacy in the chronic stress model.³³

A complex condition

No single medication or group of medications may be exclusively relied on for treating patients with chronic pain. Identifying alternatives to opioids for treating pain brings more attention to centrally-acting medications that may aid in the stabilization of the nervous system, which can decrease pathological pain perception and help patients cope with chronic painful conditions.

Bottom Line

Antipsychotics may be a valuable asset in the treatment of chronic pain, offering a potential alternative to prescribing opioids for pain. More research is needed to identify specific ways of using dopamine blockade or dopamine enhancement to help patients with chronic pain.

Continue to: Related Resource

• Tripathi A. Antipsychotics for migraines, cluster headaches, and nausea. Current Psychiatry. 2013;12(2):E1-E4.

Drug Brand Names

Aripiprazole • Abilify
Asenapine • Saphris
Brexpiprazole • Rexulti
Bupropion • Wellbutrin, Zyban
Cariprazine • Vraylar
Chlorpromazine • Thorazine
Clonidine • Catapres
Clozapine • Clozaril
Droperidol • Inapsine
Duloxetine • Cymbalta
Fluoxetine • Prozac
Haloperidol • Haldol
Iloperidone • Fanapt
Metoclopramide • Reglan
Olanzapine • Zyprexa
Paroxetine • Paxil
Pimozide • Orap
Prochlorperazine • Compazine
Promethazine • Phenergan
Quetiapine • Seroquel
Risperidone • Risperdal
Tizanidine • Zanaflex
Ziprasidone • Geodon

Our understanding of pain mechanisms continues to evolve and, accordingly, so do our treatment strategies. The fundamental differences between acute and chronic pain were only recently recognized; this lack of recognition led to the application of acute pain treatments to chronic pain, contributing to the opioid epidemic in the United States.

With the diminishing emphasis on opioid medications, researchers are exploring other pharmacologic modalities for treating pain. Many nonopioid psychiatric medications are used off-label for the treatment of pain. Psychiatric medications play a larger role in the management of pain as pain becomes more chronic (Table 1¹). For simplicity, acute pain may be seen as nociception colored by emotions, and chronic pain as emotions colored by nociception. Protracted pain connects those extremes with a diminishing role of nociception and an increasing role of emotion,¹ which may increase the potential role of psychiatric medications, including antipsychotics.

In this article, I discuss the potential role of dopamine in the perception of pain, and review the potential use of first- and second-generation antipsychotics for treating various pain syndromes.

Role of dopamine in pain

There is increasing interest in exploring antipsychotics to treat chronic pain² because dopamine dysfunction is part of pathological pain perception. Excess dopamine is associated with headaches (dopamine hypersensitivity hypothesis^3,4) and dopamine dysfunction is a part of posttraumatic stress disorder (PTSD),⁵ dissociation,⁶ paranoia,⁷ and catastrophizing.⁸ Somatic psychosis, like any psychosis, can be based on dopamine pathology. Dopaminergic neurons affect nociceptive function in the spinal dorsal horn,⁹ and dopamine receptors are altered in atypical facial pain,¹⁰ burning mouth syndrome,¹¹ and fibromyalgia.¹²

In normal circumstances, dopamine is fundamentally a protective neurotransmitter. In acute pain, dopamine is powerfully released, making the pain bearable. A patient may describe acute pain as seeming “like it was not happening to me” or “it was like a dream”; both are examples of dopamine-caused dissociation and a possible prediction of subsequent chronification. In chronic pain, pathological mechanisms settle in and take root; therefore, keeping protective dopamine levels high becomes a priority. This is especially common in patients who have experienced abuse or PTSD. The only natural way to keep dopamine up for prolonged periods of time is to decrease pain and stress thresholds. Both phenomena are readily observed in patients with pain. In extreme cases, self-mutilation and involvement in conflicts become pathologically gratifying.

The dopaminergic system is essential for pain control with a tissue injury.¹³ It becomes pathologically stimulated and increasingly dysfunctional as algopathy (a pathological pain perception) develops. At the same time, a flood or drought of any neurotransmitter is equally bad and may produce similar clinical pictures. Both a lack of and excess of dopamine are associated with pain.¹⁴ This is why opposite treatments may be beneficial in different patients with chronic pain. As an example, the use of stimulants¹⁵ and bupropion¹⁶ has been reported in the treatment of abdominal pain. And, reversely, antipsychotics, especially first-generation agents, may be associated with chronic (tardive) pain, including orofacial and genital pain.¹⁷

First-generation antipsychotics

First-generation antipsychotics (FGAs) have been used to treat various nonpsychiatric conditions (Table 2). Although they are powerful D2 receptor inhibitors, FGAs lack the intrinsic ability to counteract the unwanted adverse effects of strong inhibition. As a result, movement disorders and prolactinemia are commonly induced by FGAs. The most dangerous consequence of treatment with these agents is neuroleptic malignant syndrome (NMS).

Continue to: Haloperidol

Haloperidol is prescribed widely by nonpsychiatrists, primarily to treat agitation. Intravenous haloperidol has been used for the abortive treatment of headaches.¹⁸ Paradoxically, IV haloperidol is less likely to induce extrapyramidal symptoms (EPS) than the oral formulation because of a more pronounced anticholinergic action in IV use. Haloperidol can help relieve gastroparesis and nausea, especially in IV administration,¹⁹ but prolonged oral administration is associated with unwanted movement problems and should be avoided.²⁰

Chlorpromazine is more anticholinergic than haloperidol. It can be used in the abortive treatment of headaches (preferably via IV and IM administration), nausea, hiccups, porphyria, and serotonin syndrome, but it is very sedating and frequently produces hypotension, dangerous QT prolongation, and sensations of thought-blocking.²¹

Pimozide is reported to help with skin picking, trichotillomania, and somatic hallucinations.²²

Droperidol, promethazine, and prochlorperazine are used off-label to treat nausea and headaches. Primary care clinicians may not be aware that these commonly used medications are antipsychotics. Similar to other FGAs, these 3 agents may produce NMS and tardive dyskinesia (TD). The same applies to the prokinetic drug metoclopramide.

Second-generation antipsychotics

Second-generation antipsychotics (SGAs) work with various serotonin receptors, offsetting and enhancing the antipsychotic function of dopamine blockade. This diminishes but does not eliminate EPS and the risk of TD. Fortunately, the risk of NMS is lower with SGAs than with FGAs. Many SGAs are FDA-approved for treating schizophrenia and other psychiatric disorders, and some have relevance for pain management (Table 3). Many SGAs help with depressive symptoms and are powerful mood stabilizers. As such, they may diminish central over-firing of dopaminergic and serotonergic neurons involved in the pain cascade, which in turn decreases pain transmission and perception. The downside is that in general, SGAs increase the risk of diabetes and hyperlipidemia.

Continue to: Risperidone

Risperidone was the second FDA-approved SGA. Pain practitioners primarily prescribe it for treatmeant-resistant headaches, but patients with fibromyalgia and those with phantom and thalamic pain also may respond. Because risperidone’s properties are similar to that of many FGAs, it may potently cause EPS, TD, and prolactinemia. Neuroleptic malignant syndrome also has been reported.²³

Ziprasidone is frequently overlooked by clinicians who treat pain. Although ziprasidone may be sedating, it is powerful as both a preventive and abortive (in an IM formulation) agent for treatment-resistant headaches. This might be attributed to its effects on the 5HT9 receptor. It is approved for treating bipolar depression and has been prescribed to effectively treat anxiety. For patients receiving ziprasidone, QT prolongation needs to be monitored closely.²⁴

Olanzapine was modeled after clozapine and is effective as a mood stabilizer and an antianxiety, antipsychotic, and sleep-promoting medication. It has a useful “mellowing” effect and helps with central pain syndrome management. Patients with fibromyalgia respond well; in some cases, patients with phantom and thalamic pain also respond. Among SGAs prescribed to treat chronic pain, olanzapine has the most published studies. However, the downside is the risk of severe weight gain and diabetes. Usually, if a patient is already overweight, they gain less, but these patients typically are concerned about any additional weight gain.²⁵

Aripiprazole is a partial dopamine agonist. It increases dopamine function in the prefrontal cortex, and by doing so it possibly improves cognition, mental acuity, goal-oriented activity, and attention. At the same time, it decreases dopamine activity in the basal ganglia and limbic system, improving catastrophizing, paranoia, abnormal pain perception, and multiple homeostasis functions. This combination of effects can be invaluable for some patients, but depending on individual susceptibility, aripiprazole might be too activating (causing agitation and akathisia) or too sedating.²⁶

Brexpiprazole is a relative of aripiprazole, but for some patients it is better tolerated, and compliance with this medication usually is good. It partially antagonizes the D2 and 5HT1A receptors while antagonizing the 5HT2A receptors (which decreases the dopamine release in the striatum) and mimics the mechanism of action of an antidepressant. Through alpha-1-adrenergic receptor antagonism, it reduces EPS. All these effects are also part of the mechanisms of action of quetiapine, clozapine, and iloperidone, but brexpiprazole is considered to be the most alpha-1 antagonistic, which is a mechanism of action of other potential pain-controlling medications such as clonidine and tizanidine. In patients with pain who have an overactive noradrenergic system, this property may be beneficial. Its major problem stems from cytochrome P450 2D6 (CYP2D6) enzyme-dependent metabolism, which causes an approximately 5-fold increase in brexpiprazole blood level in poor CYP2D6 metabolizers. Therefore, combining brexpiprazole with CYP2D6 inhibitors such as fluoxetine, paroxetine, and duloxetine would be unwise. Aripiprazole and brexpiprazole are less associated with diabetes and sexual adverse effects than many other SGAs.²⁷

Continue to: Asenapine

Asenapine is an underutilized antipsychotic. Its mechanism of action spans multiple receptors and is less specific in individual receptor activity than other dopamine blockers. It is administered under the tongue due to poor absorption when swallowed, and its molecule has an anesthetic property that causes mouth and tongue numbness/paresthesia. This function may help patients with orofacial pain. Significant somnolence and weight gain (although less than with olanzapine) limit its use. Some patients cannot tolerate the taste.²⁸

Quetiapine is prescribed rather frequently due to its significant antianxiety effect. It is also reported to be beneficial in pain control.²⁹ Weight gain may be severe. In doses smaller than typically administered to patients with bipolar disorder or schizophrenia, quetiapine is widely prescribed off-label for sleep. In lower doses, it acts primarily as an antihistamine (hence the sedation), but at an increased dose it activates the adrenergic system, which offsets sedation. Quetiapine antagonizes H1 histamine and 5HT2C receptors, which may explain its associated sedation and weight gain. Constipation is common. Due to its relatively low risk for EPS, quetiapine is safer to prescribe in patients with Parkinson’s disease. It can cause withdrawal if abruptly discontinued, so it needs to be tapered. Quetiapine has become a commodity in the prison population because of its ability to diminish anxiety symptoms.³⁰ There are also reports that quetiapine may be associated with pain induction. This is consistent with the above-mentioned phenomenon that pain is associated with both the lack and excess of dopaminergic function.³¹ Pain perception is reported to be diminished in patients with schizophrenia,³² and quetiapine may increase pain just by improving cognition.

