Acalabrutinib, an oral drug that is a more specific Bruton tyrosine kinase (BTK) inhibitor related to ibrutinib, produced a high response rate and durable remissions at a median 14 months of follow-up in an uncontrolled phase I/II trial of 61 adults with relapsed chronic lymphocytic leukemia, according to a report published online Jan. 28 in the New England Journal of Medicine.

The study patients had received a median of three previous therapies for CLL; 31% had chromosome 17p13.1 deletions, and 75% had unmutated immunoglobulin heavy-chain variable genes.

At the analysis, one patient had died from pneumonia at 13 months and CLL had progressed at 16 months in another patient. The overall response rate among the 60 evaluable patients was 95%, with a partial response in 85% and a partial response with lymphocytosis in 10%. The rate of stable disease was 5%. Adverse events were mostly mild and self-limiting; eight patients (13%) discontinued treatment, said Dr. John C. Byrd of the division of hematology, Ohio State University, Columbus, and his associates.

All 18 patients with chromosome 17p13.1 deletions responded to acalabrutinib, with a partial response in 89% and a partial response with lymphocytosis in 11%. One patient with a chromosome 17p13.1 deletion had disease progression, and this patient had a C481S (major clone) mutation in BTK and an L845F (minor clone) mutation in PLCγ2.

No cases of Richter’s transformation occurred.

Patients were treated at six sites in the United States and the United Kingdom. Four different doses of oral acalabrutinib were used in the first phase of the study; the drug’s low toxicity permitted a twice-daily 100-mg dose in phase II of the study. Twice-daily dosing promoted continuous levels of drug binding to BTK, according to the researchers. It is hoped that this approach will decrease drug resistance and will perhaps lower the rate of transformation into large-cell lymphoma.

Among patients who had cytopenia at entry into the study, platelet count improved in 62%, hemoglobin levels improved in 76%, and absolute neutrophil count improved in 80%. Among patients who had B symptoms (weight loss, night sweats, and fever) at study entry, those symptoms resolved in 88% by the third cycle of treatment and in 100% by the ninth cycle, Dr. Byrd and his associates said (N Engl J Med. 2016 Jan 28. doi: 10.1056/NEJMoa1509981). The most common adverse events were headache (43% of patients), diarrhea (39%), weight gain (26%), pyrexia (23%), and upper respiratory tract infection (23%). Fewer than 2% of patients developed severe diarrhea, rash, arthralgia, myalgia, bruising, or bleeding.

These findings offered strong justification to further investigate the efficacy and safety of acalabrutinib for relapsed CLL, and a phase III trial is now underway, the investigators added.

Acalabrutinib, an oral drug that is a more specific Bruton tyrosine kinase (BTK) inhibitor related to ibrutinib, produced a high response rate and durable remissions at a median 14 months of follow-up in an uncontrolled phase I/II trial of 61 adults with relapsed chronic lymphocytic leukemia, according to a report published online Jan. 28 in the New England Journal of Medicine.

The study patients had received a median of three previous therapies for CLL; 31% had chromosome 17p13.1 deletions, and 75% had unmutated immunoglobulin heavy-chain variable genes.

At the analysis, one patient had died from pneumonia at 13 months and CLL had progressed at 16 months in another patient. The overall response rate among the 60 evaluable patients was 95%, with a partial response in 85% and a partial response with lymphocytosis in 10%. The rate of stable disease was 5%. Adverse events were mostly mild and self-limiting; eight patients (13%) discontinued treatment, said Dr. John C. Byrd of the division of hematology, Ohio State University, Columbus, and his associates.

All 18 patients with chromosome 17p13.1 deletions responded to acalabrutinib, with a partial response in 89% and a partial response with lymphocytosis in 11%. One patient with a chromosome 17p13.1 deletion had disease progression, and this patient had a C481S (major clone) mutation in BTK and an L845F (minor clone) mutation in PLCγ2.

No cases of Richter’s transformation occurred.

Patients were treated at six sites in the United States and the United Kingdom. Four different doses of oral acalabrutinib were used in the first phase of the study; the drug’s low toxicity permitted a twice-daily 100-mg dose in phase II of the study. Twice-daily dosing promoted continuous levels of drug binding to BTK, according to the researchers. It is hoped that this approach will decrease drug resistance and will perhaps lower the rate of transformation into large-cell lymphoma.

Among patients who had cytopenia at entry into the study, platelet count improved in 62%, hemoglobin levels improved in 76%, and absolute neutrophil count improved in 80%. Among patients who had B symptoms (weight loss, night sweats, and fever) at study entry, those symptoms resolved in 88% by the third cycle of treatment and in 100% by the ninth cycle, Dr. Byrd and his associates said (N Engl J Med. 2016 Jan 28. doi: 10.1056/NEJMoa1509981). The most common adverse events were headache (43% of patients), diarrhea (39%), weight gain (26%), pyrexia (23%), and upper respiratory tract infection (23%). Fewer than 2% of patients developed severe diarrhea, rash, arthralgia, myalgia, bruising, or bleeding.

These findings offered strong justification to further investigate the efficacy and safety of acalabrutinib for relapsed CLL, and a phase III trial is now underway, the investigators added.

Acalabrutinib, an oral drug that is a more specific Bruton tyrosine kinase (BTK) inhibitor related to ibrutinib, produced a high response rate and durable remissions at a median 14 months of follow-up in an uncontrolled phase I/II trial of 61 adults with relapsed chronic lymphocytic leukemia, according to a report published online Jan. 28 in the New England Journal of Medicine.

The study patients had received a median of three previous therapies for CLL; 31% had chromosome 17p13.1 deletions, and 75% had unmutated immunoglobulin heavy-chain variable genes.

At the analysis, one patient had died from pneumonia at 13 months and CLL had progressed at 16 months in another patient. The overall response rate among the 60 evaluable patients was 95%, with a partial response in 85% and a partial response with lymphocytosis in 10%. The rate of stable disease was 5%. Adverse events were mostly mild and self-limiting; eight patients (13%) discontinued treatment, said Dr. John C. Byrd of the division of hematology, Ohio State University, Columbus, and his associates.

All 18 patients with chromosome 17p13.1 deletions responded to acalabrutinib, with a partial response in 89% and a partial response with lymphocytosis in 11%. One patient with a chromosome 17p13.1 deletion had disease progression, and this patient had a C481S (major clone) mutation in BTK and an L845F (minor clone) mutation in PLCγ2.

No cases of Richter’s transformation occurred.

Patients were treated at six sites in the United States and the United Kingdom. Four different doses of oral acalabrutinib were used in the first phase of the study; the drug’s low toxicity permitted a twice-daily 100-mg dose in phase II of the study. Twice-daily dosing promoted continuous levels of drug binding to BTK, according to the researchers. It is hoped that this approach will decrease drug resistance and will perhaps lower the rate of transformation into large-cell lymphoma.

Among patients who had cytopenia at entry into the study, platelet count improved in 62%, hemoglobin levels improved in 76%, and absolute neutrophil count improved in 80%. Among patients who had B symptoms (weight loss, night sweats, and fever) at study entry, those symptoms resolved in 88% by the third cycle of treatment and in 100% by the ninth cycle, Dr. Byrd and his associates said (N Engl J Med. 2016 Jan 28. doi: 10.1056/NEJMoa1509981). The most common adverse events were headache (43% of patients), diarrhea (39%), weight gain (26%), pyrexia (23%), and upper respiratory tract infection (23%). Fewer than 2% of patients developed severe diarrhea, rash, arthralgia, myalgia, bruising, or bleeding.

These findings offered strong justification to further investigate the efficacy and safety of acalabrutinib for relapsed CLL, and a phase III trial is now underway, the investigators added.

That expression is a residue of the absurd belief during the Middle Ages that mental illness is caused by evil spirits—that justified burning the afflicted person at the stake. (Remember Joan of Arc?)

This ignorant, even maliciously unscientific, portrayal of psychiatric symptoms is an appalling disservice to all our patients who struggle with a potentially disabling neuropsychiatric disorder. Regrettably, some religious entities still propagate the fallacy of possession by an evil spirit and call for exorcism of bizarre behaviors sometimes associated with psychosis.¹ What is really needed is an exorcism of unscientific and harmful misconceptions that mental illness is the nefarious work of Beelzebub or Lucifer.

Strange manifestations beget weird explanations
I can understand how ignorance about the neurologic basis of unusual delusions and behavior can trigger absurd religious explanations for their cause. Sometimes, brain pathology can have strange clinical manifestations that are beyond the ken of the average layperson, which invites metaphysical, religious, or philosophical explanation. Here are examples of neuropsychiatric symptoms in the category of “very unusual” that might summon a demonic malfeasance.

Delusion of possession or alien control. Some people complain of being possessed²; delusional people who have a strong religious background might believe they are possessed by Satan himself. Some of my patients with psychotic depression believe this, expressing great guilt and anguish about being doomed to go to Hell.

Alternately, patients with schizophrenia often think they are under the control of an “alien force” that shapes their behavior, feelings, and thoughts (a Schneiderian first-rank symptom). In a 2012 editorial, I proposed that this “alien intruder” is the unintegrated right hemispheric consciousness,³ and that disintegration of the 200 million inter-hemispheric white matter fibers of the corpus callosum might be the cause of the loss of integration of the right hemisphere into the dominant left hemisphere.

Some people attribute external control on their lives to a government agency, a foreign country, or a spiteful neighbor; others believe it is the work of evil spirits. Whereas the foundation of the delusion is brain pathology, the content of the delusion is colored by the affected person’s cultural and religious background.

Apotemnophilia. A neurologic disorder that manifests in a bizarre clinical symptom that invites faulty explanation: A person demands amputation of a leg because “it doesn’t belong to my body.”⁴ The cause of this strange and confusing disorder has been misinterpreted as a paraphilia, a desire by the affected person to achieve greater sexual satisfaction by having a stump. It was first reported in the September/October 1972 issue of the magazine Penthouse, where it was described as the motivation to heighten one’s sexual appeal because stumps can be sexually exciting to their partners.

It took many years of neurologic research to demonstrate that apotemnophilia is caused by pathology in the parietal lobe, where the physical representation of the body is located. Incomplete neurodevelopment of the parietal lobe can cause a person to fail to recognize a leg as a “legitimate” part of his body, and he (she) then desperately seeks amputation of the so-called alien limb (see the description of xenomelia below) that is attached to his body.

When an affected person is asked to delineate the borders of an alien limb, he draws a line on the skin at the precise border between the alien limb and the rest of his body—where the amputation should take place. Requests for surgical amputation were adamantly denied when the disorder was thought to be a weird sexual practice, but elective amputation in the context of neuropsychopathology is seriously debated now—and has, in fact, been reported.⁵ The term “body impaired integrity disorder” has been proposed, but neurologists consider the disorder an example of xenomelia.

Xenomelia (‘alien limb syndrome’). An odd neurologic disorder produced by brain pathology, in which a person has a sense of estrangement about 1 or more limbs.⁵ The disorder can be caused by a neurologic lesion such as tumor, Creutzfeldt-Jakob disease, hereditary diffuse leukoencephalopathy, demyelinating disease, progressive dementia, corpus callosotomy, intracerebral hemorrhage, or thalamic degeneration.⁶

So-called “alien hand syndrome,” or asomatognosia, is a widely recognized example of xenomelia, and is associated with medial frontal lobe damage.

Another variant of xenomelia is somatoparaphrenia, unawareness of a part of one’s body.⁷

Cotard syndrome. A nihilistic delusion of the nonexistence or dissolution of a body part; in extreme form, the delusion of being dead or nonexistent.⁸ The syndrome sometimes occurs in the setting of severe depression. Research has shown an association with atrophy of the insula,⁹ which is responsible for internal proprioception (interoception).

Delusional misidentification syndrome. A set of neuropsychiatric conditions in which a person misidentifies people, places, objects, or events¹⁰:

• Capgras syndrome (one perceives a familiar person as an imposter)
• Fregoli syndrome (one perceives that a familiar person is repeatedly disguised to change appearance)
• intermetamorphosis (one perceives that a person changes his external appearance and personality or identity)
• lycanthropy (one delusionally misidentifies one’s self as an animal—eg, a wolf, rabbit, or snake, and behaves accordingly)
• Ekbom syndrome (delusional belief of being infested with parasites )
• delusion of hermaphroditism (one has merged in the same body with another person of the opposite sex)
• delusion of sexual transformation (one has changed to the opposite sex)
• delusion of being the Antichrist.

Delusional misidentification syndrome can develop after the onset of focal or diffuse brain pathology, such as right hemispheric stroke, multiple sclerosis, hyperparathyroidism, traumatic brain injury, dementia, and schizophrenia. In several studies, researchers have reported an increased risk of violence in delusional misidentification syndromes.¹¹

Neurological, not diabolical!
A disruption in brain anatomy, neurodevelopment, or circuitry/interconnectivity can produce odd beliefs and bizarre behavior that might prompt a lay observer to believe that a demon or an evil spirt is responsible for the incomprehensible symptoms. I have one response to the “blame-the-devil” proponents: It’s the brain pathology, stupid!

That expression is a residue of the absurd belief during the Middle Ages that mental illness is caused by evil spirits—that justified burning the afflicted person at the stake. (Remember Joan of Arc?)

This ignorant, even maliciously unscientific, portrayal of psychiatric symptoms is an appalling disservice to all our patients who struggle with a potentially disabling neuropsychiatric disorder. Regrettably, some religious entities still propagate the fallacy of possession by an evil spirit and call for exorcism of bizarre behaviors sometimes associated with psychosis.¹ What is really needed is an exorcism of unscientific and harmful misconceptions that mental illness is the nefarious work of Beelzebub or Lucifer.

Strange manifestations beget weird explanations
I can understand how ignorance about the neurologic basis of unusual delusions and behavior can trigger absurd religious explanations for their cause. Sometimes, brain pathology can have strange clinical manifestations that are beyond the ken of the average layperson, which invites metaphysical, religious, or philosophical explanation. Here are examples of neuropsychiatric symptoms in the category of “very unusual” that might summon a demonic malfeasance.