Cariprazine is typically well tolerated because of its benign metabolic profile. It does not increase the QT interval and is not sedating. Cariprazine is a D2 and D3 partial receptor agonist. This allows the medication to inhibit overstimulated dopamine receptors (a desirable effect in pain management) and induces them when the endogenous dopamine level is low (helping with cognition, volition, and attention). Pro-cognitive effects are always beneficial for patients with pain. Cariprazine produces less EPS due to more ventral striatum vs dorsal striatum activity. Mood improvement caused by this medication is attributed to its 5HT2A, 5HT2B, and 5HT2C inverse agonism, which modulates the serotonergic system. Cariprazine will likely have a positive future in pain management because it has shown efficacy in the chronic stress model.³³

A complex condition

No single medication or group of medications may be exclusively relied on for treating patients with chronic pain. Identifying alternatives to opioids for treating pain brings more attention to centrally-acting medications that may aid in the stabilization of the nervous system, which can decrease pathological pain perception and help patients cope with chronic painful conditions.

Bottom Line

Antipsychotics may be a valuable asset in the treatment of chronic pain, offering a potential alternative to prescribing opioids for pain. More research is needed to identify specific ways of using dopamine blockade or dopamine enhancement to help patients with chronic pain.

Continue to: Related Resource

• Tripathi A. Antipsychotics for migraines, cluster headaches, and nausea. Current Psychiatry. 2013;12(2):E1-E4.

Drug Brand Names

Aripiprazole • Abilify
Asenapine • Saphris
Brexpiprazole • Rexulti
Bupropion • Wellbutrin, Zyban
Cariprazine • Vraylar
Chlorpromazine • Thorazine
Clonidine • Catapres
Clozapine • Clozaril
Droperidol • Inapsine
Duloxetine • Cymbalta
Fluoxetine • Prozac
Haloperidol • Haldol
Iloperidone • Fanapt
Metoclopramide • Reglan
Olanzapine • Zyprexa
Paroxetine • Paxil
Pimozide • Orap
Prochlorperazine • Compazine
Promethazine • Phenergan
Quetiapine • Seroquel
Risperidone • Risperdal
Tizanidine • Zanaflex
Ziprasidone • Geodon

In general, when a medication goes off patent, marketing for it significantly slows down or comes to a halt. Studies have shown that physicians’ prescribing habits are influenced by pharmaceutical representatives and companies.¹ This phenomenon may have an unforeseen adverse effect: once an effective and inexpensive medication “goes generic,” its use may fall out of favor. Additionally, physicians may have concerns about prescribing generic medications, such as perceiving them as less effective and conferring more adverse effects compared with brand-name formulations.² One such generic medication is buspirone, which originally was branded as BuSpar.

Anxiety disorders are the most common psychiatric diagnoses, and at times are the most challenging to treat.³ Anecdotally, we often see benzodiazepines prescribed as first-line monotherapy for acute and chronic anxiety, but because these agents can cause physical dependence and a withdrawal reaction, alternative anxiolytic medications should be strongly considered. Despite its age, buspirone still plays a role in the treatment of anxiety, and its off-label use can also be useful in certain populations and scenarios. In this article, we delve into buspirone’s mechanism of action, discuss its advantages and challenges, and what you need to know when prescribing it.

How buspirone works

Buspirone was originally described as an anxiolytic agent that was pharmacologically unrelated to traditional anxiety-reducing medications (ie, benzodiazepines and barbiturates).⁴ It has a high affinity for the 5-hydroxytryptamine 1A (5HT1A) receptor and may also act as a central dopamine antagonist at D2 receptors.^4,5 It is FDA-approved only for the treatment of generalized anxiety disorder (GAD).⁴ Buspirone also is commonly used as an augmenting agent to selective serotonin reuptake inhibitors (SSRIs) in the treatment of medication-resistant or partially treated depression.⁶ When a patient who is depressed appears to have marginal to no response to an adequate trial of a first-line agent, buspirone is thought to replenish depleted stores and/or increase synthesis of serotonin. Additionally, it acts directly on 5HT1A autoreceptors to achieve the desired desensitization of those receptors. All of these proposed mechanisms are thought to improve symptoms of depression.⁶

The antidepressants vortioxetine and vilazodone exhibit dual-action at both serotonin reuptake transporters and 5HT1A receptors; thus, they work like an SSRI and buspirone combined.⁶ Although some patients may find it more convenient to take a dual-action pill over 2 separate ones, some insurance companies do not cover these newer agents. Additionally, prescribing buspirone separately allows for more precise dosing, which may lower the risk of adverse effects.

Buspirone is a major substrate for cytochrome P450 (CYP) 3A4 and a minor for CYP2D6, so caution must be advised if considering buspirone for a patient receiving any CYP3A4 inducers and/or inhibitors,⁷ including grapefruit juice.⁸

Dose adjustments are not necessary for age and sex, which allows for highly consistent dosing.⁴ However, as with prescribing medications in any geriatric population, lower starting doses and slower titration of buspirone may be necessary to avoid potential adverse effects due to the alterations of pharmacodynamic and pharmacokinetic processes that occur as patients age.⁹

Advantages of buspirone

Works well as an add-on to other medications. While buspirone in adequate doses may be helpful as monotherapy in GAD, it can also be helpful in other, more complex psychiatric scenarios. Sumiyoshi et al¹⁰ observed improvement in scores on the Digit Symbol Substitution Test when buspirone was added to a second-generation antipsychotic (SGA), which suggests buspirone may help improve attention in patients with schizophrenia. It has been postulated that buspirone may also be helpful for cognitive dysfunction in patients with Alzheimer’s disease.¹¹ Buspirone has been used to treat comorbid anxiety and alcohol use disorder, resulting in reduced anxiety, longer latency to relapse, and fewer drinking days during a 12-week treatment program.¹² Buspirone has been more effective than placebo for treating post-stroke anxiety.¹³

Continue to: Patients who receive...

Patients who receive an SSRI, such as citalopram, but are not able to achieve a substantial improvement in their depressive and/or anxious symptoms may benefit from the addition of buspirone to their treatment regimen.^14,15

A favorable adverse-effect profile. There are no absolute contraindications to buspirone except a history of hypersensitivity.⁴ Buspirone generally is well tolerated and carries a low risk of adverse effects. The most common adverse effects are dizziness and nausea.⁶ Buspirone is not sedating.

Potentially safe for patients who are pregnant. Unlike many other first-line agents for anxiety, such as SSRIs, buspirone has an FDA Category B classification, meaning animal studies have shown no adverse events during pregnancy.⁴ The FDA Pregnancy and Lactation Labeling Rule applies only to medications that entered the market on or after June 30, 2001; unfortunately, buspirone is excluded from this updated categorization.¹⁶ As with any medication being considered for pregnant or lactating women, the prescriber and patient must weigh the benefits vs the risks to determine if buspirone is appropriate for any individual patient.

No adverse events have been reported from abrupt discontinuation of buspirone.¹⁷

Inexpensive. Buspirone is generic and extremely inexpensive. According to GoodRx.com, a 30-day supply of 5-mg tablets for twice-daily dosing can cost $4.¹⁸ A maximum daily dose (prescribed as 2 pills, 15 mg twice daily) may cost approximately $18/month.¹⁸ Thus, buspirone is a good option for uninsured or underinsured patients, for whom this would be more affordable than other anxiolytic medications.

Continue to: May offset certain adverse effects

May offset certain adverse effects. Sexual dysfunction is a common adverse effect of SSRIs. One strategy to offset this phenomenon is to add bupropion. However, in a randomized controlled trial, Landén et al¹⁹ found that sexual adverse effects induced by SSRIs were greatly mitigated by adding buspirone, even within the first week of treatment. This improvement was more marked in women than in men, which is helpful because sexual dysfunction in women is generally resistant to other interventions.²⁰ Unlike bupropion, buspirone is not contraindicated in patients with seizure and/or eating disorders.⁴ Additionally, the American Psychiatric Association practice guidelines for the treatment of major depressive disorder identify buspirone as a useful strategy in treating erectile dysfunction and orgasmic dysfunction due to SSRI treatment.¹⁵

Unlikely to cause extrapyramidal symptoms (EPS). Because of its central D2 antagonism, buspirone has a low potential (<1%) to produce EPS. Buspirone has even been shown to reverse haloperidol-induced EPS.²¹

The Table⁴ highlights key points to bear in mind when prescribing buspirone.

Challenges with buspirone

Response is not immediate. Unlike benzodiazepines, buspirone does not have an immediate onset of action.²² With buspirone monotherapy, response may be seen in approximately 2 to 4 weeks.²³ Therefore, patients transitioning from a quick-onset benzodiazepine to buspirone may not report a good response. However, as noted above, when using buspirone to treat SSRI-induced sexual dysfunction, response may emerge within 1 week.¹⁹ Buspirone also lacks the euphoric and sedative qualities of benzodiazepines that patients may prefer.

Not for patients with hepatic and renal impairment. Because plasma levels of buspirone are elevated in patients with hepatic and renal impairment, this medication is not ideal for use in these populations.⁴

Continue to: Contraindicated in patients receiving MAOIs

Contraindicated in patients receiving MAOIs. Buspirone should not be prescribed to patients with depression who are receiving treatment with a monoamine oxidase inhibitor (MAOI) because the combination may precipitate a hypertensive reaction.⁴ A minimum washout period of 14 days from the MAOI is necessary before initiating buspirone.⁹

Idiosyncratic adverse effects. As with all pharmaceuticals, buspirone may produce idiosyncratic adverse effects. Faber and Sansone²⁴ reported a case of a woman who experienced hair loss 3 months into treatment with buspirone. After cessation, her alopecia resolved.

Questionable efficacy for some anxiety subtypes. Buspirone has been studied as a treatment of other common psychiatric conditions, such as social phobia and anxiety in the setting of smoking cessation. However, it has not proven to be effective over placebo in treating these anxiety subtypes.^25,26

Short half-life. Because of its relatively short half-life (2 to 3 hours), buspirone requires dosing 2 to 3 times a day, which could increase the risk of noncompliance.⁴ However, some patients might prefer multiple dosing throughout the day due to perceived better coverage of their anxiety symptoms.

Limited incentive for future research. Because buspirone is available only as a generic formulation, there is little financial incentive for pharmaceutical companies and other interested parties to study what may be valuable uses for buspirone. For example, there is no data available on comparative augmentation of buspirone and SGAs with antidepressants for depression and/or anxiety. There is also little data available about buspirone prescribing trends or why buspirone may be under­utilized in clinical practice today.

Continue to: Unfortunately, historical and longitudinal...

Unfortunately, historical and longitudinal data on the prescribing practices of buspirone is limited because the original branded medication, BuSpar, is no longer on the market. However, this medication offers multiple advantages over other agents used to treat anxiety, and it should not be forgotten when formulating a treatment regimen for patients with anxiety and/or depression.

Bottom Line

Buspirone is a safe, low-cost, effective treatment option for patients with anxiety and may be helpful as an augmenting agent for depression. Because of its efficacy and high degree of tolerability, it should be prioritized higher in our treatment algorithms and be a part of our routine pharmacologic armamentarium.

Related Resources

• Howland RH. Buspirone: Back to the future. J Psychosoc Nurs Ment Health Serv. 2015;53(11):21-24.
• Strawn JR, Mills JA, Cornwall GJ, et al. Buspirone in children and adolescents with anxiety: a review and Bayesian analysis of abandoned randomized controlled trials. J Child Adolesc Psychopharmacol. 2018;28(1):2-9.

Drug Brand Names

Bupropion • Wellbutrin, Zyban
Buspirone • BuSpar
Citalopram • Celexa
Haloperidol • Haldol
Vilazodone • Viibryd
Vortioxetine • Trintellix

In general, when a medication goes off patent, marketing for it significantly slows down or comes to a halt. Studies have shown that physicians’ prescribing habits are influenced by pharmaceutical representatives and companies.¹ This phenomenon may have an unforeseen adverse effect: once an effective and inexpensive medication “goes generic,” its use may fall out of favor. Additionally, physicians may have concerns about prescribing generic medications, such as perceiving them as less effective and conferring more adverse effects compared with brand-name formulations.² One such generic medication is buspirone, which originally was branded as BuSpar.

Anxiety disorders are the most common psychiatric diagnoses, and at times are the most challenging to treat.³ Anecdotally, we often see benzodiazepines prescribed as first-line monotherapy for acute and chronic anxiety, but because these agents can cause physical dependence and a withdrawal reaction, alternative anxiolytic medications should be strongly considered. Despite its age, buspirone still plays a role in the treatment of anxiety, and its off-label use can also be useful in certain populations and scenarios. In this article, we delve into buspirone’s mechanism of action, discuss its advantages and challenges, and what you need to know when prescribing it.

How buspirone works

Buspirone was originally described as an anxiolytic agent that was pharmacologically unrelated to traditional anxiety-reducing medications (ie, benzodiazepines and barbiturates).⁴ It has a high affinity for the 5-hydroxytryptamine 1A (5HT1A) receptor and may also act as a central dopamine antagonist at D2 receptors.^4,5 It is FDA-approved only for the treatment of generalized anxiety disorder (GAD).⁴ Buspirone also is commonly used as an augmenting agent to selective serotonin reuptake inhibitors (SSRIs) in the treatment of medication-resistant or partially treated depression.⁶ When a patient who is depressed appears to have marginal to no response to an adequate trial of a first-line agent, buspirone is thought to replenish depleted stores and/or increase synthesis of serotonin. Additionally, it acts directly on 5HT1A autoreceptors to achieve the desired desensitization of those receptors. All of these proposed mechanisms are thought to improve symptoms of depression.⁶

The antidepressants vortioxetine and vilazodone exhibit dual-action at both serotonin reuptake transporters and 5HT1A receptors; thus, they work like an SSRI and buspirone combined.⁶ Although some patients may find it more convenient to take a dual-action pill over 2 separate ones, some insurance companies do not cover these newer agents. Additionally, prescribing buspirone separately allows for more precise dosing, which may lower the risk of adverse effects.

Buspirone is a major substrate for cytochrome P450 (CYP) 3A4 and a minor for CYP2D6, so caution must be advised if considering buspirone for a patient receiving any CYP3A4 inducers and/or inhibitors,⁷ including grapefruit juice.⁸

Dose adjustments are not necessary for age and sex, which allows for highly consistent dosing.⁴ However, as with prescribing medications in any geriatric population, lower starting doses and slower titration of buspirone may be necessary to avoid potential adverse effects due to the alterations of pharmacodynamic and pharmacokinetic processes that occur as patients age.⁹

Advantages of buspirone

Works well as an add-on to other medications. While buspirone in adequate doses may be helpful as monotherapy in GAD, it can also be helpful in other, more complex psychiatric scenarios. Sumiyoshi et al¹⁰ observed improvement in scores on the Digit Symbol Substitution Test when buspirone was added to a second-generation antipsychotic (SGA), which suggests buspirone may help improve attention in patients with schizophrenia. It has been postulated that buspirone may also be helpful for cognitive dysfunction in patients with Alzheimer’s disease.¹¹ Buspirone has been used to treat comorbid anxiety and alcohol use disorder, resulting in reduced anxiety, longer latency to relapse, and fewer drinking days during a 12-week treatment program.¹² Buspirone has been more effective than placebo for treating post-stroke anxiety.¹³

Continue to: Patients who receive...

Patients who receive an SSRI, such as citalopram, but are not able to achieve a substantial improvement in their depressive and/or anxious symptoms may benefit from the addition of buspirone to their treatment regimen.^14,15

A favorable adverse-effect profile. There are no absolute contraindications to buspirone except a history of hypersensitivity.⁴ Buspirone generally is well tolerated and carries a low risk of adverse effects. The most common adverse effects are dizziness and nausea.⁶ Buspirone is not sedating.

Potentially safe for patients who are pregnant. Unlike many other first-line agents for anxiety, such as SSRIs, buspirone has an FDA Category B classification, meaning animal studies have shown no adverse events during pregnancy.⁴ The FDA Pregnancy and Lactation Labeling Rule applies only to medications that entered the market on or after June 30, 2001; unfortunately, buspirone is excluded from this updated categorization.¹⁶ As with any medication being considered for pregnant or lactating women, the prescriber and patient must weigh the benefits vs the risks to determine if buspirone is appropriate for any individual patient.

No adverse events have been reported from abrupt discontinuation of buspirone.¹⁷

Inexpensive. Buspirone is generic and extremely inexpensive. According to GoodRx.com, a 30-day supply of 5-mg tablets for twice-daily dosing can cost $4.¹⁸ A maximum daily dose (prescribed as 2 pills, 15 mg twice daily) may cost approximately $18/month.¹⁸ Thus, buspirone is a good option for uninsured or underinsured patients, for whom this would be more affordable than other anxiolytic medications.

Continue to: May offset certain adverse effects

May offset certain adverse effects. Sexual dysfunction is a common adverse effect of SSRIs. One strategy to offset this phenomenon is to add bupropion. However, in a randomized controlled trial, Landén et al¹⁹ found that sexual adverse effects induced by SSRIs were greatly mitigated by adding buspirone, even within the first week of treatment. This improvement was more marked in women than in men, which is helpful because sexual dysfunction in women is generally resistant to other interventions.²⁰ Unlike bupropion, buspirone is not contraindicated in patients with seizure and/or eating disorders.⁴ Additionally, the American Psychiatric Association practice guidelines for the treatment of major depressive disorder identify buspirone as a useful strategy in treating erectile dysfunction and orgasmic dysfunction due to SSRI treatment.¹⁵

Unlikely to cause extrapyramidal symptoms (EPS). Because of its central D2 antagonism, buspirone has a low potential (<1%) to produce EPS. Buspirone has even been shown to reverse haloperidol-induced EPS.²¹

The Table⁴ highlights key points to bear in mind when prescribing buspirone.

Challenges with buspirone

Response is not immediate. Unlike benzodiazepines, buspirone does not have an immediate onset of action.²² With buspirone monotherapy, response may be seen in approximately 2 to 4 weeks.²³ Therefore, patients transitioning from a quick-onset benzodiazepine to buspirone may not report a good response. However, as noted above, when using buspirone to treat SSRI-induced sexual dysfunction, response may emerge within 1 week.¹⁹ Buspirone also lacks the euphoric and sedative qualities of benzodiazepines that patients may prefer.

Not for patients with hepatic and renal impairment. Because plasma levels of buspirone are elevated in patients with hepatic and renal impairment, this medication is not ideal for use in these populations.⁴

Continue to: Contraindicated in patients receiving MAOIs

Contraindicated in patients receiving MAOIs. Buspirone should not be prescribed to patients with depression who are receiving treatment with a monoamine oxidase inhibitor (MAOI) because the combination may precipitate a hypertensive reaction.⁴ A minimum washout period of 14 days from the MAOI is necessary before initiating buspirone.⁹

Idiosyncratic adverse effects. As with all pharmaceuticals, buspirone may produce idiosyncratic adverse effects. Faber and Sansone²⁴ reported a case of a woman who experienced hair loss 3 months into treatment with buspirone. After cessation, her alopecia resolved.

Questionable efficacy for some anxiety subtypes. Buspirone has been studied as a treatment of other common psychiatric conditions, such as social phobia and anxiety in the setting of smoking cessation. However, it has not proven to be effective over placebo in treating these anxiety subtypes.^25,26

Short half-life. Because of its relatively short half-life (2 to 3 hours), buspirone requires dosing 2 to 3 times a day, which could increase the risk of noncompliance.⁴ However, some patients might prefer multiple dosing throughout the day due to perceived better coverage of their anxiety symptoms.

Limited incentive for future research. Because buspirone is available only as a generic formulation, there is little financial incentive for pharmaceutical companies and other interested parties to study what may be valuable uses for buspirone. For example, there is no data available on comparative augmentation of buspirone and SGAs with antidepressants for depression and/or anxiety. There is also little data available about buspirone prescribing trends or why buspirone may be under­utilized in clinical practice today.

Continue to: Unfortunately, historical and longitudinal...

Unfortunately, historical and longitudinal data on the prescribing practices of buspirone is limited because the original branded medication, BuSpar, is no longer on the market. However, this medication offers multiple advantages over other agents used to treat anxiety, and it should not be forgotten when formulating a treatment regimen for patients with anxiety and/or depression.

Bottom Line

Buspirone is a safe, low-cost, effective treatment option for patients with anxiety and may be helpful as an augmenting agent for depression. Because of its efficacy and high degree of tolerability, it should be prioritized higher in our treatment algorithms and be a part of our routine pharmacologic armamentarium.

Related Resources

• Howland RH. Buspirone: Back to the future. J Psychosoc Nurs Ment Health Serv. 2015;53(11):21-24.
• Strawn JR, Mills JA, Cornwall GJ, et al. Buspirone in children and adolescents with anxiety: a review and Bayesian analysis of abandoned randomized controlled trials. J Child Adolesc Psychopharmacol. 2018;28(1):2-9.

Drug Brand Names

Bupropion • Wellbutrin, Zyban
Buspirone • BuSpar
Citalopram • Celexa
Haloperidol • Haldol
Vilazodone • Viibryd
Vortioxetine • Trintellix

In general, when a medication goes off patent, marketing for it significantly slows down or comes to a halt. Studies have shown that physicians’ prescribing habits are influenced by pharmaceutical representatives and companies.¹ This phenomenon may have an unforeseen adverse effect: once an effective and inexpensive medication “goes generic,” its use may fall out of favor. Additionally, physicians may have concerns about prescribing generic medications, such as perceiving them as less effective and conferring more adverse effects compared with brand-name formulations.² One such generic medication is buspirone, which originally was branded as BuSpar.