Delusion of possession or alien control. Some people complain of being possessed²; delusional people who have a strong religious background might believe they are possessed by Satan himself. Some of my patients with psychotic depression believe this, expressing great guilt and anguish about being doomed to go to Hell.

Alternately, patients with schizophrenia often think they are under the control of an “alien force” that shapes their behavior, feelings, and thoughts (a Schneiderian first-rank symptom). In a 2012 editorial, I proposed that this “alien intruder” is the unintegrated right hemispheric consciousness,³ and that disintegration of the 200 million inter-hemispheric white matter fibers of the corpus callosum might be the cause of the loss of integration of the right hemisphere into the dominant left hemisphere.

Some people attribute external control on their lives to a government agency, a foreign country, or a spiteful neighbor; others believe it is the work of evil spirits. Whereas the foundation of the delusion is brain pathology, the content of the delusion is colored by the affected person’s cultural and religious background.

Apotemnophilia. A neurologic disorder that manifests in a bizarre clinical symptom that invites faulty explanation: A person demands amputation of a leg because “it doesn’t belong to my body.”⁴ The cause of this strange and confusing disorder has been misinterpreted as a paraphilia, a desire by the affected person to achieve greater sexual satisfaction by having a stump. It was first reported in the September/October 1972 issue of the magazine Penthouse, where it was described as the motivation to heighten one’s sexual appeal because stumps can be sexually exciting to their partners.

It took many years of neurologic research to demonstrate that apotemnophilia is caused by pathology in the parietal lobe, where the physical representation of the body is located. Incomplete neurodevelopment of the parietal lobe can cause a person to fail to recognize a leg as a “legitimate” part of his body, and he (she) then desperately seeks amputation of the so-called alien limb (see the description of xenomelia below) that is attached to his body.

When an affected person is asked to delineate the borders of an alien limb, he draws a line on the skin at the precise border between the alien limb and the rest of his body—where the amputation should take place. Requests for surgical amputation were adamantly denied when the disorder was thought to be a weird sexual practice, but elective amputation in the context of neuropsychopathology is seriously debated now—and has, in fact, been reported.⁵ The term “body impaired integrity disorder” has been proposed, but neurologists consider the disorder an example of xenomelia.

Xenomelia (‘alien limb syndrome’). An odd neurologic disorder produced by brain pathology, in which a person has a sense of estrangement about 1 or more limbs.⁵ The disorder can be caused by a neurologic lesion such as tumor, Creutzfeldt-Jakob disease, hereditary diffuse leukoencephalopathy, demyelinating disease, progressive dementia, corpus callosotomy, intracerebral hemorrhage, or thalamic degeneration.⁶

So-called “alien hand syndrome,” or asomatognosia, is a widely recognized example of xenomelia, and is associated with medial frontal lobe damage.

Another variant of xenomelia is somatoparaphrenia, unawareness of a part of one’s body.⁷

Cotard syndrome. A nihilistic delusion of the nonexistence or dissolution of a body part; in extreme form, the delusion of being dead or nonexistent.⁸ The syndrome sometimes occurs in the setting of severe depression. Research has shown an association with atrophy of the insula,⁹ which is responsible for internal proprioception (interoception).

Delusional misidentification syndrome. A set of neuropsychiatric conditions in which a person misidentifies people, places, objects, or events¹⁰:

• Capgras syndrome (one perceives a familiar person as an imposter)
• Fregoli syndrome (one perceives that a familiar person is repeatedly disguised to change appearance)
• intermetamorphosis (one perceives that a person changes his external appearance and personality or identity)
• lycanthropy (one delusionally misidentifies one’s self as an animal—eg, a wolf, rabbit, or snake, and behaves accordingly)
• Ekbom syndrome (delusional belief of being infested with parasites )
• delusion of hermaphroditism (one has merged in the same body with another person of the opposite sex)
• delusion of sexual transformation (one has changed to the opposite sex)
• delusion of being the Antichrist.

Delusional misidentification syndrome can develop after the onset of focal or diffuse brain pathology, such as right hemispheric stroke, multiple sclerosis, hyperparathyroidism, traumatic brain injury, dementia, and schizophrenia. In several studies, researchers have reported an increased risk of violence in delusional misidentification syndromes.¹¹

Neurological, not diabolical!
A disruption in brain anatomy, neurodevelopment, or circuitry/interconnectivity can produce odd beliefs and bizarre behavior that might prompt a lay observer to believe that a demon or an evil spirt is responsible for the incomprehensible symptoms. I have one response to the “blame-the-devil” proponents: It’s the brain pathology, stupid!

That expression is a residue of the absurd belief during the Middle Ages that mental illness is caused by evil spirits—that justified burning the afflicted person at the stake. (Remember Joan of Arc?)

This ignorant, even maliciously unscientific, portrayal of psychiatric symptoms is an appalling disservice to all our patients who struggle with a potentially disabling neuropsychiatric disorder. Regrettably, some religious entities still propagate the fallacy of possession by an evil spirit and call for exorcism of bizarre behaviors sometimes associated with psychosis.¹ What is really needed is an exorcism of unscientific and harmful misconceptions that mental illness is the nefarious work of Beelzebub or Lucifer.

Strange manifestations beget weird explanations
I can understand how ignorance about the neurologic basis of unusual delusions and behavior can trigger absurd religious explanations for their cause. Sometimes, brain pathology can have strange clinical manifestations that are beyond the ken of the average layperson, which invites metaphysical, religious, or philosophical explanation. Here are examples of neuropsychiatric symptoms in the category of “very unusual” that might summon a demonic malfeasance.

Delusion of possession or alien control. Some people complain of being possessed²; delusional people who have a strong religious background might believe they are possessed by Satan himself. Some of my patients with psychotic depression believe this, expressing great guilt and anguish about being doomed to go to Hell.

Alternately, patients with schizophrenia often think they are under the control of an “alien force” that shapes their behavior, feelings, and thoughts (a Schneiderian first-rank symptom). In a 2012 editorial, I proposed that this “alien intruder” is the unintegrated right hemispheric consciousness,³ and that disintegration of the 200 million inter-hemispheric white matter fibers of the corpus callosum might be the cause of the loss of integration of the right hemisphere into the dominant left hemisphere.

Some people attribute external control on their lives to a government agency, a foreign country, or a spiteful neighbor; others believe it is the work of evil spirits. Whereas the foundation of the delusion is brain pathology, the content of the delusion is colored by the affected person’s cultural and religious background.

Apotemnophilia. A neurologic disorder that manifests in a bizarre clinical symptom that invites faulty explanation: A person demands amputation of a leg because “it doesn’t belong to my body.”⁴ The cause of this strange and confusing disorder has been misinterpreted as a paraphilia, a desire by the affected person to achieve greater sexual satisfaction by having a stump. It was first reported in the September/October 1972 issue of the magazine Penthouse, where it was described as the motivation to heighten one’s sexual appeal because stumps can be sexually exciting to their partners.

It took many years of neurologic research to demonstrate that apotemnophilia is caused by pathology in the parietal lobe, where the physical representation of the body is located. Incomplete neurodevelopment of the parietal lobe can cause a person to fail to recognize a leg as a “legitimate” part of his body, and he (she) then desperately seeks amputation of the so-called alien limb (see the description of xenomelia below) that is attached to his body.

When an affected person is asked to delineate the borders of an alien limb, he draws a line on the skin at the precise border between the alien limb and the rest of his body—where the amputation should take place. Requests for surgical amputation were adamantly denied when the disorder was thought to be a weird sexual practice, but elective amputation in the context of neuropsychopathology is seriously debated now—and has, in fact, been reported.⁵ The term “body impaired integrity disorder” has been proposed, but neurologists consider the disorder an example of xenomelia.

Xenomelia (‘alien limb syndrome’). An odd neurologic disorder produced by brain pathology, in which a person has a sense of estrangement about 1 or more limbs.⁵ The disorder can be caused by a neurologic lesion such as tumor, Creutzfeldt-Jakob disease, hereditary diffuse leukoencephalopathy, demyelinating disease, progressive dementia, corpus callosotomy, intracerebral hemorrhage, or thalamic degeneration.⁶

So-called “alien hand syndrome,” or asomatognosia, is a widely recognized example of xenomelia, and is associated with medial frontal lobe damage.

Another variant of xenomelia is somatoparaphrenia, unawareness of a part of one’s body.⁷

Cotard syndrome. A nihilistic delusion of the nonexistence or dissolution of a body part; in extreme form, the delusion of being dead or nonexistent.⁸ The syndrome sometimes occurs in the setting of severe depression. Research has shown an association with atrophy of the insula,⁹ which is responsible for internal proprioception (interoception).

Delusional misidentification syndrome. A set of neuropsychiatric conditions in which a person misidentifies people, places, objects, or events¹⁰:

• Capgras syndrome (one perceives a familiar person as an imposter)
• Fregoli syndrome (one perceives that a familiar person is repeatedly disguised to change appearance)
• intermetamorphosis (one perceives that a person changes his external appearance and personality or identity)
• lycanthropy (one delusionally misidentifies one’s self as an animal—eg, a wolf, rabbit, or snake, and behaves accordingly)
• Ekbom syndrome (delusional belief of being infested with parasites )
• delusion of hermaphroditism (one has merged in the same body with another person of the opposite sex)
• delusion of sexual transformation (one has changed to the opposite sex)
• delusion of being the Antichrist.

Delusional misidentification syndrome can develop after the onset of focal or diffuse brain pathology, such as right hemispheric stroke, multiple sclerosis, hyperparathyroidism, traumatic brain injury, dementia, and schizophrenia. In several studies, researchers have reported an increased risk of violence in delusional misidentification syndromes.¹¹

Neurological, not diabolical!
A disruption in brain anatomy, neurodevelopment, or circuitry/interconnectivity can produce odd beliefs and bizarre behavior that might prompt a lay observer to believe that a demon or an evil spirt is responsible for the incomprehensible symptoms. I have one response to the “blame-the-devil” proponents: It’s the brain pathology, stupid!

New analyses of multiple sclerosis patients taking natalizumab reemphasize the need to monitor John Cunningham virus (JCV) seroconversion and the level of anti-JCV antibody titers via JCV index values, according to a study of a pair of German and French cohorts.

Longitudinal data available for 525 German patients and 711 French patients with relapsing-remitting multiple sclerosis (MS) revealed seroconversion rates of 8.5%-10.3% per year, seroprevalence increases of 5%-6% during 15-24 months of follow-up, and increases in JCV index values of 0.091 units (12.9%) per year, which “clearly support the facilitation [of progressive multifocal leukoencephalopathy (PML)] by treatment with natalizumab [Tysabri]” and are “at least 8 to 10 times as much as would be expected by age,” reported Nicholas Schwab, Ph.D., of the University of Münster (Germany) and his colleagues (Neurol Neuroimmunol Neuroinflamm. 2016;3:e195. doi: 10.1212/NXI.0000000000000195).

Of the longitudinally followed German patients, 186 (35.4%) were initially seropositive and 43 (12.7%) became seropositive during a mean follow-up duration of 14.8 months, or 10.3% per year. The group of 711 longitudinally followed French patients included 468 (65.8%) who were initially JCV positive. A total of 20 (8.2%) patients who were initially JCV negative seroconverted in the first year, and another 21 (8.6%) did so in the second year, for an overall rate of 8.5% per year.

A total of 525 patients had changes in the level of anti-JCV antibodies in serum (and therefore had changes in JCV index value) during the observation period. Patients with a JCV index value less than 0.4 (very low PML risk) declined from 65.1% to 61.3%, and those with values 0.4-0.9 (low risk) declined from 8.0% to 7.8%. The proportion grew from 4.6% to 5.9% for values 0.9-1.5 (medium risk) and from 22.3% to 25.0% for values greater than 1.5 (high risk). In addition to reflecting the patients’ change in serostatus, the change in PML risk levels “suggested that patients who changed serostatus directly presented with high anti-JCV antibody titers afterward, as the groups of low and medium risk did not grow substantially over time,” the researchers wrote.

A group of 201 patients who were followed over time after becoming seropositive had a mean JCV index value that rose significantly from 2.046 to 2.158 and was not attributable to aging. Rises in JCV index values of more than 30% over the course of 14.8 months occurred in 17% of the patients, compared with stable values in 80% and decreases of more than 30% in 3%. Altogether, the index value of all 201 patients rose by a mean of 0.091 units (12.9%) per year.

“Because as yet there are no studies on the influence of other treatments on JCV index values ... we cannot be certain that it was the treatment with natalizumab that led to the rising index values in our study,” the investigators wrote, although they noted that a recent study of more than 7,000 control patients with MS showed that the duration of non–natalizumab MS treatment did not influence JCV seroprevalence after adjustment for age, sex, and country of origin.

Also, even though the mean index value for JCV-positive patients was greater than 2, putting them in the highest PML risk category, the investigators noted that very few of these patients will ultimately develop PML, so “JCV serology should not be the only PML risk biomarker used in the stratification of patients treated with natalizumab.”

The study was funded by various German and French institutional and governmental grants. Many authors reported financial ties to companies marketing MS drugs, including Biogen, the manufacturer of natalizumab.

[email protected]

New analyses of multiple sclerosis patients taking natalizumab reemphasize the need to monitor John Cunningham virus (JCV) seroconversion and the level of anti-JCV antibody titers via JCV index values, according to a study of a pair of German and French cohorts.

Longitudinal data available for 525 German patients and 711 French patients with relapsing-remitting multiple sclerosis (MS) revealed seroconversion rates of 8.5%-10.3% per year, seroprevalence increases of 5%-6% during 15-24 months of follow-up, and increases in JCV index values of 0.091 units (12.9%) per year, which “clearly support the facilitation [of progressive multifocal leukoencephalopathy (PML)] by treatment with natalizumab [Tysabri]” and are “at least 8 to 10 times as much as would be expected by age,” reported Nicholas Schwab, Ph.D., of the University of Münster (Germany) and his colleagues (Neurol Neuroimmunol Neuroinflamm. 2016;3:e195. doi: 10.1212/NXI.0000000000000195).