Anxiety disorders are the most common psychiatric diagnoses, and at times are the most challenging to treat.³ Anecdotally, we often see benzodiazepines prescribed as first-line monotherapy for acute and chronic anxiety, but because these agents can cause physical dependence and a withdrawal reaction, alternative anxiolytic medications should be strongly considered. Despite its age, buspirone still plays a role in the treatment of anxiety, and its off-label use can also be useful in certain populations and scenarios. In this article, we delve into buspirone’s mechanism of action, discuss its advantages and challenges, and what you need to know when prescribing it.

How buspirone works

Buspirone was originally described as an anxiolytic agent that was pharmacologically unrelated to traditional anxiety-reducing medications (ie, benzodiazepines and barbiturates).⁴ It has a high affinity for the 5-hydroxytryptamine 1A (5HT1A) receptor and may also act as a central dopamine antagonist at D2 receptors.^4,5 It is FDA-approved only for the treatment of generalized anxiety disorder (GAD).⁴ Buspirone also is commonly used as an augmenting agent to selective serotonin reuptake inhibitors (SSRIs) in the treatment of medication-resistant or partially treated depression.⁶ When a patient who is depressed appears to have marginal to no response to an adequate trial of a first-line agent, buspirone is thought to replenish depleted stores and/or increase synthesis of serotonin. Additionally, it acts directly on 5HT1A autoreceptors to achieve the desired desensitization of those receptors. All of these proposed mechanisms are thought to improve symptoms of depression.⁶

The antidepressants vortioxetine and vilazodone exhibit dual-action at both serotonin reuptake transporters and 5HT1A receptors; thus, they work like an SSRI and buspirone combined.⁶ Although some patients may find it more convenient to take a dual-action pill over 2 separate ones, some insurance companies do not cover these newer agents. Additionally, prescribing buspirone separately allows for more precise dosing, which may lower the risk of adverse effects.

Buspirone is a major substrate for cytochrome P450 (CYP) 3A4 and a minor for CYP2D6, so caution must be advised if considering buspirone for a patient receiving any CYP3A4 inducers and/or inhibitors,⁷ including grapefruit juice.⁸

Dose adjustments are not necessary for age and sex, which allows for highly consistent dosing.⁴ However, as with prescribing medications in any geriatric population, lower starting doses and slower titration of buspirone may be necessary to avoid potential adverse effects due to the alterations of pharmacodynamic and pharmacokinetic processes that occur as patients age.⁹

Advantages of buspirone

Works well as an add-on to other medications. While buspirone in adequate doses may be helpful as monotherapy in GAD, it can also be helpful in other, more complex psychiatric scenarios. Sumiyoshi et al¹⁰ observed improvement in scores on the Digit Symbol Substitution Test when buspirone was added to a second-generation antipsychotic (SGA), which suggests buspirone may help improve attention in patients with schizophrenia. It has been postulated that buspirone may also be helpful for cognitive dysfunction in patients with Alzheimer’s disease.¹¹ Buspirone has been used to treat comorbid anxiety and alcohol use disorder, resulting in reduced anxiety, longer latency to relapse, and fewer drinking days during a 12-week treatment program.¹² Buspirone has been more effective than placebo for treating post-stroke anxiety.¹³

Continue to: Patients who receive...

Patients who receive an SSRI, such as citalopram, but are not able to achieve a substantial improvement in their depressive and/or anxious symptoms may benefit from the addition of buspirone to their treatment regimen.^14,15

A favorable adverse-effect profile. There are no absolute contraindications to buspirone except a history of hypersensitivity.⁴ Buspirone generally is well tolerated and carries a low risk of adverse effects. The most common adverse effects are dizziness and nausea.⁶ Buspirone is not sedating.

Potentially safe for patients who are pregnant. Unlike many other first-line agents for anxiety, such as SSRIs, buspirone has an FDA Category B classification, meaning animal studies have shown no adverse events during pregnancy.⁴ The FDA Pregnancy and Lactation Labeling Rule applies only to medications that entered the market on or after June 30, 2001; unfortunately, buspirone is excluded from this updated categorization.¹⁶ As with any medication being considered for pregnant or lactating women, the prescriber and patient must weigh the benefits vs the risks to determine if buspirone is appropriate for any individual patient.

No adverse events have been reported from abrupt discontinuation of buspirone.¹⁷

Inexpensive. Buspirone is generic and extremely inexpensive. According to GoodRx.com, a 30-day supply of 5-mg tablets for twice-daily dosing can cost $4.¹⁸ A maximum daily dose (prescribed as 2 pills, 15 mg twice daily) may cost approximately $18/month.¹⁸ Thus, buspirone is a good option for uninsured or underinsured patients, for whom this would be more affordable than other anxiolytic medications.

Continue to: May offset certain adverse effects

May offset certain adverse effects. Sexual dysfunction is a common adverse effect of SSRIs. One strategy to offset this phenomenon is to add bupropion. However, in a randomized controlled trial, Landén et al¹⁹ found that sexual adverse effects induced by SSRIs were greatly mitigated by adding buspirone, even within the first week of treatment. This improvement was more marked in women than in men, which is helpful because sexual dysfunction in women is generally resistant to other interventions.²⁰ Unlike bupropion, buspirone is not contraindicated in patients with seizure and/or eating disorders.⁴ Additionally, the American Psychiatric Association practice guidelines for the treatment of major depressive disorder identify buspirone as a useful strategy in treating erectile dysfunction and orgasmic dysfunction due to SSRI treatment.¹⁵

Unlikely to cause extrapyramidal symptoms (EPS). Because of its central D2 antagonism, buspirone has a low potential (<1%) to produce EPS. Buspirone has even been shown to reverse haloperidol-induced EPS.²¹

The Table⁴ highlights key points to bear in mind when prescribing buspirone.

Challenges with buspirone

Response is not immediate. Unlike benzodiazepines, buspirone does not have an immediate onset of action.²² With buspirone monotherapy, response may be seen in approximately 2 to 4 weeks.²³ Therefore, patients transitioning from a quick-onset benzodiazepine to buspirone may not report a good response. However, as noted above, when using buspirone to treat SSRI-induced sexual dysfunction, response may emerge within 1 week.¹⁹ Buspirone also lacks the euphoric and sedative qualities of benzodiazepines that patients may prefer.

Not for patients with hepatic and renal impairment. Because plasma levels of buspirone are elevated in patients with hepatic and renal impairment, this medication is not ideal for use in these populations.⁴

Continue to: Contraindicated in patients receiving MAOIs

Contraindicated in patients receiving MAOIs. Buspirone should not be prescribed to patients with depression who are receiving treatment with a monoamine oxidase inhibitor (MAOI) because the combination may precipitate a hypertensive reaction.⁴ A minimum washout period of 14 days from the MAOI is necessary before initiating buspirone.⁹

Idiosyncratic adverse effects. As with all pharmaceuticals, buspirone may produce idiosyncratic adverse effects. Faber and Sansone²⁴ reported a case of a woman who experienced hair loss 3 months into treatment with buspirone. After cessation, her alopecia resolved.

Questionable efficacy for some anxiety subtypes. Buspirone has been studied as a treatment of other common psychiatric conditions, such as social phobia and anxiety in the setting of smoking cessation. However, it has not proven to be effective over placebo in treating these anxiety subtypes.^25,26

Short half-life. Because of its relatively short half-life (2 to 3 hours), buspirone requires dosing 2 to 3 times a day, which could increase the risk of noncompliance.⁴ However, some patients might prefer multiple dosing throughout the day due to perceived better coverage of their anxiety symptoms.

Limited incentive for future research. Because buspirone is available only as a generic formulation, there is little financial incentive for pharmaceutical companies and other interested parties to study what may be valuable uses for buspirone. For example, there is no data available on comparative augmentation of buspirone and SGAs with antidepressants for depression and/or anxiety. There is also little data available about buspirone prescribing trends or why buspirone may be under­utilized in clinical practice today.

Continue to: Unfortunately, historical and longitudinal...

Unfortunately, historical and longitudinal data on the prescribing practices of buspirone is limited because the original branded medication, BuSpar, is no longer on the market. However, this medication offers multiple advantages over other agents used to treat anxiety, and it should not be forgotten when formulating a treatment regimen for patients with anxiety and/or depression.

Bottom Line

Buspirone is a safe, low-cost, effective treatment option for patients with anxiety and may be helpful as an augmenting agent for depression. Because of its efficacy and high degree of tolerability, it should be prioritized higher in our treatment algorithms and be a part of our routine pharmacologic armamentarium.

Related Resources

• Howland RH. Buspirone: Back to the future. J Psychosoc Nurs Ment Health Serv. 2015;53(11):21-24.
• Strawn JR, Mills JA, Cornwall GJ, et al. Buspirone in children and adolescents with anxiety: a review and Bayesian analysis of abandoned randomized controlled trials. J Child Adolesc Psychopharmacol. 2018;28(1):2-9.

Drug Brand Names

Bupropion • Wellbutrin, Zyban
Buspirone • BuSpar
Citalopram • Celexa
Haloperidol • Haldol
Vilazodone • Viibryd
Vortioxetine • Trintellix

Medical knowledge is growing faster than ever, as is the challenge of keeping up with this ever-growing body of information. Clinicians need a system or method to help them sort and evaluate the quality of new information before they can apply it to clinical care. Without such a system, when facing an overload of information, most of us tend to take the first or the most easily accessed information, without considering the quality of such information. As a result, the use of poor-quality information affects the quality and outcome of care we provide, and costs billions of dollars annually in problems associated with underuse, overuse, and misuse of treatments.

In an effort to sort and evaluate recently published research that is ready for clinical use, the first author (SAS) used the following 3-step methodology:

1. Searched literature for research findings suggesting readiness for clinical utilization published between July 1, 2018 and June 30, 2019.

2. Surveyed members of the American Association of Chairs of Departments of Psychiatry, the American Association of Community Psychiatrists, the American Association of Psychiatric Administrators, the North Carolina Psychiatric Association, the Group for the Advancement of Psychiatry, and many other colleagues by asking them: “Among the articles published from July 1, 2018 to June 30, 2019, which ones in your opinion have (or are likely to have or should have) affected/changed the clinical practice of psychiatry?”

3. Looked for appraisals in post-publication reviews such as NEJM Journal Watch, F1000 Prime, Evidence-Based Mental Health, commentaries in peer-reviewed journals, and other sources (see Related Resources).

We chose 12 articles based on their clinical relevance/applicability. Here in Part 1 we present brief descriptions of the 6 of top 12 papers chosen by this methodology; these studies are summarized in the Table.^1-6 The order in which they appear in this article is arbitrary. The remaining 6 studies will be reviewed in Part 2 in the February 2020 issue of Current Psychiatry.

1. Ray WA, Stein CM, Murray KT, et al. Association of antipsychotic treatment with risk of unexpected death among children and youths. JAMA Psychiatry. 2019;76(2):162-171.

Children and young adults are increasingly being prescribed antipsychotic medications. Studies have suggested that when these medications are used in adults and older patients, they are associated with an increased risk of death.^7-9 Whether or not these medications are associated with an increased risk of death in children and youth has been unknown. Ray et al¹ compared the risk of unexpected death among children and youths who were beginning treatment with an antipsychotic or control medications.

Study design

• This retrospective cohort study evaluated children and young adults age 5 to 24 who were enrolled in Medicaid in Tennessee between 1999 and 2014.
• New antipsychotic use at both a higher dose (>50 mg chlorpromazine equivalents) and a lower dose (≤50 mg chlorpromazine equivalents) was compared with new use of a control medication, including attention-deficit/hyperactivity disorder medications, antidepressants, and mood stabilizers.
• There were 189,361 participants in the control group, 28,377 participants in the lower-dose antipsychotic group, and 30,120 participants in the higher-dose antipsychotic group.

Outcomes

• The primary outcome was death due to injury or suicide or unexpected death occurring during study follow-up.
• The incidence of death in the higher-dose antipsychotic group (146.2 per 100,000 person-years) was significantly higher (P < .001) than the incidence of death in the control medications group (54.5 per 100,000 person years).
• There was no similar significant difference between the lower-dose antipsychotic group and the control medications group.

Continue to: Conclusion

Conclusion

• Higher-dose antipsychotic use is associated with increased rates of unexpected deaths in children and young adults.
• As with all association studies, no direct line connected cause and effect. However, these results reinforce recommendations for careful prescribing and monitoring of antipsychotic regimens for children and youths, and the need for larger antipsychotic safety studies in this population.
• Examining risks associated with specific antipsychotics will require larger datasets, but will be critical for our understanding of the risks and benefits.

2. Daly EJ, Trivedi MH, Janik A, et al. Efficacy of esketamine nasal spray plus oral antidepressant treatment for relapse prevention in patients with treatment-resistant depression: a randomized clinical trial. JAMA Psychiatry. 2019;76(9):893-903.

Controlled studies have shown esketamine has efficacy for treatment-resistant depression (TRD), but these studies have been only short-term, and the long-term effects of esketamine for TRD have not been established. To fill that gap, Daly et al² assessed the efficacy of esketamine nasal spray plus an oral antidepressant vs a placebo nasal spray plus an oral antidepressant in delaying relapse of depressive symptoms in patients with TRD. All patients were in stable remission after an optimization course of esketamine nasal spray plus an oral antidepressant.

Study design

• Between October 2015 and February 2018, researchers conducted a phase III, multicenter, double-blind, randomized withdrawal study to evaluate the effect of continuation of esketamine on rates of relapse in patients with TRD who had responded to initial treatment with esketamine.
• Initially, 705 adults were enrolled. Of these participants, 455 proceeded to the optimization phase, in which they were treated with esketamine nasal spray plus an oral antidepressant.
• After 16 weeks of optimization treatment, 297 participants achieved remission or stable response and were randomized to a treatment group, which received continued esketamine nasal spray plus an oral antidepressant, or to a control group, which received a placebo nasal spray plus an oral antidepressant.

Outcomes

• Treatment with esketamine nasal spray and an oral antidepressant was associated with decreased rates of relapse compared with treatment with placebo nasal spray and an oral antidepressant. This was the case among patients who had achieved remission as well as those who had achieved stable response.
• Continued treatment with esketamine decreased the risk of relapse by 51%, with 40 participants in the treatment group experiencing relapse compared with 73 participants in the placebo group.

Continue to: Conclusion

Conclusion

• In patients with TRD who responded to initial treatment with esketamine, continuing esketamine plus an oral antidepressant resulted in clinically meaningful superiority in preventing relapse compared with a placebo nasal spray plus an oral antidepressant.

3. Williams NR, Heifets BD, Blasey C, et al. Attenuation of antidepressant effects of ketamine by opioid receptor antagonism. Am J Psychiatry. 2018;175(12):1205-1215.

Many studies have documented the efficacy of ketamine as a rapid-onset antidepressant. Studies investigating the mechanism of this effect have focused on antagonism of N-methyl-D-aspartate (NMDA) receptors. However, several clinical trials that attempted to replicate this rapid antidepressant effect with other NMDA receptor antagonists had only limited success. Williams et al³ conducted the first human study that presents evidence that opioid receptor activation may be necessary for ketamine’s acute antidepressant effect.

Study design

• This double-blind crossover study evaluated if opioid receptor activation is necessary for ketamine to have an antidepressant effect in patients with TRD.
• Twelve participants completed both sides of the study in a randomized order. Participants received placebo or naltrexone prior to an IV infusion of ketamine.
• Researchers measured patients’ scores on the Hamilton Depression Rating Scale (HAM-D) at baseline and 1 day after infusion. Response was defined as a ≥50% reduction in HAM-D score.

Outcomes

• Reductions in HAM-D scores among participants in the ketamine plus naltrexone group were significantly lower than those of participants in the ketamine plus placebo group.
• Dissociation related to ketamine use did not differ significantly between the naltrexone group and the placebo group.

Continue to: Conclusion

Conclusion

• This small study found a significant decrease in the antidepressant effect of ketamine infusion in patients with TRD when opioid receptors are blocked with naltrexone prior to infusion, which suggests opioid receptor activation is necessary for ketamine to be effective as an antidepressant.
• This appears to be consistent with observations of buprenorphine’s antidepressant effects. Caution is indicated until additional studies can further elucidate the mechanism of action of ketamine’s antidepressant effects (see "Ketamine/esketamine: Putative mechanism of action," page 32).

4. Nidich S, Mills PJ, Rainforth M, et al. Non-trauma-focused meditation versus exposure therapy in veterans with post-traumatic stress disorder: a randomised controlled trial. Lancet Psychiatry. 2018;5(12):975-986.

Posttraumatic stress disorder (PTSD) is a common and important public health problem. Evidence-based treatments for PTSD include trauma-focused therapies such as prolonged exposure therapy (PE). However, some patients may not respond to PE, drop out, or elect not to pursue it. Researchers continue to explore treatments that are non-trauma-focused, such as mindfulness meditation and interpersonal psychotherapy. In a 3-group comparative effectiveness trial, Nidich et al⁴ examined the efficacy of a non-trauma-focused intervention, transcendental meditation (TM), in reducing PTSD symptom severity and depression in veterans.

Study design

• Researchers recruited 203 veterans with PTSD from the Department of Veterans Affairs (VA) San Diego Healthcare System between June 2013 and October 2016.
• Participants were randomly assigned to 1 of 3 groups: 68 to TM, 68 to PE, and 67 to PTSD health education (HE).
• Each group received 12 sessions over 12 weeks. In addition to group and individual sessions, all participants received daily practice or assignments.
• The Clinician-Administered PTSD Scale (CAPS) was used to assess symptoms before and after treatment.

Outcomes

• The primary outcome assessed was change in PTSD symptom severity at the end of the study compared with baseline as measured by change in CAPS score.
• Transcendental meditation was found to be significantly non-inferior to PE, with a mean change in CAPS score of −16.1 in the TM group and −11.2 in the PE group.
• Both the TM and PE groups also had significant reductions in CAPS scores compared with the HE group, which had a mean change in CAPS score of −2.5.

Continue to: Conclusion

Conclusion

• Transcendental meditation is significantly not inferior to PE in the treatment of veterans with PTSD.
• The findings from this first comparative effectiveness trial comparing TM with an established psychotherapy for PTSD suggests the feasibility and efficacy of TM as an alternative therapy for veterans with PTSD.
• Because TM is self-administered after an initial expert training, it may offer an easy-to-implement approach that may be more accessible to veterans than other treatments.

5. Raskind MA, Peskind ER, Chow B, et al. Trial of prazosin for post-traumatic stress disorder in military veterans. N Engl J Med. 2018;378(6):507-517.

Several smaller randomized trials of prazosin involving a total of 283 active-duty service members, veterans, and civilian participants have shown efficacy of prazosin for PTSD-related nightmares, sleep disturbance, and overall clinical functioning. However, in a recent trial, Raskind et al⁵ failed to demonstrate such efficacy.

Study design

• Veterans with chronic PTSD nightmares were recruited from 13 VA medical centers to participate in a 26-week, double-blind, randomized controlled trial.
• A total of 304 participants were randomized to a prazosin treatment group (n = 152) or a placebo control group (n = 152).
• During the first 10 weeks, prazosin or placebo were administered in an escalating fashion up to a maximum dose.
• The CAPS, Pittsburgh Sleep Quality Index (PSQI), and Clinical Global Impressions of Change (CGIC) scores were measured at baseline, after 10 weeks, and after 26 weeks.

Outcomes

• Three primary outcomes measures were assessed: change in score from baseline to 10 weeks on CAPS item B2, the PSQI, and the CGIC.
• A secondary measure was change in score from baseline of the same measures at 26 weeks.
• There was no significant difference between the prazosin group and the placebo group in any of the primary or secondary measures.

Continue to: Conclusion

Conclusion

• Compared with placebo, prazosin was not associated with improvement in nightmares or sleep quality for veterans with chronic PTSD nightmares.
• Because psychosocial instability was an exclusion criterion, it is possible that a selection bias resulting from recruitment of patients who were mainly in clinically stable condition accounted for these negative results, since symptoms in such patients were less likely to be ameliorated with antiadrenergic treatment.

6. Yesavage JA, Fairchild JK, Mi Z, et al. Effect of repetitive transcranial magnetic stimulation on treatment-resistant major depression in US veterans: a randomized clinical trial. JAMA Psychiatry. 2018;75(9):884-893.

Treatment-resistant depression in veterans is a major clinical challenge because of these patients’ increased risk of suicide. Repetitive transcranial magnetic stimulation (rTMS) has shown promising results for TRD. In a randomized trial, Yesavage et al⁶ compared rTMS vs sham rTMS in veterans with TRD.

Study design

• Veterans with TRD were recruited from 9 VA medical centers throughout the United States between September 2012 and May 2016.
• Researchers randomized 164 participants into 1 of 2 groups in a double-blind fashion. The treatment group (n = 81) received left prefrontal rTMS, and the control group (n = 83) received sham rTMS.

Outcomes

• In an intention-to-treat analysis, remission rate (defined as a HAM-D score of ≤10) was assessed as the primary outcome measure.
• Remission was seen in both groups, with 40.7% of the treatment group achieving remission and 37.4% of the control group achieving remission. However, the difference between the 2 groups was not significant (P = .67), with an odds ratio of 1.16.

Continue to: Conclusion

Conclusion

• In this study, treatment with rTMS did not show a statistically significant difference in rates of remission from TRD in veterans compared with sham rTMS. This differs from previous rTMS trials in non-veteran patients.
• The findings of this study also differed from those of other rTMS research in terms of the high remission rates that were seen in both the active and sham groups.