Of the longitudinally followed German patients, 186 (35.4%) were initially seropositive and 43 (12.7%) became seropositive during a mean follow-up duration of 14.8 months, or 10.3% per year. The group of 711 longitudinally followed French patients included 468 (65.8%) who were initially JCV positive. A total of 20 (8.2%) patients who were initially JCV negative seroconverted in the first year, and another 21 (8.6%) did so in the second year, for an overall rate of 8.5% per year.

A total of 525 patients had changes in the level of anti-JCV antibodies in serum (and therefore had changes in JCV index value) during the observation period. Patients with a JCV index value less than 0.4 (very low PML risk) declined from 65.1% to 61.3%, and those with values 0.4-0.9 (low risk) declined from 8.0% to 7.8%. The proportion grew from 4.6% to 5.9% for values 0.9-1.5 (medium risk) and from 22.3% to 25.0% for values greater than 1.5 (high risk). In addition to reflecting the patients’ change in serostatus, the change in PML risk levels “suggested that patients who changed serostatus directly presented with high anti-JCV antibody titers afterward, as the groups of low and medium risk did not grow substantially over time,” the researchers wrote.

A group of 201 patients who were followed over time after becoming seropositive had a mean JCV index value that rose significantly from 2.046 to 2.158 and was not attributable to aging. Rises in JCV index values of more than 30% over the course of 14.8 months occurred in 17% of the patients, compared with stable values in 80% and decreases of more than 30% in 3%. Altogether, the index value of all 201 patients rose by a mean of 0.091 units (12.9%) per year.

“Because as yet there are no studies on the influence of other treatments on JCV index values ... we cannot be certain that it was the treatment with natalizumab that led to the rising index values in our study,” the investigators wrote, although they noted that a recent study of more than 7,000 control patients with MS showed that the duration of non–natalizumab MS treatment did not influence JCV seroprevalence after adjustment for age, sex, and country of origin.

Also, even though the mean index value for JCV-positive patients was greater than 2, putting them in the highest PML risk category, the investigators noted that very few of these patients will ultimately develop PML, so “JCV serology should not be the only PML risk biomarker used in the stratification of patients treated with natalizumab.”

The study was funded by various German and French institutional and governmental grants. Many authors reported financial ties to companies marketing MS drugs, including Biogen, the manufacturer of natalizumab.

[email protected]

New analyses of multiple sclerosis patients taking natalizumab reemphasize the need to monitor John Cunningham virus (JCV) seroconversion and the level of anti-JCV antibody titers via JCV index values, according to a study of a pair of German and French cohorts.

Longitudinal data available for 525 German patients and 711 French patients with relapsing-remitting multiple sclerosis (MS) revealed seroconversion rates of 8.5%-10.3% per year, seroprevalence increases of 5%-6% during 15-24 months of follow-up, and increases in JCV index values of 0.091 units (12.9%) per year, which “clearly support the facilitation [of progressive multifocal leukoencephalopathy (PML)] by treatment with natalizumab [Tysabri]” and are “at least 8 to 10 times as much as would be expected by age,” reported Nicholas Schwab, Ph.D., of the University of Münster (Germany) and his colleagues (Neurol Neuroimmunol Neuroinflamm. 2016;3:e195. doi: 10.1212/NXI.0000000000000195).

Of the longitudinally followed German patients, 186 (35.4%) were initially seropositive and 43 (12.7%) became seropositive during a mean follow-up duration of 14.8 months, or 10.3% per year. The group of 711 longitudinally followed French patients included 468 (65.8%) who were initially JCV positive. A total of 20 (8.2%) patients who were initially JCV negative seroconverted in the first year, and another 21 (8.6%) did so in the second year, for an overall rate of 8.5% per year.

A total of 525 patients had changes in the level of anti-JCV antibodies in serum (and therefore had changes in JCV index value) during the observation period. Patients with a JCV index value less than 0.4 (very low PML risk) declined from 65.1% to 61.3%, and those with values 0.4-0.9 (low risk) declined from 8.0% to 7.8%. The proportion grew from 4.6% to 5.9% for values 0.9-1.5 (medium risk) and from 22.3% to 25.0% for values greater than 1.5 (high risk). In addition to reflecting the patients’ change in serostatus, the change in PML risk levels “suggested that patients who changed serostatus directly presented with high anti-JCV antibody titers afterward, as the groups of low and medium risk did not grow substantially over time,” the researchers wrote.

A group of 201 patients who were followed over time after becoming seropositive had a mean JCV index value that rose significantly from 2.046 to 2.158 and was not attributable to aging. Rises in JCV index values of more than 30% over the course of 14.8 months occurred in 17% of the patients, compared with stable values in 80% and decreases of more than 30% in 3%. Altogether, the index value of all 201 patients rose by a mean of 0.091 units (12.9%) per year.

“Because as yet there are no studies on the influence of other treatments on JCV index values ... we cannot be certain that it was the treatment with natalizumab that led to the rising index values in our study,” the investigators wrote, although they noted that a recent study of more than 7,000 control patients with MS showed that the duration of non–natalizumab MS treatment did not influence JCV seroprevalence after adjustment for age, sex, and country of origin.

Also, even though the mean index value for JCV-positive patients was greater than 2, putting them in the highest PML risk category, the investigators noted that very few of these patients will ultimately develop PML, so “JCV serology should not be the only PML risk biomarker used in the stratification of patients treated with natalizumab.”

The study was funded by various German and French institutional and governmental grants. Many authors reported financial ties to companies marketing MS drugs, including Biogen, the manufacturer of natalizumab.

[email protected]

Any discussion of the relationship between major depressive disorder (MDD) and chronic pain encounters an obstacle immediately: Neither has a singular pathophysiology. Furthermore, MDD and, to a significant extent, chronic pain are defined more by their symptoms than by a presumed etiology and pathogenesis.

Why does this matter to a busy clinician?
Explicitly or implicitly, we often align our treatment approaches with what we assume is the underlying pathophysiology of the conditions we are addressing. An overview of shared pathophysiology of chronic pain conditions and MDD therefore can be useful in practice.

What is chronic pain? Defined as “pain that persists past the healing phase following an injury,”¹ chronic pain often is subdivided into 4 types^2,3:

• nociceptive (caused by a lesion or potential tissue damage)
• inflammatory
• neuropathic (spontaneous pain or hypersensitivity to pain related to neurologic illness or injury)
• functional (hypersensitivity to pain due to abnormal central processing of a normal input).

Although fibromyalgia often is categorized as a dysfunctional pain syndrome, persons who suffer from it, much like those who suffer neuropathic pain, commonly report hyperalgesia (augmented sensitivity to painful stimuli), allodynia (abnormal pain response to non-noxious stimuli), and paresthesias. These shared clinical features of fibromyalgia and neuropathic pain are consistent with central sensitization, which suggests overlapping pathophysiology.⁴

Comorbidity between depression and pain is common. A 30% to 60% co-occurrence rate of MDD and chronic pain has been reported.⁵ Some subtypes of chronic pain, such as fibromyalgia, are so commonly comorbid with psychiatric conditions that they have spawned a scientific debate as to whether the conditions are most parsimoniously considered (1) separate illnesses with high comorbidity or (2) different symptomatic manifestations of a single underlying condition.⁶ Moreover, cumulative evidence suggests that chronic pain and depression do not just co-occur; each one facilitates development of the other, such that chronic pain is a strong predictor of subsequent onset of MDD, and vice versa.

When pain and depression are comorbid, they also tend to make treatment of each condition more difficult. For example, pain presents (1) a major obstacle to achieving remission when treating depression^7,8 and (2) significant risk of relapse.⁹ A 3-year longitudinal study showed that painful symptoms substantially reduced the chance of recovery in a group of older depressed patients (n = 327). A substantially greater percentage of patients with MDD alone attained recovery (47%), compared with only 9% in whom MDD and painful symptoms were comorbid.¹⁰ Furthermore, a higher level of pain can delay remission when treating MDD,¹¹ thus reducing the likelihood of an optimal outcome.¹²

Understanding shared processes. Recent developments in neuroscience and psycho-immunology point to the fact that comorbid pain and depression might be driven by overlapping pathophysiological processes in the brain and body. In the 2 parts of this article, we (1) review scientific understanding of these shared processes and (2) demonstrate how recent advances in the epidemiology, phenomenology, and etiology of chronic pain and MDD provide important clues for more effective diagnosis (Part 1) and treatment (Part 2, March 2016)—and, therefore, better outcomes. Our focus is primarily on the relationship between MDD and the best-studied comorbid chronic pain conditions: fibromyalgia, neuropathic pain, chronic back pain, and rheumatoid arthritis.

The societal burden of chronic pain conditions is enormous
A recent epidemiological study¹³ projected that as many as 100 million people in the United States—30.7% of the population—suffer some form of chronic pain, including arthritis and joint pain. A World Health Organization survey yielded a similar (and staggering) 37% prevalence of chronic pain in the population of 10 developed countries.¹⁴

Estimates are that various forms of neuropathic pain, including diabetic neuropathy, postherpetic neuralgia, trigeminal neuralgia, spinal cord injury, and radiculopathy, alone afflict as many as 26 million people worldwide, including approximately 1.5% of the U.S. population.^15,16

Chronic low back pain is epidemic. With a projected point prevalence of 30%, the condition is the most common cause of activity limitation among people age <45, and the most frequent reason in the United States for visiting a physician.¹

Functional somatic syndromes, including fibromyalgia and irritable bowel syndrome, impose an astounding strain on health care: These syndromes account for 25% to 50% of all outpatient visits, or approximately 400 million clinic visits annually in the United States.¹⁷

Why should you care about these numbers? The answer is that comorbidity among chronic pain, mood disorders, anxiety disorders, sleep disorders, cognitive impairment, fatigue, and chronic stress presents an enormous clinical challenge because it not only complicates the diagnosis of these conditions but also compromises treatment outcomes and imposes severe limitations on daily functioning and quality of life of those afflicted.^5,17-24

A complex relationship and a daunting clinical challenge
Chronic pain enhances the risk of MDD by 2-fold to 5-fold. The risk appears to be mediated by the number of pain conditions rather than by the severity of pain.²³ Some authors have noted a kind of dose-response relationship among pain, depression, and anxiety. Among patients who experienced chronic pain that affected 1 body region, the prevalence of generalized anxiety disorder (GAD) and MDD was 30% and 20%, respectively; in patients who experienced pain in ≥2 regions, the prevalence of GAD and MDD was elevated to 54% and 32%.²⁵ Moreover, patients with fibromyalgia were 4.3 times more likely than healthy controls to develop MDD at some point in their lives and 4.7 times more likely to develop an anxiety disorder.²⁶

Although women are more likely to suffer from fibromyalgia, the risk for people of either sex of developing subsequent MDD is comparable once the condition has developed.²⁷ Overall, depression and anxiety are among the most common comorbidities of fibromyalgia, with prevalence ranging from 20% to 80% and 13% to 63.8%, respectively.²⁸

High comorbidity between depression and pain also is relevant for patients with neuropathic pain. A survey from Australia reported depression in 34% and anxiety in 25% of patients with neuropathic pain.²⁹ Pain severity tended to be enduring and associated with significantly impaired functioning. A significant percentage of patients suffering from rheumatoid arthritis and systemic lupus erythematosus tend to manifest anxiety and depression (93% to 94%), cognitive impairment (66%), fatigue (40%), and sleep disorders (72%).²²

The relationship between depression and pain appears to be bidirectional. For example, recent studies demonstrate that 30% to 60% of depressed patients also suffer from a painful condition.⁵

The complex history of patients presenting with concomitant complaints of depression, anxiety, chronic pain, sleep disturbance, cognitive impairment, and fatigue present a daunting diagnostic task. Pain tends to be associated with greater fatigue and sleep disturbance, which in turn depletes a patient’s ability to enjoy life and enhances negative affect.^19,20,30 The take-home message might be to screen all chronic pain patients for MDD, anxiety, and sleep disorders, and vice versa.

Furthermore, comorbidity among chronic pain, MDD, anxiety, and sleep disorders can introduce specific intricacies into our treatment approach. Although, in general, comorbidities tend to have a negative impact on treatment outcomes, many pharmacotherapeutic and non-drug interventions targeting chronic pain might ameliorate sleep problems, low energy, anxiety, depression, and anhedonia.^18,20,30-32 On the other hand, we should consider that opioid treatment for chronic pain might represent a risk factor for subsequent depression. It is conceivable that chronic opioid treatment and associated sedation can erode self-efficacy and social relationships, thereby compromising sources of support.^33,34 It is equally important to keep in mind that, even if we are successful in attaining remission when treating depression and pain, residual pain symptoms might persist, requiring more specific interventions.²⁴

MDD and chronic pain each have, on their own, a well-established association with suicide attempts and completion. Researchers are investigating whether a pathophysiologic suicide-promoting synergy between the 2 disorders exists when they are comorbid (Box^35-37).

Shared genetics and pathophysiology
Several candidate genes have been identified as risk genes for chronic pain, depression, and anxiety. One of those studied the most is 5-HTTLPR, involved in regulating synthesis of serotonin transporter. The short form of this gene has been implicated in a diverse set of conditions, including MDD, anxiety disorders, and substance abuse—and fibromyalgia. Other genes associated with the risk of MDD and pain disorders are ones that code for:

• serotonin 5-HT2A and 5-HT1A receptors
• catechol-O-methyltransferase, an enzyme involved in catecholamine metabolism
• dopamine D4 receptor
• proinflammatory cytokines interleukin-1 and interleukin-6.⁴

Both monoamines and inflammatory cytokines play a role in modulating γ-aminobutyric acid (GABA) and glutamate neurons, as well as glia cells constituting peripheral pain pathways and central circuits that participate in the pain response and regulation of mood.^4,17,38

The ‘pain matrix’
Brain circuitry that is involved in processing pain stimuli—often referred to as the pain matrix—shares many structural components with circuitry involved in the stress response and emotional modulation.⁴ Emerging evidence indicates that the pain matrix might not be pain-specific but, instead, a complex aggregate of interconnected brain structures involved in evoking defensive responses to a number of offending stimuli, including pain, threat, danger, loss, and social rejection or isolation.