Bottom Line

The risk of death might be increased in children and young adults who receive highdose antipsychotics. Continued treatment with intranasal esketamine may help prevent relapse in patients with treatment-resistant depression (TRD) who initially respond to esketamine. The antidepressant effects of ketamine might be associated with opioid receptor activation. Transcendental meditation may be helpful for patients with posttraumatic stress disorder (PTSD), while prazosin might not improve nightmares or sleep quality in patients with PTSD. Repetitive transcranial magnetic stimulation (rTMS) might not be any more effective than sham rTMS for veterans with TRD.

Related Resources

• NEJM Journal Watch. www.jwatch.org.
• F1000 Prime. https://f1000.com/prime/home.
• BMJ Journals Evidence-Based Mental Health. https://ebmh.bmj.com.

Drug Brand Names

Buprenorphine • Subutex
Chlorpromazine • Thorazine
Esketamine nasal spray • Spravato
Ketamine • Ketalar
Naltrexone • Narcan
Prazosin • Minipress

Medical knowledge is growing faster than ever, as is the challenge of keeping up with this ever-growing body of information. Clinicians need a system or method to help them sort and evaluate the quality of new information before they can apply it to clinical care. Without such a system, when facing an overload of information, most of us tend to take the first or the most easily accessed information, without considering the quality of such information. As a result, the use of poor-quality information affects the quality and outcome of care we provide, and costs billions of dollars annually in problems associated with underuse, overuse, and misuse of treatments.

In an effort to sort and evaluate recently published research that is ready for clinical use, the first author (SAS) used the following 3-step methodology:

1. Searched literature for research findings suggesting readiness for clinical utilization published between July 1, 2018 and June 30, 2019.

2. Surveyed members of the American Association of Chairs of Departments of Psychiatry, the American Association of Community Psychiatrists, the American Association of Psychiatric Administrators, the North Carolina Psychiatric Association, the Group for the Advancement of Psychiatry, and many other colleagues by asking them: “Among the articles published from July 1, 2018 to June 30, 2019, which ones in your opinion have (or are likely to have or should have) affected/changed the clinical practice of psychiatry?”

3. Looked for appraisals in post-publication reviews such as NEJM Journal Watch, F1000 Prime, Evidence-Based Mental Health, commentaries in peer-reviewed journals, and other sources (see Related Resources).

We chose 12 articles based on their clinical relevance/applicability. Here in Part 1 we present brief descriptions of the 6 of top 12 papers chosen by this methodology; these studies are summarized in the Table.^1-6 The order in which they appear in this article is arbitrary. The remaining 6 studies will be reviewed in Part 2 in the February 2020 issue of Current Psychiatry.

1. Ray WA, Stein CM, Murray KT, et al. Association of antipsychotic treatment with risk of unexpected death among children and youths. JAMA Psychiatry. 2019;76(2):162-171.

Children and young adults are increasingly being prescribed antipsychotic medications. Studies have suggested that when these medications are used in adults and older patients, they are associated with an increased risk of death.^7-9 Whether or not these medications are associated with an increased risk of death in children and youth has been unknown. Ray et al¹ compared the risk of unexpected death among children and youths who were beginning treatment with an antipsychotic or control medications.

Study design

• This retrospective cohort study evaluated children and young adults age 5 to 24 who were enrolled in Medicaid in Tennessee between 1999 and 2014.
• New antipsychotic use at both a higher dose (>50 mg chlorpromazine equivalents) and a lower dose (≤50 mg chlorpromazine equivalents) was compared with new use of a control medication, including attention-deficit/hyperactivity disorder medications, antidepressants, and mood stabilizers.
• There were 189,361 participants in the control group, 28,377 participants in the lower-dose antipsychotic group, and 30,120 participants in the higher-dose antipsychotic group.

Outcomes

• The primary outcome was death due to injury or suicide or unexpected death occurring during study follow-up.
• The incidence of death in the higher-dose antipsychotic group (146.2 per 100,000 person-years) was significantly higher (P < .001) than the incidence of death in the control medications group (54.5 per 100,000 person years).
• There was no similar significant difference between the lower-dose antipsychotic group and the control medications group.

Continue to: Conclusion

Conclusion

• Higher-dose antipsychotic use is associated with increased rates of unexpected deaths in children and young adults.
• As with all association studies, no direct line connected cause and effect. However, these results reinforce recommendations for careful prescribing and monitoring of antipsychotic regimens for children and youths, and the need for larger antipsychotic safety studies in this population.
• Examining risks associated with specific antipsychotics will require larger datasets, but will be critical for our understanding of the risks and benefits.

2. Daly EJ, Trivedi MH, Janik A, et al. Efficacy of esketamine nasal spray plus oral antidepressant treatment for relapse prevention in patients with treatment-resistant depression: a randomized clinical trial. JAMA Psychiatry. 2019;76(9):893-903.

Controlled studies have shown esketamine has efficacy for treatment-resistant depression (TRD), but these studies have been only short-term, and the long-term effects of esketamine for TRD have not been established. To fill that gap, Daly et al² assessed the efficacy of esketamine nasal spray plus an oral antidepressant vs a placebo nasal spray plus an oral antidepressant in delaying relapse of depressive symptoms in patients with TRD. All patients were in stable remission after an optimization course of esketamine nasal spray plus an oral antidepressant.

Study design

• Between October 2015 and February 2018, researchers conducted a phase III, multicenter, double-blind, randomized withdrawal study to evaluate the effect of continuation of esketamine on rates of relapse in patients with TRD who had responded to initial treatment with esketamine.
• Initially, 705 adults were enrolled. Of these participants, 455 proceeded to the optimization phase, in which they were treated with esketamine nasal spray plus an oral antidepressant.
• After 16 weeks of optimization treatment, 297 participants achieved remission or stable response and were randomized to a treatment group, which received continued esketamine nasal spray plus an oral antidepressant, or to a control group, which received a placebo nasal spray plus an oral antidepressant.

Outcomes

• Treatment with esketamine nasal spray and an oral antidepressant was associated with decreased rates of relapse compared with treatment with placebo nasal spray and an oral antidepressant. This was the case among patients who had achieved remission as well as those who had achieved stable response.
• Continued treatment with esketamine decreased the risk of relapse by 51%, with 40 participants in the treatment group experiencing relapse compared with 73 participants in the placebo group.

Continue to: Conclusion

Conclusion

• In patients with TRD who responded to initial treatment with esketamine, continuing esketamine plus an oral antidepressant resulted in clinically meaningful superiority in preventing relapse compared with a placebo nasal spray plus an oral antidepressant.

3. Williams NR, Heifets BD, Blasey C, et al. Attenuation of antidepressant effects of ketamine by opioid receptor antagonism. Am J Psychiatry. 2018;175(12):1205-1215.

Many studies have documented the efficacy of ketamine as a rapid-onset antidepressant. Studies investigating the mechanism of this effect have focused on antagonism of N-methyl-D-aspartate (NMDA) receptors. However, several clinical trials that attempted to replicate this rapid antidepressant effect with other NMDA receptor antagonists had only limited success. Williams et al³ conducted the first human study that presents evidence that opioid receptor activation may be necessary for ketamine’s acute antidepressant effect.

Study design

• This double-blind crossover study evaluated if opioid receptor activation is necessary for ketamine to have an antidepressant effect in patients with TRD.
• Twelve participants completed both sides of the study in a randomized order. Participants received placebo or naltrexone prior to an IV infusion of ketamine.
• Researchers measured patients’ scores on the Hamilton Depression Rating Scale (HAM-D) at baseline and 1 day after infusion. Response was defined as a ≥50% reduction in HAM-D score.

Outcomes

• Reductions in HAM-D scores among participants in the ketamine plus naltrexone group were significantly lower than those of participants in the ketamine plus placebo group.
• Dissociation related to ketamine use did not differ significantly between the naltrexone group and the placebo group.

Continue to: Conclusion

Conclusion

• This small study found a significant decrease in the antidepressant effect of ketamine infusion in patients with TRD when opioid receptors are blocked with naltrexone prior to infusion, which suggests opioid receptor activation is necessary for ketamine to be effective as an antidepressant.
• This appears to be consistent with observations of buprenorphine’s antidepressant effects. Caution is indicated until additional studies can further elucidate the mechanism of action of ketamine’s antidepressant effects (see "Ketamine/esketamine: Putative mechanism of action," page 32).

4. Nidich S, Mills PJ, Rainforth M, et al. Non-trauma-focused meditation versus exposure therapy in veterans with post-traumatic stress disorder: a randomised controlled trial. Lancet Psychiatry. 2018;5(12):975-986.

Posttraumatic stress disorder (PTSD) is a common and important public health problem. Evidence-based treatments for PTSD include trauma-focused therapies such as prolonged exposure therapy (PE). However, some patients may not respond to PE, drop out, or elect not to pursue it. Researchers continue to explore treatments that are non-trauma-focused, such as mindfulness meditation and interpersonal psychotherapy. In a 3-group comparative effectiveness trial, Nidich et al⁴ examined the efficacy of a non-trauma-focused intervention, transcendental meditation (TM), in reducing PTSD symptom severity and depression in veterans.

Study design

• Researchers recruited 203 veterans with PTSD from the Department of Veterans Affairs (VA) San Diego Healthcare System between June 2013 and October 2016.
• Participants were randomly assigned to 1 of 3 groups: 68 to TM, 68 to PE, and 67 to PTSD health education (HE).
• Each group received 12 sessions over 12 weeks. In addition to group and individual sessions, all participants received daily practice or assignments.
• The Clinician-Administered PTSD Scale (CAPS) was used to assess symptoms before and after treatment.

Outcomes

• The primary outcome assessed was change in PTSD symptom severity at the end of the study compared with baseline as measured by change in CAPS score.
• Transcendental meditation was found to be significantly non-inferior to PE, with a mean change in CAPS score of −16.1 in the TM group and −11.2 in the PE group.
• Both the TM and PE groups also had significant reductions in CAPS scores compared with the HE group, which had a mean change in CAPS score of −2.5.

Continue to: Conclusion

Conclusion

• Transcendental meditation is significantly not inferior to PE in the treatment of veterans with PTSD.
• The findings from this first comparative effectiveness trial comparing TM with an established psychotherapy for PTSD suggests the feasibility and efficacy of TM as an alternative therapy for veterans with PTSD.
• Because TM is self-administered after an initial expert training, it may offer an easy-to-implement approach that may be more accessible to veterans than other treatments.

5. Raskind MA, Peskind ER, Chow B, et al. Trial of prazosin for post-traumatic stress disorder in military veterans. N Engl J Med. 2018;378(6):507-517.

Several smaller randomized trials of prazosin involving a total of 283 active-duty service members, veterans, and civilian participants have shown efficacy of prazosin for PTSD-related nightmares, sleep disturbance, and overall clinical functioning. However, in a recent trial, Raskind et al⁵ failed to demonstrate such efficacy.