It is remarkable, in this regard, that imaging studies show that the dorsal anterior cingulate, central to experiencing negative affect in response to physical pain, also mediates distress in response to the “pain” of social exclusion.³⁹ Emerging functional and structural imaging provides evidence of continuous reorganization of prefrontal cortices as a consequence of enduring chronic pain.¹ Of particular interest are findings of (1) a reduction of gray matter in the dorsolateral prefrontal cortex (DLPFC) and (2) functional activation of the medial prefrontal cortex (mPFC), both of which correlate with the duration and experience of chronic back pain.¹ It is tempting to speculate that structural decline of the DLPFC, observed in MDD and chronic pain, is linked to cognitive and executive function deficits, which are readily observed in patients with either disorder—given that DLPFC is a “hub” of the so-called “cognitive-executive functional network.”^1,4

Likewise, the mPFC is a key component of the default mode network (DMN), a functional network also comprising the posterior cingulate cortex and hippocampus. DMN performs a diverse set of activities, including self-reflection, daydreaming, reminiscing, planning, processing of social information, and creative thinking. Negative neuroplastic changes in the DMN are a common finding in MDD and chronic pain, and might be associated with a tendency toward rumination and catastrophizing—key clinical manifestations of MDD and chronic pain—and linked with pervasive negative affect and sleep disturbance.^4,32

Furthermore, functional and structural changes in the amygdala and hippocampus have been described in MDD, fibromyalgia, and neuropathic pain.⁴ Dysfunction of these limbic formations may be a contributing factor in the disruption of neuroendocrine, autonomic, and immune function, which could further contribute to aggravated mood and pain symptoms.^4,17,40

Consequently, excessive hypothalamic-pituitary-adrenal axis and sympathetic activation, combined with elevation of proinflammatory cytokine production and release, likely plays a role in the pathophysiology of MDD and chronic pain disorders.^4,17,40 Moreover, at cellular, subcellular, and molecular levels, chronic pain and MDD are associated with:

• perturbed neuron-glia relationships
• altered glutamatergic, GABA, glycine, substance-P, opioid, 5-HT, norepinephrine, and dopamine signaling
• dysfunction of intracellular signaling cascades and neurotrophic signaling.^{4,20,30,31,38}

The Figure that describes how homeostatic function of prefrontal cortical-limbic circuitry is compromised in MDD and chronic pain—thus disrupting autonomic, neuroendocrine, and neuroimmune regulation.

Disturbance in monoamine signaling in chronic pain and MDD might give rise to profound anhedonia, cognitive impairment, anxiety, insomnia, sensitivity to stress, and inadequate functioning of descending pain-regulatory pathways, which primarily use norepinephrine and 5-HT.^{4,9,20,30,31,38} Using pharmacotherapeutic agents that successfully modulate monoamines, therefore, might ameliorate the function of brain networks innervated by neurotransmitter systems involved in the regulation of pain, mood, cognition, stress response, and sleep. Notably, the same monoamines serve as transmitters in descending pain pathways.

In summary, convergent evidence indicates that MDD and chronic pain states amplify each other, thus contributing to treatment resistance in both disorders.

On the bright side, timely and effective treatment of MDD might optimize the chance of remission and minimize the risk of enduring structural brain changes in MDD and chronic pain.^1,4,31,32 The obverse is also true: Emphasizing the importance of the resolution of painful symptoms in the context of MDD, a study reported a significantly greater remission rate of 36.2% in those who had >50% reduction of pain on a visual analogue scale following treatment with a serotonin-norepinephrine reuptake inhibitor, compared with a 17.8% remission rate in persons who experienced <50% pain reduction on the scale.³

Editors’ note: In Part 2 of this article (March 2016), the authors review pharmacotherapeutic and non-drug strategies for managing comorbid chronic pain conditions and MDD.

Any discussion of the relationship between major depressive disorder (MDD) and chronic pain encounters an obstacle immediately: Neither has a singular pathophysiology. Furthermore, MDD and, to a significant extent, chronic pain are defined more by their symptoms than by a presumed etiology and pathogenesis.

Why does this matter to a busy clinician?
Explicitly or implicitly, we often align our treatment approaches with what we assume is the underlying pathophysiology of the conditions we are addressing. An overview of shared pathophysiology of chronic pain conditions and MDD therefore can be useful in practice.

What is chronic pain? Defined as “pain that persists past the healing phase following an injury,”¹ chronic pain often is subdivided into 4 types^2,3:

• nociceptive (caused by a lesion or potential tissue damage)
• inflammatory
• neuropathic (spontaneous pain or hypersensitivity to pain related to neurologic illness or injury)
• functional (hypersensitivity to pain due to abnormal central processing of a normal input).

Although fibromyalgia often is categorized as a dysfunctional pain syndrome, persons who suffer from it, much like those who suffer neuropathic pain, commonly report hyperalgesia (augmented sensitivity to painful stimuli), allodynia (abnormal pain response to non-noxious stimuli), and paresthesias. These shared clinical features of fibromyalgia and neuropathic pain are consistent with central sensitization, which suggests overlapping pathophysiology.⁴

Comorbidity between depression and pain is common. A 30% to 60% co-occurrence rate of MDD and chronic pain has been reported.⁵ Some subtypes of chronic pain, such as fibromyalgia, are so commonly comorbid with psychiatric conditions that they have spawned a scientific debate as to whether the conditions are most parsimoniously considered (1) separate illnesses with high comorbidity or (2) different symptomatic manifestations of a single underlying condition.⁶ Moreover, cumulative evidence suggests that chronic pain and depression do not just co-occur; each one facilitates development of the other, such that chronic pain is a strong predictor of subsequent onset of MDD, and vice versa.

When pain and depression are comorbid, they also tend to make treatment of each condition more difficult. For example, pain presents (1) a major obstacle to achieving remission when treating depression^7,8 and (2) significant risk of relapse.⁹ A 3-year longitudinal study showed that painful symptoms substantially reduced the chance of recovery in a group of older depressed patients (n = 327). A substantially greater percentage of patients with MDD alone attained recovery (47%), compared with only 9% in whom MDD and painful symptoms were comorbid.¹⁰ Furthermore, a higher level of pain can delay remission when treating MDD,¹¹ thus reducing the likelihood of an optimal outcome.¹²

Understanding shared processes. Recent developments in neuroscience and psycho-immunology point to the fact that comorbid pain and depression might be driven by overlapping pathophysiological processes in the brain and body. In the 2 parts of this article, we (1) review scientific understanding of these shared processes and (2) demonstrate how recent advances in the epidemiology, phenomenology, and etiology of chronic pain and MDD provide important clues for more effective diagnosis (Part 1) and treatment (Part 2, March 2016)—and, therefore, better outcomes. Our focus is primarily on the relationship between MDD and the best-studied comorbid chronic pain conditions: fibromyalgia, neuropathic pain, chronic back pain, and rheumatoid arthritis.

The societal burden of chronic pain conditions is enormous
A recent epidemiological study¹³ projected that as many as 100 million people in the United States—30.7% of the population—suffer some form of chronic pain, including arthritis and joint pain. A World Health Organization survey yielded a similar (and staggering) 37% prevalence of chronic pain in the population of 10 developed countries.¹⁴

Estimates are that various forms of neuropathic pain, including diabetic neuropathy, postherpetic neuralgia, trigeminal neuralgia, spinal cord injury, and radiculopathy, alone afflict as many as 26 million people worldwide, including approximately 1.5% of the U.S. population.^15,16

Chronic low back pain is epidemic. With a projected point prevalence of 30%, the condition is the most common cause of activity limitation among people age <45, and the most frequent reason in the United States for visiting a physician.¹

Functional somatic syndromes, including fibromyalgia and irritable bowel syndrome, impose an astounding strain on health care: These syndromes account for 25% to 50% of all outpatient visits, or approximately 400 million clinic visits annually in the United States.¹⁷

Why should you care about these numbers? The answer is that comorbidity among chronic pain, mood disorders, anxiety disorders, sleep disorders, cognitive impairment, fatigue, and chronic stress presents an enormous clinical challenge because it not only complicates the diagnosis of these conditions but also compromises treatment outcomes and imposes severe limitations on daily functioning and quality of life of those afflicted.^5,17-24

A complex relationship and a daunting clinical challenge
Chronic pain enhances the risk of MDD by 2-fold to 5-fold. The risk appears to be mediated by the number of pain conditions rather than by the severity of pain.²³ Some authors have noted a kind of dose-response relationship among pain, depression, and anxiety. Among patients who experienced chronic pain that affected 1 body region, the prevalence of generalized anxiety disorder (GAD) and MDD was 30% and 20%, respectively; in patients who experienced pain in ≥2 regions, the prevalence of GAD and MDD was elevated to 54% and 32%.²⁵ Moreover, patients with fibromyalgia were 4.3 times more likely than healthy controls to develop MDD at some point in their lives and 4.7 times more likely to develop an anxiety disorder.²⁶

Although women are more likely to suffer from fibromyalgia, the risk for people of either sex of developing subsequent MDD is comparable once the condition has developed.²⁷ Overall, depression and anxiety are among the most common comorbidities of fibromyalgia, with prevalence ranging from 20% to 80% and 13% to 63.8%, respectively.²⁸

High comorbidity between depression and pain also is relevant for patients with neuropathic pain. A survey from Australia reported depression in 34% and anxiety in 25% of patients with neuropathic pain.²⁹ Pain severity tended to be enduring and associated with significantly impaired functioning. A significant percentage of patients suffering from rheumatoid arthritis and systemic lupus erythematosus tend to manifest anxiety and depression (93% to 94%), cognitive impairment (66%), fatigue (40%), and sleep disorders (72%).²²

The relationship between depression and pain appears to be bidirectional. For example, recent studies demonstrate that 30% to 60% of depressed patients also suffer from a painful condition.⁵

The complex history of patients presenting with concomitant complaints of depression, anxiety, chronic pain, sleep disturbance, cognitive impairment, and fatigue present a daunting diagnostic task. Pain tends to be associated with greater fatigue and sleep disturbance, which in turn depletes a patient’s ability to enjoy life and enhances negative affect.^19,20,30 The take-home message might be to screen all chronic pain patients for MDD, anxiety, and sleep disorders, and vice versa.

Furthermore, comorbidity among chronic pain, MDD, anxiety, and sleep disorders can introduce specific intricacies into our treatment approach. Although, in general, comorbidities tend to have a negative impact on treatment outcomes, many pharmacotherapeutic and non-drug interventions targeting chronic pain might ameliorate sleep problems, low energy, anxiety, depression, and anhedonia.^18,20,30-32 On the other hand, we should consider that opioid treatment for chronic pain might represent a risk factor for subsequent depression. It is conceivable that chronic opioid treatment and associated sedation can erode self-efficacy and social relationships, thereby compromising sources of support.^33,34 It is equally important to keep in mind that, even if we are successful in attaining remission when treating depression and pain, residual pain symptoms might persist, requiring more specific interventions.²⁴

MDD and chronic pain each have, on their own, a well-established association with suicide attempts and completion. Researchers are investigating whether a pathophysiologic suicide-promoting synergy between the 2 disorders exists when they are comorbid (Box^35-37).

Shared genetics and pathophysiology
Several candidate genes have been identified as risk genes for chronic pain, depression, and anxiety. One of those studied the most is 5-HTTLPR, involved in regulating synthesis of serotonin transporter. The short form of this gene has been implicated in a diverse set of conditions, including MDD, anxiety disorders, and substance abuse—and fibromyalgia. Other genes associated with the risk of MDD and pain disorders are ones that code for:

• serotonin 5-HT2A and 5-HT1A receptors
• catechol-O-methyltransferase, an enzyme involved in catecholamine metabolism
• dopamine D4 receptor
• proinflammatory cytokines interleukin-1 and interleukin-6.⁴

Both monoamines and inflammatory cytokines play a role in modulating γ-aminobutyric acid (GABA) and glutamate neurons, as well as glia cells constituting peripheral pain pathways and central circuits that participate in the pain response and regulation of mood.^4,17,38

The ‘pain matrix’
Brain circuitry that is involved in processing pain stimuli—often referred to as the pain matrix—shares many structural components with circuitry involved in the stress response and emotional modulation.⁴ Emerging evidence indicates that the pain matrix might not be pain-specific but, instead, a complex aggregate of interconnected brain structures involved in evoking defensive responses to a number of offending stimuli, including pain, threat, danger, loss, and social rejection or isolation.

It is remarkable, in this regard, that imaging studies show that the dorsal anterior cingulate, central to experiencing negative affect in response to physical pain, also mediates distress in response to the “pain” of social exclusion.³⁹ Emerging functional and structural imaging provides evidence of continuous reorganization of prefrontal cortices as a consequence of enduring chronic pain.¹ Of particular interest are findings of (1) a reduction of gray matter in the dorsolateral prefrontal cortex (DLPFC) and (2) functional activation of the medial prefrontal cortex (mPFC), both of which correlate with the duration and experience of chronic back pain.¹ It is tempting to speculate that structural decline of the DLPFC, observed in MDD and chronic pain, is linked to cognitive and executive function deficits, which are readily observed in patients with either disorder—given that DLPFC is a “hub” of the so-called “cognitive-executive functional network.”^1,4

Likewise, the mPFC is a key component of the default mode network (DMN), a functional network also comprising the posterior cingulate cortex and hippocampus. DMN performs a diverse set of activities, including self-reflection, daydreaming, reminiscing, planning, processing of social information, and creative thinking. Negative neuroplastic changes in the DMN are a common finding in MDD and chronic pain, and might be associated with a tendency toward rumination and catastrophizing—key clinical manifestations of MDD and chronic pain—and linked with pervasive negative affect and sleep disturbance.^4,32

Furthermore, functional and structural changes in the amygdala and hippocampus have been described in MDD, fibromyalgia, and neuropathic pain.⁴ Dysfunction of these limbic formations may be a contributing factor in the disruption of neuroendocrine, autonomic, and immune function, which could further contribute to aggravated mood and pain symptoms.^4,17,40

Consequently, excessive hypothalamic-pituitary-adrenal axis and sympathetic activation, combined with elevation of proinflammatory cytokine production and release, likely plays a role in the pathophysiology of MDD and chronic pain disorders.^4,17,40 Moreover, at cellular, subcellular, and molecular levels, chronic pain and MDD are associated with:

• perturbed neuron-glia relationships
• altered glutamatergic, GABA, glycine, substance-P, opioid, 5-HT, norepinephrine, and dopamine signaling
• dysfunction of intracellular signaling cascades and neurotrophic signaling.^{4,20,30,31,38}

The Figure that describes how homeostatic function of prefrontal cortical-limbic circuitry is compromised in MDD and chronic pain—thus disrupting autonomic, neuroendocrine, and neuroimmune regulation.

Disturbance in monoamine signaling in chronic pain and MDD might give rise to profound anhedonia, cognitive impairment, anxiety, insomnia, sensitivity to stress, and inadequate functioning of descending pain-regulatory pathways, which primarily use norepinephrine and 5-HT.^{4,9,20,30,31,38} Using pharmacotherapeutic agents that successfully modulate monoamines, therefore, might ameliorate the function of brain networks innervated by neurotransmitter systems involved in the regulation of pain, mood, cognition, stress response, and sleep. Notably, the same monoamines serve as transmitters in descending pain pathways.

In summary, convergent evidence indicates that MDD and chronic pain states amplify each other, thus contributing to treatment resistance in both disorders.

On the bright side, timely and effective treatment of MDD might optimize the chance of remission and minimize the risk of enduring structural brain changes in MDD and chronic pain.^1,4,31,32 The obverse is also true: Emphasizing the importance of the resolution of painful symptoms in the context of MDD, a study reported a significantly greater remission rate of 36.2% in those who had >50% reduction of pain on a visual analogue scale following treatment with a serotonin-norepinephrine reuptake inhibitor, compared with a 17.8% remission rate in persons who experienced <50% pain reduction on the scale.³

Editors’ note: In Part 2 of this article (March 2016), the authors review pharmacotherapeutic and non-drug strategies for managing comorbid chronic pain conditions and MDD.

Any discussion of the relationship between major depressive disorder (MDD) and chronic pain encounters an obstacle immediately: Neither has a singular pathophysiology. Furthermore, MDD and, to a significant extent, chronic pain are defined more by their symptoms than by a presumed etiology and pathogenesis.

Why does this matter to a busy clinician?
Explicitly or implicitly, we often align our treatment approaches with what we assume is the underlying pathophysiology of the conditions we are addressing. An overview of shared pathophysiology of chronic pain conditions and MDD therefore can be useful in practice.

What is chronic pain? Defined as “pain that persists past the healing phase following an injury,”¹ chronic pain often is subdivided into 4 types^2,3:

• nociceptive (caused by a lesion or potential tissue damage)
• inflammatory
• neuropathic (spontaneous pain or hypersensitivity to pain related to neurologic illness or injury)
• functional (hypersensitivity to pain due to abnormal central processing of a normal input).

Although fibromyalgia often is categorized as a dysfunctional pain syndrome, persons who suffer from it, much like those who suffer neuropathic pain, commonly report hyperalgesia (augmented sensitivity to painful stimuli), allodynia (abnormal pain response to non-noxious stimuli), and paresthesias. These shared clinical features of fibromyalgia and neuropathic pain are consistent with central sensitization, which suggests overlapping pathophysiology.⁴

Comorbidity between depression and pain is common. A 30% to 60% co-occurrence rate of MDD and chronic pain has been reported.⁵ Some subtypes of chronic pain, such as fibromyalgia, are so commonly comorbid with psychiatric conditions that they have spawned a scientific debate as to whether the conditions are most parsimoniously considered (1) separate illnesses with high comorbidity or (2) different symptomatic manifestations of a single underlying condition.⁶ Moreover, cumulative evidence suggests that chronic pain and depression do not just co-occur; each one facilitates development of the other, such that chronic pain is a strong predictor of subsequent onset of MDD, and vice versa.

When pain and depression are comorbid, they also tend to make treatment of each condition more difficult. For example, pain presents (1) a major obstacle to achieving remission when treating depression^7,8 and (2) significant risk of relapse.⁹ A 3-year longitudinal study showed that painful symptoms substantially reduced the chance of recovery in a group of older depressed patients (n = 327). A substantially greater percentage of patients with MDD alone attained recovery (47%), compared with only 9% in whom MDD and painful symptoms were comorbid.¹⁰ Furthermore, a higher level of pain can delay remission when treating MDD,¹¹ thus reducing the likelihood of an optimal outcome.¹²

Understanding shared processes. Recent developments in neuroscience and psycho-immunology point to the fact that comorbid pain and depression might be driven by overlapping pathophysiological processes in the brain and body. In the 2 parts of this article, we (1) review scientific understanding of these shared processes and (2) demonstrate how recent advances in the epidemiology, phenomenology, and etiology of chronic pain and MDD provide important clues for more effective diagnosis (Part 1) and treatment (Part 2, March 2016)—and, therefore, better outcomes. Our focus is primarily on the relationship between MDD and the best-studied comorbid chronic pain conditions: fibromyalgia, neuropathic pain, chronic back pain, and rheumatoid arthritis.

The societal burden of chronic pain conditions is enormous
A recent epidemiological study¹³ projected that as many as 100 million people in the United States—30.7% of the population—suffer some form of chronic pain, including arthritis and joint pain. A World Health Organization survey yielded a similar (and staggering) 37% prevalence of chronic pain in the population of 10 developed countries.¹⁴

Estimates are that various forms of neuropathic pain, including diabetic neuropathy, postherpetic neuralgia, trigeminal neuralgia, spinal cord injury, and radiculopathy, alone afflict as many as 26 million people worldwide, including approximately 1.5% of the U.S. population.^15,16

Chronic low back pain is epidemic. With a projected point prevalence of 30%, the condition is the most common cause of activity limitation among people age <45, and the most frequent reason in the United States for visiting a physician.¹

Functional somatic syndromes, including fibromyalgia and irritable bowel syndrome, impose an astounding strain on health care: These syndromes account for 25% to 50% of all outpatient visits, or approximately 400 million clinic visits annually in the United States.¹⁷

Why should you care about these numbers? The answer is that comorbidity among chronic pain, mood disorders, anxiety disorders, sleep disorders, cognitive impairment, fatigue, and chronic stress presents an enormous clinical challenge because it not only complicates the diagnosis of these conditions but also compromises treatment outcomes and imposes severe limitations on daily functioning and quality of life of those afflicted.^5,17-24

A complex relationship and a daunting clinical challenge
Chronic pain enhances the risk of MDD by 2-fold to 5-fold. The risk appears to be mediated by the number of pain conditions rather than by the severity of pain.²³ Some authors have noted a kind of dose-response relationship among pain, depression, and anxiety. Among patients who experienced chronic pain that affected 1 body region, the prevalence of generalized anxiety disorder (GAD) and MDD was 30% and 20%, respectively; in patients who experienced pain in ≥2 regions, the prevalence of GAD and MDD was elevated to 54% and 32%.²⁵ Moreover, patients with fibromyalgia were 4.3 times more likely than healthy controls to develop MDD at some point in their lives and 4.7 times more likely to develop an anxiety disorder.²⁶

Although women are more likely to suffer from fibromyalgia, the risk for people of either sex of developing subsequent MDD is comparable once the condition has developed.²⁷ Overall, depression and anxiety are among the most common comorbidities of fibromyalgia, with prevalence ranging from 20% to 80% and 13% to 63.8%, respectively.²⁸

High comorbidity between depression and pain also is relevant for patients with neuropathic pain. A survey from Australia reported depression in 34% and anxiety in 25% of patients with neuropathic pain.²⁹ Pain severity tended to be enduring and associated with significantly impaired functioning. A significant percentage of patients suffering from rheumatoid arthritis and systemic lupus erythematosus tend to manifest anxiety and depression (93% to 94%), cognitive impairment (66%), fatigue (40%), and sleep disorders (72%).²²

The relationship between depression and pain appears to be bidirectional. For example, recent studies demonstrate that 30% to 60% of depressed patients also suffer from a painful condition.⁵

The complex history of patients presenting with concomitant complaints of depression, anxiety, chronic pain, sleep disturbance, cognitive impairment, and fatigue present a daunting diagnostic task. Pain tends to be associated with greater fatigue and sleep disturbance, which in turn depletes a patient’s ability to enjoy life and enhances negative affect.^19,20,30 The take-home message might be to screen all chronic pain patients for MDD, anxiety, and sleep disorders, and vice versa.

Furthermore, comorbidity among chronic pain, MDD, anxiety, and sleep disorders can introduce specific intricacies into our treatment approach. Although, in general, comorbidities tend to have a negative impact on treatment outcomes, many pharmacotherapeutic and non-drug interventions targeting chronic pain might ameliorate sleep problems, low energy, anxiety, depression, and anhedonia.^18,20,30-32 On the other hand, we should consider that opioid treatment for chronic pain might represent a risk factor for subsequent depression. It is conceivable that chronic opioid treatment and associated sedation can erode self-efficacy and social relationships, thereby compromising sources of support.^33,34 It is equally important to keep in mind that, even if we are successful in attaining remission when treating depression and pain, residual pain symptoms might persist, requiring more specific interventions.²⁴

MDD and chronic pain each have, on their own, a well-established association with suicide attempts and completion. Researchers are investigating whether a pathophysiologic suicide-promoting synergy between the 2 disorders exists when they are comorbid (Box^35-37).

Shared genetics and pathophysiology
Several candidate genes have been identified as risk genes for chronic pain, depression, and anxiety. One of those studied the most is 5-HTTLPR, involved in regulating synthesis of serotonin transporter. The short form of this gene has been implicated in a diverse set of conditions, including MDD, anxiety disorders, and substance abuse—and fibromyalgia. Other genes associated with the risk of MDD and pain disorders are ones that code for:

• serotonin 5-HT2A and 5-HT1A receptors
• catechol-O-methyltransferase, an enzyme involved in catecholamine metabolism
• dopamine D4 receptor
• proinflammatory cytokines interleukin-1 and interleukin-6.⁴

Both monoamines and inflammatory cytokines play a role in modulating γ-aminobutyric acid (GABA) and glutamate neurons, as well as glia cells constituting peripheral pain pathways and central circuits that participate in the pain response and regulation of mood.^4,17,38

The ‘pain matrix’
Brain circuitry that is involved in processing pain stimuli—often referred to as the pain matrix—shares many structural components with circuitry involved in the stress response and emotional modulation.⁴ Emerging evidence indicates that the pain matrix might not be pain-specific but, instead, a complex aggregate of interconnected brain structures involved in evoking defensive responses to a number of offending stimuli, including pain, threat, danger, loss, and social rejection or isolation.

It is remarkable, in this regard, that imaging studies show that the dorsal anterior cingulate, central to experiencing negative affect in response to physical pain, also mediates distress in response to the “pain” of social exclusion.³⁹ Emerging functional and structural imaging provides evidence of continuous reorganization of prefrontal cortices as a consequence of enduring chronic pain.¹ Of particular interest are findings of (1) a reduction of gray matter in the dorsolateral prefrontal cortex (DLPFC) and (2) functional activation of the medial prefrontal cortex (mPFC), both of which correlate with the duration and experience of chronic back pain.¹ It is tempting to speculate that structural decline of the DLPFC, observed in MDD and chronic pain, is linked to cognitive and executive function deficits, which are readily observed in patients with either disorder—given that DLPFC is a “hub” of the so-called “cognitive-executive functional network.”^1,4

Likewise, the mPFC is a key component of the default mode network (DMN), a functional network also comprising the posterior cingulate cortex and hippocampus. DMN performs a diverse set of activities, including self-reflection, daydreaming, reminiscing, planning, processing of social information, and creative thinking. Negative neuroplastic changes in the DMN are a common finding in MDD and chronic pain, and might be associated with a tendency toward rumination and catastrophizing—key clinical manifestations of MDD and chronic pain—and linked with pervasive negative affect and sleep disturbance.^4,32

Furthermore, functional and structural changes in the amygdala and hippocampus have been described in MDD, fibromyalgia, and neuropathic pain.⁴ Dysfunction of these limbic formations may be a contributing factor in the disruption of neuroendocrine, autonomic, and immune function, which could further contribute to aggravated mood and pain symptoms.^4,17,40

Consequently, excessive hypothalamic-pituitary-adrenal axis and sympathetic activation, combined with elevation of proinflammatory cytokine production and release, likely plays a role in the pathophysiology of MDD and chronic pain disorders.^4,17,40 Moreover, at cellular, subcellular, and molecular levels, chronic pain and MDD are associated with:

• perturbed neuron-glia relationships
• altered glutamatergic, GABA, glycine, substance-P, opioid, 5-HT, norepinephrine, and dopamine signaling
• dysfunction of intracellular signaling cascades and neurotrophic signaling.^{4,20,30,31,38}

The Figure that describes how homeostatic function of prefrontal cortical-limbic circuitry is compromised in MDD and chronic pain—thus disrupting autonomic, neuroendocrine, and neuroimmune regulation.

Disturbance in monoamine signaling in chronic pain and MDD might give rise to profound anhedonia, cognitive impairment, anxiety, insomnia, sensitivity to stress, and inadequate functioning of descending pain-regulatory pathways, which primarily use norepinephrine and 5-HT.^{4,9,20,30,31,38} Using pharmacotherapeutic agents that successfully modulate monoamines, therefore, might ameliorate the function of brain networks innervated by neurotransmitter systems involved in the regulation of pain, mood, cognition, stress response, and sleep. Notably, the same monoamines serve as transmitters in descending pain pathways.