Study design

• Veterans with chronic PTSD nightmares were recruited from 13 VA medical centers to participate in a 26-week, double-blind, randomized controlled trial.
• A total of 304 participants were randomized to a prazosin treatment group (n = 152) or a placebo control group (n = 152).
• During the first 10 weeks, prazosin or placebo were administered in an escalating fashion up to a maximum dose.
• The CAPS, Pittsburgh Sleep Quality Index (PSQI), and Clinical Global Impressions of Change (CGIC) scores were measured at baseline, after 10 weeks, and after 26 weeks.

Outcomes

• Three primary outcomes measures were assessed: change in score from baseline to 10 weeks on CAPS item B2, the PSQI, and the CGIC.
• A secondary measure was change in score from baseline of the same measures at 26 weeks.
• There was no significant difference between the prazosin group and the placebo group in any of the primary or secondary measures.

Continue to: Conclusion

Conclusion

• Compared with placebo, prazosin was not associated with improvement in nightmares or sleep quality for veterans with chronic PTSD nightmares.
• Because psychosocial instability was an exclusion criterion, it is possible that a selection bias resulting from recruitment of patients who were mainly in clinically stable condition accounted for these negative results, since symptoms in such patients were less likely to be ameliorated with antiadrenergic treatment.

6. Yesavage JA, Fairchild JK, Mi Z, et al. Effect of repetitive transcranial magnetic stimulation on treatment-resistant major depression in US veterans: a randomized clinical trial. JAMA Psychiatry. 2018;75(9):884-893.

Treatment-resistant depression in veterans is a major clinical challenge because of these patients’ increased risk of suicide. Repetitive transcranial magnetic stimulation (rTMS) has shown promising results for TRD. In a randomized trial, Yesavage et al⁶ compared rTMS vs sham rTMS in veterans with TRD.

Study design

• Veterans with TRD were recruited from 9 VA medical centers throughout the United States between September 2012 and May 2016.
• Researchers randomized 164 participants into 1 of 2 groups in a double-blind fashion. The treatment group (n = 81) received left prefrontal rTMS, and the control group (n = 83) received sham rTMS.

Outcomes

• In an intention-to-treat analysis, remission rate (defined as a HAM-D score of ≤10) was assessed as the primary outcome measure.
• Remission was seen in both groups, with 40.7% of the treatment group achieving remission and 37.4% of the control group achieving remission. However, the difference between the 2 groups was not significant (P = .67), with an odds ratio of 1.16.

Continue to: Conclusion

Conclusion

• In this study, treatment with rTMS did not show a statistically significant difference in rates of remission from TRD in veterans compared with sham rTMS. This differs from previous rTMS trials in non-veteran patients.
• The findings of this study also differed from those of other rTMS research in terms of the high remission rates that were seen in both the active and sham groups.

Bottom Line

The risk of death might be increased in children and young adults who receive highdose antipsychotics. Continued treatment with intranasal esketamine may help prevent relapse in patients with treatment-resistant depression (TRD) who initially respond to esketamine. The antidepressant effects of ketamine might be associated with opioid receptor activation. Transcendental meditation may be helpful for patients with posttraumatic stress disorder (PTSD), while prazosin might not improve nightmares or sleep quality in patients with PTSD. Repetitive transcranial magnetic stimulation (rTMS) might not be any more effective than sham rTMS for veterans with TRD.

Related Resources

• NEJM Journal Watch. www.jwatch.org.
• F1000 Prime. https://f1000.com/prime/home.
• BMJ Journals Evidence-Based Mental Health. https://ebmh.bmj.com.

Drug Brand Names

Buprenorphine • Subutex
Chlorpromazine • Thorazine
Esketamine nasal spray • Spravato
Ketamine • Ketalar
Naltrexone • Narcan
Prazosin • Minipress

Medical knowledge is growing faster than ever, as is the challenge of keeping up with this ever-growing body of information. Clinicians need a system or method to help them sort and evaluate the quality of new information before they can apply it to clinical care. Without such a system, when facing an overload of information, most of us tend to take the first or the most easily accessed information, without considering the quality of such information. As a result, the use of poor-quality information affects the quality and outcome of care we provide, and costs billions of dollars annually in problems associated with underuse, overuse, and misuse of treatments.

In an effort to sort and evaluate recently published research that is ready for clinical use, the first author (SAS) used the following 3-step methodology:

1. Searched literature for research findings suggesting readiness for clinical utilization published between July 1, 2018 and June 30, 2019.

2. Surveyed members of the American Association of Chairs of Departments of Psychiatry, the American Association of Community Psychiatrists, the American Association of Psychiatric Administrators, the North Carolina Psychiatric Association, the Group for the Advancement of Psychiatry, and many other colleagues by asking them: “Among the articles published from July 1, 2018 to June 30, 2019, which ones in your opinion have (or are likely to have or should have) affected/changed the clinical practice of psychiatry?”

3. Looked for appraisals in post-publication reviews such as NEJM Journal Watch, F1000 Prime, Evidence-Based Mental Health, commentaries in peer-reviewed journals, and other sources (see Related Resources).

We chose 12 articles based on their clinical relevance/applicability. Here in Part 1 we present brief descriptions of the 6 of top 12 papers chosen by this methodology; these studies are summarized in the Table.^1-6 The order in which they appear in this article is arbitrary. The remaining 6 studies will be reviewed in Part 2 in the February 2020 issue of Current Psychiatry.

1. Ray WA, Stein CM, Murray KT, et al. Association of antipsychotic treatment with risk of unexpected death among children and youths. JAMA Psychiatry. 2019;76(2):162-171.

Children and young adults are increasingly being prescribed antipsychotic medications. Studies have suggested that when these medications are used in adults and older patients, they are associated with an increased risk of death.^7-9 Whether or not these medications are associated with an increased risk of death in children and youth has been unknown. Ray et al¹ compared the risk of unexpected death among children and youths who were beginning treatment with an antipsychotic or control medications.

Study design

• This retrospective cohort study evaluated children and young adults age 5 to 24 who were enrolled in Medicaid in Tennessee between 1999 and 2014.
• New antipsychotic use at both a higher dose (>50 mg chlorpromazine equivalents) and a lower dose (≤50 mg chlorpromazine equivalents) was compared with new use of a control medication, including attention-deficit/hyperactivity disorder medications, antidepressants, and mood stabilizers.
• There were 189,361 participants in the control group, 28,377 participants in the lower-dose antipsychotic group, and 30,120 participants in the higher-dose antipsychotic group.

Outcomes

• The primary outcome was death due to injury or suicide or unexpected death occurring during study follow-up.
• The incidence of death in the higher-dose antipsychotic group (146.2 per 100,000 person-years) was significantly higher (P < .001) than the incidence of death in the control medications group (54.5 per 100,000 person years).
• There was no similar significant difference between the lower-dose antipsychotic group and the control medications group.

Continue to: Conclusion

Conclusion

• Higher-dose antipsychotic use is associated with increased rates of unexpected deaths in children and young adults.
• As with all association studies, no direct line connected cause and effect. However, these results reinforce recommendations for careful prescribing and monitoring of antipsychotic regimens for children and youths, and the need for larger antipsychotic safety studies in this population.
• Examining risks associated with specific antipsychotics will require larger datasets, but will be critical for our understanding of the risks and benefits.

2. Daly EJ, Trivedi MH, Janik A, et al. Efficacy of esketamine nasal spray plus oral antidepressant treatment for relapse prevention in patients with treatment-resistant depression: a randomized clinical trial. JAMA Psychiatry. 2019;76(9):893-903.

Controlled studies have shown esketamine has efficacy for treatment-resistant depression (TRD), but these studies have been only short-term, and the long-term effects of esketamine for TRD have not been established. To fill that gap, Daly et al² assessed the efficacy of esketamine nasal spray plus an oral antidepressant vs a placebo nasal spray plus an oral antidepressant in delaying relapse of depressive symptoms in patients with TRD. All patients were in stable remission after an optimization course of esketamine nasal spray plus an oral antidepressant.

Study design

• Between October 2015 and February 2018, researchers conducted a phase III, multicenter, double-blind, randomized withdrawal study to evaluate the effect of continuation of esketamine on rates of relapse in patients with TRD who had responded to initial treatment with esketamine.
• Initially, 705 adults were enrolled. Of these participants, 455 proceeded to the optimization phase, in which they were treated with esketamine nasal spray plus an oral antidepressant.
• After 16 weeks of optimization treatment, 297 participants achieved remission or stable response and were randomized to a treatment group, which received continued esketamine nasal spray plus an oral antidepressant, or to a control group, which received a placebo nasal spray plus an oral antidepressant.

Outcomes

• Treatment with esketamine nasal spray and an oral antidepressant was associated with decreased rates of relapse compared with treatment with placebo nasal spray and an oral antidepressant. This was the case among patients who had achieved remission as well as those who had achieved stable response.
• Continued treatment with esketamine decreased the risk of relapse by 51%, with 40 participants in the treatment group experiencing relapse compared with 73 participants in the placebo group.

Continue to: Conclusion

Conclusion

• In patients with TRD who responded to initial treatment with esketamine, continuing esketamine plus an oral antidepressant resulted in clinically meaningful superiority in preventing relapse compared with a placebo nasal spray plus an oral antidepressant.

3. Williams NR, Heifets BD, Blasey C, et al. Attenuation of antidepressant effects of ketamine by opioid receptor antagonism. Am J Psychiatry. 2018;175(12):1205-1215.

Many studies have documented the efficacy of ketamine as a rapid-onset antidepressant. Studies investigating the mechanism of this effect have focused on antagonism of N-methyl-D-aspartate (NMDA) receptors. However, several clinical trials that attempted to replicate this rapid antidepressant effect with other NMDA receptor antagonists had only limited success. Williams et al³ conducted the first human study that presents evidence that opioid receptor activation may be necessary for ketamine’s acute antidepressant effect.

Study design

• This double-blind crossover study evaluated if opioid receptor activation is necessary for ketamine to have an antidepressant effect in patients with TRD.
• Twelve participants completed both sides of the study in a randomized order. Participants received placebo or naltrexone prior to an IV infusion of ketamine.
• Researchers measured patients’ scores on the Hamilton Depression Rating Scale (HAM-D) at baseline and 1 day after infusion. Response was defined as a ≥50% reduction in HAM-D score.

Outcomes

• Reductions in HAM-D scores among participants in the ketamine plus naltrexone group were significantly lower than those of participants in the ketamine plus placebo group.
• Dissociation related to ketamine use did not differ significantly between the naltrexone group and the placebo group.

Continue to: Conclusion

Conclusion

• This small study found a significant decrease in the antidepressant effect of ketamine infusion in patients with TRD when opioid receptors are blocked with naltrexone prior to infusion, which suggests opioid receptor activation is necessary for ketamine to be effective as an antidepressant.
• This appears to be consistent with observations of buprenorphine’s antidepressant effects. Caution is indicated until additional studies can further elucidate the mechanism of action of ketamine’s antidepressant effects (see "Ketamine/esketamine: Putative mechanism of action," page 32).

4. Nidich S, Mills PJ, Rainforth M, et al. Non-trauma-focused meditation versus exposure therapy in veterans with post-traumatic stress disorder: a randomised controlled trial. Lancet Psychiatry. 2018;5(12):975-986.