In summary, convergent evidence indicates that MDD and chronic pain states amplify each other, thus contributing to treatment resistance in both disorders.

On the bright side, timely and effective treatment of MDD might optimize the chance of remission and minimize the risk of enduring structural brain changes in MDD and chronic pain.^1,4,31,32 The obverse is also true: Emphasizing the importance of the resolution of painful symptoms in the context of MDD, a study reported a significantly greater remission rate of 36.2% in those who had >50% reduction of pain on a visual analogue scale following treatment with a serotonin-norepinephrine reuptake inhibitor, compared with a 17.8% remission rate in persons who experienced <50% pain reduction on the scale.³

Editors’ note: In Part 2 of this article (March 2016), the authors review pharmacotherapeutic and non-drug strategies for managing comorbid chronic pain conditions and MDD.

An 81-year-old man is brought in by his wife for evaluation of a very itchy rash on his bilateral lower tibial areas. He says the problem started about six months ago, after a spate of summer yardwork during which he sustained what he assumed was a bug bite. It was itchy, so he scratched it.

Of course, in the way of most itches, the scratching offered temporary relief, after which the itching resumed. The patient tried any number of OTC products, including rubbing alcohol, hydrogen peroxide, tea tree oil, several different essential oils, and triple-antibiotic cream and ointment. The worse the itching became, the more products he applied—all to no avail.

The patient describes his health as otherwise decent. He does have type 2 diabetes, which he says is in good control.

EXAMINATION
The lower anterior tibial areas of both legs are covered by a scaly red rash. The left leg is more heavily affected, and obvious edema can be seen distal to the rash on that leg. The surface scales of the rash have a polygonal look, resembling a dried lake bed or finely cracked porcelain. The edges of the cracks turn upward, resulting in a rough feel on palpation.

The patient’s skin is quite dry in general but otherwise within normal limits.

What is the diagnosis?

DISCUSSION
Leg skin is unique in many respects. For one thing, it’s down there, where gravity takes and often holds blood and other fluids that might not accumulate elsewhere. It’s also a long trip for blood to get out to the extremities and often a longer return trip.

Leg skin is also remarkable because it has far fewer sebaceous glands than the scalp, face, and chest, which means it tends to be quite dry. This is especially true in older patients already prone to dry skin and in those who seldom moisturize to counteract this problem (in other words, men!).

This is why most patients with asteatotic eczema (AE) are men. Also known as eczema craquele and xerotic eczema, AE is especially common in the dry winter months, when long, hot showers are so appealing, as are wearing warmer clothes and sleeping under heavy covers.

Patients with AE, including this one, often make matters worse by applying a multiplicity of contactants. The edema noted in the exam, although due to the AE, also served to worsen the condition by making the skin tighter and drier still.

At this point, the problem often starts to take on aspects of lichen simplex chronicus, in which more scratching leads to more itching (and then more scratching, and so on). Clearly, what this patient needed (and got) was a definitive diagnosis and a treatment plan dictated by that diagnosis.

AE can be a challenge to treat, but the first step is to help the patient understand the nature of the problem and his role in the solution. The patient also needs to stop applying nonprescribed/recommended contactants, which don’t help and may exacerbate the problem.

To achieve relief, the patient can soak the leg with wet compresses for 10 minutes, remove excess water, and then apply a medium-strength steroid ointment (eg, triamcinolone 0.5%) in a thin but thorough coat. The area can then be covered with an occlusive covering, such as saran wrap, taped in place. This should be left on all night. During the day, the patient should apply only petroleum jelly to the affected area.

This approach will take 90% of patients out of the crisis stage. After a week or two, attention must shift to preventing recurrence, with generous use of emollients such as petroleum jelly. The patient should also be instructed to avoid using harsh (colored, scented, high pH) soaps, switch to shorter, relatively cool showers, and stop using anything but his hand to wash with (ie, no washcloths or loofahs).

For nondiabetic patients with severe AE that persists despite these measures, an intramuscular injection of a glucocorticoid (eg, triamcinolone 40 - 60 mg) can work wonders.

TAKE-HOME LEARNING POINTS
• Asteatotic eczema (AE), also called xerotic eczema or eczema craquele, is quite common, especially on the lower legs of older men.

• The particular rash of AE is said to resemble the cracked surface of a porcelain vessel.

• AE is often accompanied by edema distal to the rash.

• A topical steroid ointment applied to water-soaked skin, held in place overnight with an occlusive dressing, usually takes the patient out of the crisis phase.

• Prevention is then directed at avoiding drying of the affected areas.

An 81-year-old man is brought in by his wife for evaluation of a very itchy rash on his bilateral lower tibial areas. He says the problem started about six months ago, after a spate of summer yardwork during which he sustained what he assumed was a bug bite. It was itchy, so he scratched it.

Of course, in the way of most itches, the scratching offered temporary relief, after which the itching resumed. The patient tried any number of OTC products, including rubbing alcohol, hydrogen peroxide, tea tree oil, several different essential oils, and triple-antibiotic cream and ointment. The worse the itching became, the more products he applied—all to no avail.

The patient describes his health as otherwise decent. He does have type 2 diabetes, which he says is in good control.

EXAMINATION
The lower anterior tibial areas of both legs are covered by a scaly red rash. The left leg is more heavily affected, and obvious edema can be seen distal to the rash on that leg. The surface scales of the rash have a polygonal look, resembling a dried lake bed or finely cracked porcelain. The edges of the cracks turn upward, resulting in a rough feel on palpation.

The patient’s skin is quite dry in general but otherwise within normal limits.

What is the diagnosis?

DISCUSSION
Leg skin is unique in many respects. For one thing, it’s down there, where gravity takes and often holds blood and other fluids that might not accumulate elsewhere. It’s also a long trip for blood to get out to the extremities and often a longer return trip.

Leg skin is also remarkable because it has far fewer sebaceous glands than the scalp, face, and chest, which means it tends to be quite dry. This is especially true in older patients already prone to dry skin and in those who seldom moisturize to counteract this problem (in other words, men!).

This is why most patients with asteatotic eczema (AE) are men. Also known as eczema craquele and xerotic eczema, AE is especially common in the dry winter months, when long, hot showers are so appealing, as are wearing warmer clothes and sleeping under heavy covers.

Patients with AE, including this one, often make matters worse by applying a multiplicity of contactants. The edema noted in the exam, although due to the AE, also served to worsen the condition by making the skin tighter and drier still.

At this point, the problem often starts to take on aspects of lichen simplex chronicus, in which more scratching leads to more itching (and then more scratching, and so on). Clearly, what this patient needed (and got) was a definitive diagnosis and a treatment plan dictated by that diagnosis.

AE can be a challenge to treat, but the first step is to help the patient understand the nature of the problem and his role in the solution. The patient also needs to stop applying nonprescribed/recommended contactants, which don’t help and may exacerbate the problem.

To achieve relief, the patient can soak the leg with wet compresses for 10 minutes, remove excess water, and then apply a medium-strength steroid ointment (eg, triamcinolone 0.5%) in a thin but thorough coat. The area can then be covered with an occlusive covering, such as saran wrap, taped in place. This should be left on all night. During the day, the patient should apply only petroleum jelly to the affected area.

This approach will take 90% of patients out of the crisis stage. After a week or two, attention must shift to preventing recurrence, with generous use of emollients such as petroleum jelly. The patient should also be instructed to avoid using harsh (colored, scented, high pH) soaps, switch to shorter, relatively cool showers, and stop using anything but his hand to wash with (ie, no washcloths or loofahs).

For nondiabetic patients with severe AE that persists despite these measures, an intramuscular injection of a glucocorticoid (eg, triamcinolone 40 - 60 mg) can work wonders.

TAKE-HOME LEARNING POINTS
• Asteatotic eczema (AE), also called xerotic eczema or eczema craquele, is quite common, especially on the lower legs of older men.

• The particular rash of AE is said to resemble the cracked surface of a porcelain vessel.

• AE is often accompanied by edema distal to the rash.

• A topical steroid ointment applied to water-soaked skin, held in place overnight with an occlusive dressing, usually takes the patient out of the crisis phase.

• Prevention is then directed at avoiding drying of the affected areas.

An 81-year-old man is brought in by his wife for evaluation of a very itchy rash on his bilateral lower tibial areas. He says the problem started about six months ago, after a spate of summer yardwork during which he sustained what he assumed was a bug bite. It was itchy, so he scratched it.

Of course, in the way of most itches, the scratching offered temporary relief, after which the itching resumed. The patient tried any number of OTC products, including rubbing alcohol, hydrogen peroxide, tea tree oil, several different essential oils, and triple-antibiotic cream and ointment. The worse the itching became, the more products he applied—all to no avail.

The patient describes his health as otherwise decent. He does have type 2 diabetes, which he says is in good control.

EXAMINATION
The lower anterior tibial areas of both legs are covered by a scaly red rash. The left leg is more heavily affected, and obvious edema can be seen distal to the rash on that leg. The surface scales of the rash have a polygonal look, resembling a dried lake bed or finely cracked porcelain. The edges of the cracks turn upward, resulting in a rough feel on palpation.

The patient’s skin is quite dry in general but otherwise within normal limits.

What is the diagnosis?

DISCUSSION
Leg skin is unique in many respects. For one thing, it’s down there, where gravity takes and often holds blood and other fluids that might not accumulate elsewhere. It’s also a long trip for blood to get out to the extremities and often a longer return trip.

Leg skin is also remarkable because it has far fewer sebaceous glands than the scalp, face, and chest, which means it tends to be quite dry. This is especially true in older patients already prone to dry skin and in those who seldom moisturize to counteract this problem (in other words, men!).

This is why most patients with asteatotic eczema (AE) are men. Also known as eczema craquele and xerotic eczema, AE is especially common in the dry winter months, when long, hot showers are so appealing, as are wearing warmer clothes and sleeping under heavy covers.

Patients with AE, including this one, often make matters worse by applying a multiplicity of contactants. The edema noted in the exam, although due to the AE, also served to worsen the condition by making the skin tighter and drier still.

At this point, the problem often starts to take on aspects of lichen simplex chronicus, in which more scratching leads to more itching (and then more scratching, and so on). Clearly, what this patient needed (and got) was a definitive diagnosis and a treatment plan dictated by that diagnosis.

AE can be a challenge to treat, but the first step is to help the patient understand the nature of the problem and his role in the solution. The patient also needs to stop applying nonprescribed/recommended contactants, which don’t help and may exacerbate the problem.

To achieve relief, the patient can soak the leg with wet compresses for 10 minutes, remove excess water, and then apply a medium-strength steroid ointment (eg, triamcinolone 0.5%) in a thin but thorough coat. The area can then be covered with an occlusive covering, such as saran wrap, taped in place. This should be left on all night. During the day, the patient should apply only petroleum jelly to the affected area.

This approach will take 90% of patients out of the crisis stage. After a week or two, attention must shift to preventing recurrence, with generous use of emollients such as petroleum jelly. The patient should also be instructed to avoid using harsh (colored, scented, high pH) soaps, switch to shorter, relatively cool showers, and stop using anything but his hand to wash with (ie, no washcloths or loofahs).

For nondiabetic patients with severe AE that persists despite these measures, an intramuscular injection of a glucocorticoid (eg, triamcinolone 40 - 60 mg) can work wonders.

TAKE-HOME LEARNING POINTS
• Asteatotic eczema (AE), also called xerotic eczema or eczema craquele, is quite common, especially on the lower legs of older men.

• The particular rash of AE is said to resemble the cracked surface of a porcelain vessel.

• AE is often accompanied by edema distal to the rash.

• A topical steroid ointment applied to water-soaked skin, held in place overnight with an occlusive dressing, usually takes the patient out of the crisis phase.

• Prevention is then directed at avoiding drying of the affected areas.

A consensus document that summarizes the status of basic, translational, and clinical hematology research and identifies areas of unmet scientific and medical needs in Europe has been published in the February 2016 issue of Haematologica.

“For the first time, hematologists in Europe came together to develop a road map to guide hematology research in Europe,” Professor Andreas Engert, chair of the European Hematology Association’s Research Roadmap Task Force, said in a written statement. “Hematology ... must focus and collaborate to be efficient and remain successful in improving patient outcomes.”

Some 300 experts from over 20 countries in Europe helped to draft the road map. A wide variety of stakeholders, such as national hematology societies, patient organizations, hematology trial groups, and other European organizations, were consulted to comment on the final draft.

“The document reflects the views of the hematological research community in Europe, Professor Tony Green, president of the European Hematology Association (EHA), noted in the statement. “This is crucial if we want to convince policy makers to support the realization of this important research.”

“With an aging population, the slow recovery from the financial and Euro crises, costly medical breakthroughs and innovations – quite a few of which involve hematology researchers, Europe faces increased health expenditures while budgets are limited,” Professor Ulrich Jäger, chair of the EHA European Affairs Committee, said in the statement. “So it is our responsibility to provide the policy makers with the information and evidence they need to decide where their support impacts knowledge and health most efficiently, to the benefit of patients and society. ... Now it is up to the policy makers in the EU to deliver, too.”

You may find the full article in Haematologica 2016 Jan. doi: 10.3324/haematol.2015.136739.

A consensus document that summarizes the status of basic, translational, and clinical hematology research and identifies areas of unmet scientific and medical needs in Europe has been published in the February 2016 issue of Haematologica.

“For the first time, hematologists in Europe came together to develop a road map to guide hematology research in Europe,” Professor Andreas Engert, chair of the European Hematology Association’s Research Roadmap Task Force, said in a written statement. “Hematology ... must focus and collaborate to be efficient and remain successful in improving patient outcomes.”

Some 300 experts from over 20 countries in Europe helped to draft the road map. A wide variety of stakeholders, such as national hematology societies, patient organizations, hematology trial groups, and other European organizations, were consulted to comment on the final draft.

“The document reflects the views of the hematological research community in Europe, Professor Tony Green, president of the European Hematology Association (EHA), noted in the statement. “This is crucial if we want to convince policy makers to support the realization of this important research.”

“With an aging population, the slow recovery from the financial and Euro crises, costly medical breakthroughs and innovations – quite a few of which involve hematology researchers, Europe faces increased health expenditures while budgets are limited,” Professor Ulrich Jäger, chair of the EHA European Affairs Committee, said in the statement. “So it is our responsibility to provide the policy makers with the information and evidence they need to decide where their support impacts knowledge and health most efficiently, to the benefit of patients and society. ... Now it is up to the policy makers in the EU to deliver, too.”

You may find the full article in Haematologica 2016 Jan. doi: 10.3324/haematol.2015.136739.

A consensus document that summarizes the status of basic, translational, and clinical hematology research and identifies areas of unmet scientific and medical needs in Europe has been published in the February 2016 issue of Haematologica.

“For the first time, hematologists in Europe came together to develop a road map to guide hematology research in Europe,” Professor Andreas Engert, chair of the European Hematology Association’s Research Roadmap Task Force, said in a written statement. “Hematology ... must focus and collaborate to be efficient and remain successful in improving patient outcomes.”

Some 300 experts from over 20 countries in Europe helped to draft the road map. A wide variety of stakeholders, such as national hematology societies, patient organizations, hematology trial groups, and other European organizations, were consulted to comment on the final draft.

“The document reflects the views of the hematological research community in Europe, Professor Tony Green, president of the European Hematology Association (EHA), noted in the statement. “This is crucial if we want to convince policy makers to support the realization of this important research.”

“With an aging population, the slow recovery from the financial and Euro crises, costly medical breakthroughs and innovations – quite a few of which involve hematology researchers, Europe faces increased health expenditures while budgets are limited,” Professor Ulrich Jäger, chair of the EHA European Affairs Committee, said in the statement. “So it is our responsibility to provide the policy makers with the information and evidence they need to decide where their support impacts knowledge and health most efficiently, to the benefit of patients and society. ... Now it is up to the policy makers in the EU to deliver, too.”

You may find the full article in Haematologica 2016 Jan. doi: 10.3324/haematol.2015.136739.

Background Effective palliation in patients with locally advanced head and neck cancer is important. Cyclical hypofractionated radiotherapy (Quad Shot) is a short-course palliative regimen with good patient compliance, low rates of acute toxicity, and delayed late fibrosis.

Objective To review use of the Quad Shot technique at our institution in order to quantify the palliative response in locally advanced head and neck cancer.

Methods The medical records of 70 patients with head and neck squamous cell carcinoma who had been treated with the Quad Shot technique were analyzed retrospectively (36 had been treated with intensity-modulated radiation therapy and 34 with 3-D conformal radiotherapy). They had received cyclical hypofractionated radiotherapy administrated as 14.8 Gy in 4 fractions over 2 days, twice daily, repeated every 3 weeks for a total of 3 cycles. The total prescribed dose was 44.4 Gy. Primary endpoints were improvement in pain using a verbal numeric pain rating scale (range 1-10, 10 being severe pain) and dysphagia using the Food Intake Level Scale, and the secondary endpoints included overall survival (OS), local regional recurrence-free survival (LRRFS), progression-free survival (PFS) and time to progression.

Results Pain response occurred in 61% of the patients. The mean pain scores decreased significantly from pre to post treatment (5.81 to 2.55, P = .009). The mean initial dysphagia score improved from 2.20 to 4.77 55 (P = .045). 26% of patients developed mucositis (≤ grade 2), with 9% developing grade 3-level mucositis. 12 patients had tumor recurrence. The estimated 1-year PFS was 20.7%. The median survival was 3.85 months with an estimated 1-year OS of 22.6%. Pain response (hazard ratio [HR], 2.69; 95% confidence index [CI], I.552-1.77) and completion of all 3 cycles (HR, 1.71; 95% CI, 1.003-2.907) were predictive for improved OS.

Limitations This study is a retrospective analysis.

Conclusion Quad Shot is an appropriate palliative regimen for locally advanced head and neck cancer.

Click on the PDF icon at the top of this introduction to read the full article.

Background Effective palliation in patients with locally advanced head and neck cancer is important. Cyclical hypofractionated radiotherapy (Quad Shot) is a short-course palliative regimen with good patient compliance, low rates of acute toxicity, and delayed late fibrosis.

Objective To review use of the Quad Shot technique at our institution in order to quantify the palliative response in locally advanced head and neck cancer.

Methods The medical records of 70 patients with head and neck squamous cell carcinoma who had been treated with the Quad Shot technique were analyzed retrospectively (36 had been treated with intensity-modulated radiation therapy and 34 with 3-D conformal radiotherapy). They had received cyclical hypofractionated radiotherapy administrated as 14.8 Gy in 4 fractions over 2 days, twice daily, repeated every 3 weeks for a total of 3 cycles. The total prescribed dose was 44.4 Gy. Primary endpoints were improvement in pain using a verbal numeric pain rating scale (range 1-10, 10 being severe pain) and dysphagia using the Food Intake Level Scale, and the secondary endpoints included overall survival (OS), local regional recurrence-free survival (LRRFS), progression-free survival (PFS) and time to progression.

Results Pain response occurred in 61% of the patients. The mean pain scores decreased significantly from pre to post treatment (5.81 to 2.55, P = .009). The mean initial dysphagia score improved from 2.20 to 4.77 55 (P = .045). 26% of patients developed mucositis (≤ grade 2), with 9% developing grade 3-level mucositis. 12 patients had tumor recurrence. The estimated 1-year PFS was 20.7%. The median survival was 3.85 months with an estimated 1-year OS of 22.6%. Pain response (hazard ratio [HR], 2.69; 95% confidence index [CI], I.552-1.77) and completion of all 3 cycles (HR, 1.71; 95% CI, 1.003-2.907) were predictive for improved OS.

Limitations This study is a retrospective analysis.

Conclusion Quad Shot is an appropriate palliative regimen for locally advanced head and neck cancer.

Click on the PDF icon at the top of this introduction to read the full article.

Background Effective palliation in patients with locally advanced head and neck cancer is important. Cyclical hypofractionated radiotherapy (Quad Shot) is a short-course palliative regimen with good patient compliance, low rates of acute toxicity, and delayed late fibrosis.

Objective To review use of the Quad Shot technique at our institution in order to quantify the palliative response in locally advanced head and neck cancer.

Methods The medical records of 70 patients with head and neck squamous cell carcinoma who had been treated with the Quad Shot technique were analyzed retrospectively (36 had been treated with intensity-modulated radiation therapy and 34 with 3-D conformal radiotherapy). They had received cyclical hypofractionated radiotherapy administrated as 14.8 Gy in 4 fractions over 2 days, twice daily, repeated every 3 weeks for a total of 3 cycles. The total prescribed dose was 44.4 Gy. Primary endpoints were improvement in pain using a verbal numeric pain rating scale (range 1-10, 10 being severe pain) and dysphagia using the Food Intake Level Scale, and the secondary endpoints included overall survival (OS), local regional recurrence-free survival (LRRFS), progression-free survival (PFS) and time to progression.

Results Pain response occurred in 61% of the patients. The mean pain scores decreased significantly from pre to post treatment (5.81 to 2.55, P = .009). The mean initial dysphagia score improved from 2.20 to 4.77 55 (P = .045). 26% of patients developed mucositis (≤ grade 2), with 9% developing grade 3-level mucositis. 12 patients had tumor recurrence. The estimated 1-year PFS was 20.7%. The median survival was 3.85 months with an estimated 1-year OS of 22.6%. Pain response (hazard ratio [HR], 2.69; 95% confidence index [CI], I.552-1.77) and completion of all 3 cycles (HR, 1.71; 95% CI, 1.003-2.907) were predictive for improved OS.

Limitations This study is a retrospective analysis.

Conclusion Quad Shot is an appropriate palliative regimen for locally advanced head and neck cancer.

Click on the PDF icon at the top of this introduction to read the full article.

SNOWMASS, COLO. – How would you manage anticoagulation in a newly pregnant 23-year-old with a mechanical heart valve who has been on warfarin at 3 mg/day?

A) Weight-adjusted low-molecular-weight heparin during the first trimester, then warfarin in the second and third until switching to unfractionated heparin for delivery.

B) Low-molecular-weight heparin throughout pregnancy.

C) Warfarin throughout pregnancy.

D) Unfractionated heparin in the first trimester, warfarin in the second and third until returning to unfractionated heparin peridelivery.

The correct answer, according to both the ACC/AHA guidelines (Circulation. 2014 Jun 10;129[23]:e521-643) and European Society of Cardiology guidelines (Eur Heart J. 2011 Dec;32[24]:3147-97), is C in women who are on 5 mg/day of warfarin or less.

Creatas Images

“Oral anticoagulants throughout pregnancy are much better for the mother, and this is where the guidelines have moved,” Dr. Carole A. Warnes said at the Annual Cardiovascular Conference at Snowmass.

Both sets of guidelines give a class I recommendation to warfarin during the second and third trimesters, because the risk of warfarin embryopathy is confined to weeks 6-12. During the first trimester, warfarin at 5 mg/day or less gets a class IIa rating – making it preferable to unfractionated or low-molecular-weight heparin – because heparin is a far less effective anticoagulant. Plus, multiple small studies indicate the risk of embryopathy is low – roughly 1%-2% – when the mother is on warfarin at 5 mg/day or less.

In a woman on more than 5 mg/day of warfarin, the risk of warfarin embryopathy is about 6%, so the guidelines recommend replacing the drug with heparin during weeks 6-12.

“It’s not a walk in the park,” said Dr. Warnes, director of the Snowmass conference and professor of medicine at the Mayo Clinic in Rochester, Minn.

The major concern in using heparin for anticoagulation in pregnancy is valve thrombosis. It doubles the risk.

“Pregnancy is the most prothrombotic state there is,” she said. “It’s not like managing a patient through a hip replacement or prostate surgery. Women with a mechanical prosthetic valve should be managed by a heart valve team with expertise in treatment during pregnancy.”

The alternatives to warfarin are adjusted-dose unfractionated heparin, which must be given in a continuous intravenous infusion with meticulous monitoring of activated partial thromboplastin time, or twice-daily low-molecular-weight heparin with dose adjustment by weight and maintenance of a target anti–Factor Xa level of 1.0-1.2 IU/mL.

“If you use low-molecular-weight heparin, you’re going to be seeing that patient every week to monitor anti–Factor Xa 4-6 hours post injection. You’ll find it’s not that easy to stay in the sweet spot, with excellent anticoagulation without an increased risk of maternal thromboembolism, or at the other extreme, fetal bleeding. What might look initially as a relatively easy strategy with a lot of appeal turns out to entail considerable risk,” Dr. Warnes said.

This was underscored in a cautionary report by highly experienced University of Toronto investigators. In their series of 23 pregnancies in 17 women with mechanical heart valves on low-molecular-weight heparin throughout pregnancy with careful monitoring, there was one maternal thromboembolic event resulting in maternal and fetal death despite a documented therapeutic anti–Factor Xa level (Am J Cardiol. 2009 Nov 1;104[9]:1259-63).

Although warfarin is clearly the better anticoagulant for the mother, the fetus pays the price. This was highlighted in a recent report from the ESC Registry of Pregnancy and Cardiac Disease (ROPAC) that compared pregnancy outcomes in 212 patients with a mechanical heart valve, 134 with a tissue valve, and 2,620 women without a prosthetic heart valve. Use of warfarin or another vitamin K antagonist in the first trimester was associated with a higher rate of miscarriage than heparin – 28.6% vs. 9.2% – as well as a 7.1% incidence of late fetal death, compared with just 0.7% with heparin.

On the other hand, the mechanical valve thrombosis rate was 4.7%, with half of those serious events occurring during the first trimester in patients after they’d been switched to heparin (Circulation. 2015 Jul 14;132[2]:132-42).

Hemorrhagic events occurred in 23.1% of mothers with a mechanical heart valve, 5.1% of those with a bioprosthetic valve, and 4.9% of patients without a prosthetic valve. A point worth incorporating into prepregnancy patient counseling, Dr. Warnes noted, is that only 58% of ROPAC participants with a mechanical heart valve had an uncomplicated pregnancy with a live birth, in contrast to 79% of those with a tissue valve and 78% of controls.

Because warfarin crosses the placenta, and it takes about a week for the fetus to eliminate the drug following maternal discontinuation, the guidelines recommend stopping warfarin at about week 36 and changing to a continuous infusion of dose-adjusted unfractionated heparin peridelivery. The heparin should be stopped for as short a time as possible before delivery and resumed 6-12 hours post delivery in order to protect against valve thrombosis.

Of course, opting for a bioprosthetic rather than a mechanical heart valve avoids all these difficult anticoagulation-related issues. But it poses a different serious problem: The younger the patient at the time of tissue valve implantation, the greater the risk of rapid calcification and structural valve deterioration. Indeed, among patients who are age 16-39 when they receive a bioprosthetic valve, the rate of structural valve deterioration is 50% at 10 years and 90% at 15 years.

“There is no ideal valve prosthesis. If you elect a tissue prosthesis, you have to discuss the risk of reoperation in that young woman,” Dr. Warnes advised.

Recent data from the Society of Thoracic Surgeons database indicate the mortality associated with redo elective aortic valve replacement in a 35-year-old woman with no comorbidities averages 1.63%, with a 2% mortality rate for redo mitral valve replacement.

Dr. Warnes reported having no financial conflicts regarding her presentation.

[email protected]

SNOWMASS, COLO. – How would you manage anticoagulation in a newly pregnant 23-year-old with a mechanical heart valve who has been on warfarin at 3 mg/day?

A) Weight-adjusted low-molecular-weight heparin during the first trimester, then warfarin in the second and third until switching to unfractionated heparin for delivery.

B) Low-molecular-weight heparin throughout pregnancy.