Posttraumatic stress disorder (PTSD) is a common and important public health problem. Evidence-based treatments for PTSD include trauma-focused therapies such as prolonged exposure therapy (PE). However, some patients may not respond to PE, drop out, or elect not to pursue it. Researchers continue to explore treatments that are non-trauma-focused, such as mindfulness meditation and interpersonal psychotherapy. In a 3-group comparative effectiveness trial, Nidich et al⁴ examined the efficacy of a non-trauma-focused intervention, transcendental meditation (TM), in reducing PTSD symptom severity and depression in veterans.

Study design

• Researchers recruited 203 veterans with PTSD from the Department of Veterans Affairs (VA) San Diego Healthcare System between June 2013 and October 2016.
• Participants were randomly assigned to 1 of 3 groups: 68 to TM, 68 to PE, and 67 to PTSD health education (HE).
• Each group received 12 sessions over 12 weeks. In addition to group and individual sessions, all participants received daily practice or assignments.
• The Clinician-Administered PTSD Scale (CAPS) was used to assess symptoms before and after treatment.

Outcomes

• The primary outcome assessed was change in PTSD symptom severity at the end of the study compared with baseline as measured by change in CAPS score.
• Transcendental meditation was found to be significantly non-inferior to PE, with a mean change in CAPS score of −16.1 in the TM group and −11.2 in the PE group.
• Both the TM and PE groups also had significant reductions in CAPS scores compared with the HE group, which had a mean change in CAPS score of −2.5.

Continue to: Conclusion

Conclusion

• Transcendental meditation is significantly not inferior to PE in the treatment of veterans with PTSD.
• The findings from this first comparative effectiveness trial comparing TM with an established psychotherapy for PTSD suggests the feasibility and efficacy of TM as an alternative therapy for veterans with PTSD.
• Because TM is self-administered after an initial expert training, it may offer an easy-to-implement approach that may be more accessible to veterans than other treatments.

5. Raskind MA, Peskind ER, Chow B, et al. Trial of prazosin for post-traumatic stress disorder in military veterans. N Engl J Med. 2018;378(6):507-517.

Several smaller randomized trials of prazosin involving a total of 283 active-duty service members, veterans, and civilian participants have shown efficacy of prazosin for PTSD-related nightmares, sleep disturbance, and overall clinical functioning. However, in a recent trial, Raskind et al⁵ failed to demonstrate such efficacy.

Study design

• Veterans with chronic PTSD nightmares were recruited from 13 VA medical centers to participate in a 26-week, double-blind, randomized controlled trial.
• A total of 304 participants were randomized to a prazosin treatment group (n = 152) or a placebo control group (n = 152).
• During the first 10 weeks, prazosin or placebo were administered in an escalating fashion up to a maximum dose.
• The CAPS, Pittsburgh Sleep Quality Index (PSQI), and Clinical Global Impressions of Change (CGIC) scores were measured at baseline, after 10 weeks, and after 26 weeks.

Outcomes

• Three primary outcomes measures were assessed: change in score from baseline to 10 weeks on CAPS item B2, the PSQI, and the CGIC.
• A secondary measure was change in score from baseline of the same measures at 26 weeks.
• There was no significant difference between the prazosin group and the placebo group in any of the primary or secondary measures.

Continue to: Conclusion

Conclusion

• Compared with placebo, prazosin was not associated with improvement in nightmares or sleep quality for veterans with chronic PTSD nightmares.
• Because psychosocial instability was an exclusion criterion, it is possible that a selection bias resulting from recruitment of patients who were mainly in clinically stable condition accounted for these negative results, since symptoms in such patients were less likely to be ameliorated with antiadrenergic treatment.

6. Yesavage JA, Fairchild JK, Mi Z, et al. Effect of repetitive transcranial magnetic stimulation on treatment-resistant major depression in US veterans: a randomized clinical trial. JAMA Psychiatry. 2018;75(9):884-893.

Treatment-resistant depression in veterans is a major clinical challenge because of these patients’ increased risk of suicide. Repetitive transcranial magnetic stimulation (rTMS) has shown promising results for TRD. In a randomized trial, Yesavage et al⁶ compared rTMS vs sham rTMS in veterans with TRD.

Study design

• Veterans with TRD were recruited from 9 VA medical centers throughout the United States between September 2012 and May 2016.
• Researchers randomized 164 participants into 1 of 2 groups in a double-blind fashion. The treatment group (n = 81) received left prefrontal rTMS, and the control group (n = 83) received sham rTMS.

Outcomes

• In an intention-to-treat analysis, remission rate (defined as a HAM-D score of ≤10) was assessed as the primary outcome measure.
• Remission was seen in both groups, with 40.7% of the treatment group achieving remission and 37.4% of the control group achieving remission. However, the difference between the 2 groups was not significant (P = .67), with an odds ratio of 1.16.

Continue to: Conclusion

Conclusion

• In this study, treatment with rTMS did not show a statistically significant difference in rates of remission from TRD in veterans compared with sham rTMS. This differs from previous rTMS trials in non-veteran patients.
• The findings of this study also differed from those of other rTMS research in terms of the high remission rates that were seen in both the active and sham groups.

Bottom Line

The risk of death might be increased in children and young adults who receive highdose antipsychotics. Continued treatment with intranasal esketamine may help prevent relapse in patients with treatment-resistant depression (TRD) who initially respond to esketamine. The antidepressant effects of ketamine might be associated with opioid receptor activation. Transcendental meditation may be helpful for patients with posttraumatic stress disorder (PTSD), while prazosin might not improve nightmares or sleep quality in patients with PTSD. Repetitive transcranial magnetic stimulation (rTMS) might not be any more effective than sham rTMS for veterans with TRD.

Related Resources

• NEJM Journal Watch. www.jwatch.org.
• F1000 Prime. https://f1000.com/prime/home.
• BMJ Journals Evidence-Based Mental Health. https://ebmh.bmj.com.

Drug Brand Names

Buprenorphine • Subutex
Chlorpromazine • Thorazine
Esketamine nasal spray • Spravato
Ketamine • Ketalar
Naltrexone • Narcan
Prazosin • Minipress

Hematology News welcomes Ifeyinwa (Ify) Osunkwo, MD, MPH, as the new editor in chief.

Dr. Osunkwo is a professor of medicine at Atrium Health and the director of the Sickle Cell Enterprise at the Levine Cancer Institute, part of Atrium Health, in Charlotte, N.C.

She has made it her personal mission to improve the quality of life for patients with sickle cell disease, a passion that began during time spent in Nigeria as a child, where 150,000 children are born each year with the condition. In 2014, Dr. Osunkwo created a comprehensive sickle cell center in Charlotte with a multidisciplinary team of providers that includes physicians, nurses, social workers, psychologists, and nurse managers. She has also been an instrumental part of the Carolinas Sickle Cell Collaborative, which seeks to match sickle cell patients in the community with blood donors who have similar blood characteristics.

“As a practicing hematologist and researcher, I have a deep appreciation for the timely and relevant content provided by Hematology News,” Dr. Osunkwo said. “I hope to use my experience to help make this publication even better.”

She is a member of the National Adult Sickle Cell Provider Network and leads the Transition/Medical Home Committee for the Southeast Regional Genetics Network. Her interests include health literacy, adolescent transition of care, and chronic pain management.

Dr. Osunkwo graduated from medical school at the University of Nigeria, Enugu, performed her residency at the New Jersey Medical School, Newark, and completed her fellowship training at Columbia University, New York.

Dr. Osunkwo takes the reigns at Hematology News from Matt Kalaycio, MD, of the Cleveland Clinic Taussig Cancer Center. Dr. Kalaycio was the first editor in chief of Hematology News and held the post for 3 years.

[email protected]

Hematology News welcomes Ifeyinwa (Ify) Osunkwo, MD, MPH, as the new editor in chief.

Dr. Osunkwo is a professor of medicine at Atrium Health and the director of the Sickle Cell Enterprise at the Levine Cancer Institute, part of Atrium Health, in Charlotte, N.C.

She has made it her personal mission to improve the quality of life for patients with sickle cell disease, a passion that began during time spent in Nigeria as a child, where 150,000 children are born each year with the condition. In 2014, Dr. Osunkwo created a comprehensive sickle cell center in Charlotte with a multidisciplinary team of providers that includes physicians, nurses, social workers, psychologists, and nurse managers. She has also been an instrumental part of the Carolinas Sickle Cell Collaborative, which seeks to match sickle cell patients in the community with blood donors who have similar blood characteristics.

“As a practicing hematologist and researcher, I have a deep appreciation for the timely and relevant content provided by Hematology News,” Dr. Osunkwo said. “I hope to use my experience to help make this publication even better.”

She is a member of the National Adult Sickle Cell Provider Network and leads the Transition/Medical Home Committee for the Southeast Regional Genetics Network. Her interests include health literacy, adolescent transition of care, and chronic pain management.

Dr. Osunkwo graduated from medical school at the University of Nigeria, Enugu, performed her residency at the New Jersey Medical School, Newark, and completed her fellowship training at Columbia University, New York.

Dr. Osunkwo takes the reigns at Hematology News from Matt Kalaycio, MD, of the Cleveland Clinic Taussig Cancer Center. Dr. Kalaycio was the first editor in chief of Hematology News and held the post for 3 years.

[email protected]

Hematology News welcomes Ifeyinwa (Ify) Osunkwo, MD, MPH, as the new editor in chief.

Dr. Osunkwo is a professor of medicine at Atrium Health and the director of the Sickle Cell Enterprise at the Levine Cancer Institute, part of Atrium Health, in Charlotte, N.C.

She has made it her personal mission to improve the quality of life for patients with sickle cell disease, a passion that began during time spent in Nigeria as a child, where 150,000 children are born each year with the condition. In 2014, Dr. Osunkwo created a comprehensive sickle cell center in Charlotte with a multidisciplinary team of providers that includes physicians, nurses, social workers, psychologists, and nurse managers. She has also been an instrumental part of the Carolinas Sickle Cell Collaborative, which seeks to match sickle cell patients in the community with blood donors who have similar blood characteristics.

“As a practicing hematologist and researcher, I have a deep appreciation for the timely and relevant content provided by Hematology News,” Dr. Osunkwo said. “I hope to use my experience to help make this publication even better.”

She is a member of the National Adult Sickle Cell Provider Network and leads the Transition/Medical Home Committee for the Southeast Regional Genetics Network. Her interests include health literacy, adolescent transition of care, and chronic pain management.

Dr. Osunkwo graduated from medical school at the University of Nigeria, Enugu, performed her residency at the New Jersey Medical School, Newark, and completed her fellowship training at Columbia University, New York.

Dr. Osunkwo takes the reigns at Hematology News from Matt Kalaycio, MD, of the Cleveland Clinic Taussig Cancer Center. Dr. Kalaycio was the first editor in chief of Hematology News and held the post for 3 years.

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