C) Warfarin throughout pregnancy.

D) Unfractionated heparin in the first trimester, warfarin in the second and third until returning to unfractionated heparin peridelivery.

The correct answer, according to both the ACC/AHA guidelines (Circulation. 2014 Jun 10;129[23]:e521-643) and European Society of Cardiology guidelines (Eur Heart J. 2011 Dec;32[24]:3147-97), is C in women who are on 5 mg/day of warfarin or less.

Creatas Images

“Oral anticoagulants throughout pregnancy are much better for the mother, and this is where the guidelines have moved,” Dr. Carole A. Warnes said at the Annual Cardiovascular Conference at Snowmass.

Both sets of guidelines give a class I recommendation to warfarin during the second and third trimesters, because the risk of warfarin embryopathy is confined to weeks 6-12. During the first trimester, warfarin at 5 mg/day or less gets a class IIa rating – making it preferable to unfractionated or low-molecular-weight heparin – because heparin is a far less effective anticoagulant. Plus, multiple small studies indicate the risk of embryopathy is low – roughly 1%-2% – when the mother is on warfarin at 5 mg/day or less.

In a woman on more than 5 mg/day of warfarin, the risk of warfarin embryopathy is about 6%, so the guidelines recommend replacing the drug with heparin during weeks 6-12.

“It’s not a walk in the park,” said Dr. Warnes, director of the Snowmass conference and professor of medicine at the Mayo Clinic in Rochester, Minn.

The major concern in using heparin for anticoagulation in pregnancy is valve thrombosis. It doubles the risk.

“Pregnancy is the most prothrombotic state there is,” she said. “It’s not like managing a patient through a hip replacement or prostate surgery. Women with a mechanical prosthetic valve should be managed by a heart valve team with expertise in treatment during pregnancy.”

The alternatives to warfarin are adjusted-dose unfractionated heparin, which must be given in a continuous intravenous infusion with meticulous monitoring of activated partial thromboplastin time, or twice-daily low-molecular-weight heparin with dose adjustment by weight and maintenance of a target anti–Factor Xa level of 1.0-1.2 IU/mL.

“If you use low-molecular-weight heparin, you’re going to be seeing that patient every week to monitor anti–Factor Xa 4-6 hours post injection. You’ll find it’s not that easy to stay in the sweet spot, with excellent anticoagulation without an increased risk of maternal thromboembolism, or at the other extreme, fetal bleeding. What might look initially as a relatively easy strategy with a lot of appeal turns out to entail considerable risk,” Dr. Warnes said.

This was underscored in a cautionary report by highly experienced University of Toronto investigators. In their series of 23 pregnancies in 17 women with mechanical heart valves on low-molecular-weight heparin throughout pregnancy with careful monitoring, there was one maternal thromboembolic event resulting in maternal and fetal death despite a documented therapeutic anti–Factor Xa level (Am J Cardiol. 2009 Nov 1;104[9]:1259-63).

Although warfarin is clearly the better anticoagulant for the mother, the fetus pays the price. This was highlighted in a recent report from the ESC Registry of Pregnancy and Cardiac Disease (ROPAC) that compared pregnancy outcomes in 212 patients with a mechanical heart valve, 134 with a tissue valve, and 2,620 women without a prosthetic heart valve. Use of warfarin or another vitamin K antagonist in the first trimester was associated with a higher rate of miscarriage than heparin – 28.6% vs. 9.2% – as well as a 7.1% incidence of late fetal death, compared with just 0.7% with heparin.

On the other hand, the mechanical valve thrombosis rate was 4.7%, with half of those serious events occurring during the first trimester in patients after they’d been switched to heparin (Circulation. 2015 Jul 14;132[2]:132-42).

Hemorrhagic events occurred in 23.1% of mothers with a mechanical heart valve, 5.1% of those with a bioprosthetic valve, and 4.9% of patients without a prosthetic valve. A point worth incorporating into prepregnancy patient counseling, Dr. Warnes noted, is that only 58% of ROPAC participants with a mechanical heart valve had an uncomplicated pregnancy with a live birth, in contrast to 79% of those with a tissue valve and 78% of controls.

Because warfarin crosses the placenta, and it takes about a week for the fetus to eliminate the drug following maternal discontinuation, the guidelines recommend stopping warfarin at about week 36 and changing to a continuous infusion of dose-adjusted unfractionated heparin peridelivery. The heparin should be stopped for as short a time as possible before delivery and resumed 6-12 hours post delivery in order to protect against valve thrombosis.

Of course, opting for a bioprosthetic rather than a mechanical heart valve avoids all these difficult anticoagulation-related issues. But it poses a different serious problem: The younger the patient at the time of tissue valve implantation, the greater the risk of rapid calcification and structural valve deterioration. Indeed, among patients who are age 16-39 when they receive a bioprosthetic valve, the rate of structural valve deterioration is 50% at 10 years and 90% at 15 years.

“There is no ideal valve prosthesis. If you elect a tissue prosthesis, you have to discuss the risk of reoperation in that young woman,” Dr. Warnes advised.

Recent data from the Society of Thoracic Surgeons database indicate the mortality associated with redo elective aortic valve replacement in a 35-year-old woman with no comorbidities averages 1.63%, with a 2% mortality rate for redo mitral valve replacement.

Dr. Warnes reported having no financial conflicts regarding her presentation.

[email protected]

SNOWMASS, COLO. – How would you manage anticoagulation in a newly pregnant 23-year-old with a mechanical heart valve who has been on warfarin at 3 mg/day?

A) Weight-adjusted low-molecular-weight heparin during the first trimester, then warfarin in the second and third until switching to unfractionated heparin for delivery.

B) Low-molecular-weight heparin throughout pregnancy.

C) Warfarin throughout pregnancy.

D) Unfractionated heparin in the first trimester, warfarin in the second and third until returning to unfractionated heparin peridelivery.

The correct answer, according to both the ACC/AHA guidelines (Circulation. 2014 Jun 10;129[23]:e521-643) and European Society of Cardiology guidelines (Eur Heart J. 2011 Dec;32[24]:3147-97), is C in women who are on 5 mg/day of warfarin or less.

Creatas Images

“Oral anticoagulants throughout pregnancy are much better for the mother, and this is where the guidelines have moved,” Dr. Carole A. Warnes said at the Annual Cardiovascular Conference at Snowmass.

Both sets of guidelines give a class I recommendation to warfarin during the second and third trimesters, because the risk of warfarin embryopathy is confined to weeks 6-12. During the first trimester, warfarin at 5 mg/day or less gets a class IIa rating – making it preferable to unfractionated or low-molecular-weight heparin – because heparin is a far less effective anticoagulant. Plus, multiple small studies indicate the risk of embryopathy is low – roughly 1%-2% – when the mother is on warfarin at 5 mg/day or less.

In a woman on more than 5 mg/day of warfarin, the risk of warfarin embryopathy is about 6%, so the guidelines recommend replacing the drug with heparin during weeks 6-12.

“It’s not a walk in the park,” said Dr. Warnes, director of the Snowmass conference and professor of medicine at the Mayo Clinic in Rochester, Minn.

The major concern in using heparin for anticoagulation in pregnancy is valve thrombosis. It doubles the risk.

“Pregnancy is the most prothrombotic state there is,” she said. “It’s not like managing a patient through a hip replacement or prostate surgery. Women with a mechanical prosthetic valve should be managed by a heart valve team with expertise in treatment during pregnancy.”

The alternatives to warfarin are adjusted-dose unfractionated heparin, which must be given in a continuous intravenous infusion with meticulous monitoring of activated partial thromboplastin time, or twice-daily low-molecular-weight heparin with dose adjustment by weight and maintenance of a target anti–Factor Xa level of 1.0-1.2 IU/mL.

“If you use low-molecular-weight heparin, you’re going to be seeing that patient every week to monitor anti–Factor Xa 4-6 hours post injection. You’ll find it’s not that easy to stay in the sweet spot, with excellent anticoagulation without an increased risk of maternal thromboembolism, or at the other extreme, fetal bleeding. What might look initially as a relatively easy strategy with a lot of appeal turns out to entail considerable risk,” Dr. Warnes said.

This was underscored in a cautionary report by highly experienced University of Toronto investigators. In their series of 23 pregnancies in 17 women with mechanical heart valves on low-molecular-weight heparin throughout pregnancy with careful monitoring, there was one maternal thromboembolic event resulting in maternal and fetal death despite a documented therapeutic anti–Factor Xa level (Am J Cardiol. 2009 Nov 1;104[9]:1259-63).

Although warfarin is clearly the better anticoagulant for the mother, the fetus pays the price. This was highlighted in a recent report from the ESC Registry of Pregnancy and Cardiac Disease (ROPAC) that compared pregnancy outcomes in 212 patients with a mechanical heart valve, 134 with a tissue valve, and 2,620 women without a prosthetic heart valve. Use of warfarin or another vitamin K antagonist in the first trimester was associated with a higher rate of miscarriage than heparin – 28.6% vs. 9.2% – as well as a 7.1% incidence of late fetal death, compared with just 0.7% with heparin.

On the other hand, the mechanical valve thrombosis rate was 4.7%, with half of those serious events occurring during the first trimester in patients after they’d been switched to heparin (Circulation. 2015 Jul 14;132[2]:132-42).

Hemorrhagic events occurred in 23.1% of mothers with a mechanical heart valve, 5.1% of those with a bioprosthetic valve, and 4.9% of patients without a prosthetic valve. A point worth incorporating into prepregnancy patient counseling, Dr. Warnes noted, is that only 58% of ROPAC participants with a mechanical heart valve had an uncomplicated pregnancy with a live birth, in contrast to 79% of those with a tissue valve and 78% of controls.

Because warfarin crosses the placenta, and it takes about a week for the fetus to eliminate the drug following maternal discontinuation, the guidelines recommend stopping warfarin at about week 36 and changing to a continuous infusion of dose-adjusted unfractionated heparin peridelivery. The heparin should be stopped for as short a time as possible before delivery and resumed 6-12 hours post delivery in order to protect against valve thrombosis.

Of course, opting for a bioprosthetic rather than a mechanical heart valve avoids all these difficult anticoagulation-related issues. But it poses a different serious problem: The younger the patient at the time of tissue valve implantation, the greater the risk of rapid calcification and structural valve deterioration. Indeed, among patients who are age 16-39 when they receive a bioprosthetic valve, the rate of structural valve deterioration is 50% at 10 years and 90% at 15 years.

“There is no ideal valve prosthesis. If you elect a tissue prosthesis, you have to discuss the risk of reoperation in that young woman,” Dr. Warnes advised.

Recent data from the Society of Thoracic Surgeons database indicate the mortality associated with redo elective aortic valve replacement in a 35-year-old woman with no comorbidities averages 1.63%, with a 2% mortality rate for redo mitral valve replacement.

Dr. Warnes reported having no financial conflicts regarding her presentation.

[email protected]

Psychogenic nonepileptic seizure (PNES) patients reported having more frequent and longer-lasting migraines than patients diagnosed with epilepsy, in an observational study conducted in the United States.

Researchers questioned 29 patients with epilepsy and 43 PNES patients about their migraines and seizures through the use of standardized questionnaires and a standardized interview. All study participants were found in a clinician database of patients who had been evaluated in the Mayo Clinic epilepsy monitoring unit between 2008 and 2014. Their ages ranged from 20 years to 82 years. Patients who were diagnosed with both PNES and epilepsy were excluded from the research project.

©DKart/iStockphoto

PNES patients reported having significantly more migraine attacks and longer-duration migraines (when untreated) than patients with epilepsy. Specifically, on average, PNES patients said they experienced 6.5 migraine attacks per month and migraines with a length of 39.5 hours, whereas patients with epilepsy said they had, on average, 3.8 migraine attacks per month and migraines lasting 27.3 hours. Another significant difference between the two groups of patients occurred in the numbers of nonvisual migraine aura symptoms reported. While 22 of the PNES patients (78.6%) reported experiencing such symptoms, 7 of the epilepsy patients (46.7%) reported having nonvisual aura symptoms (P = .033).

“Our study adds to the existing literature [on the relationship between PNES and migraine] by detailing specific migraine characteristics in patients with PNES,” wrote Morgan A. Shepard and colleagues. The researchers noted that PNES patients could have overreported the severity of their migraine symptoms and that a high level of somatization has been found in patients with PNES.

The results of this research project “justify the need for clinicians to assess PNES patients for the presence of migraine and when present, to treat them appropriately for migraine,” according to the researchers.

The study’s authors did not report any conflicts of interest.

Read the study in Seizure (doi: 10.1016/j.seizure.2015.12.006).

[email protected]

Psychogenic nonepileptic seizure (PNES) patients reported having more frequent and longer-lasting migraines than patients diagnosed with epilepsy, in an observational study conducted in the United States.

Researchers questioned 29 patients with epilepsy and 43 PNES patients about their migraines and seizures through the use of standardized questionnaires and a standardized interview. All study participants were found in a clinician database of patients who had been evaluated in the Mayo Clinic epilepsy monitoring unit between 2008 and 2014. Their ages ranged from 20 years to 82 years. Patients who were diagnosed with both PNES and epilepsy were excluded from the research project.

©DKart/iStockphoto

PNES patients reported having significantly more migraine attacks and longer-duration migraines (when untreated) than patients with epilepsy. Specifically, on average, PNES patients said they experienced 6.5 migraine attacks per month and migraines with a length of 39.5 hours, whereas patients with epilepsy said they had, on average, 3.8 migraine attacks per month and migraines lasting 27.3 hours. Another significant difference between the two groups of patients occurred in the numbers of nonvisual migraine aura symptoms reported. While 22 of the PNES patients (78.6%) reported experiencing such symptoms, 7 of the epilepsy patients (46.7%) reported having nonvisual aura symptoms (P = .033).

“Our study adds to the existing literature [on the relationship between PNES and migraine] by detailing specific migraine characteristics in patients with PNES,” wrote Morgan A. Shepard and colleagues. The researchers noted that PNES patients could have overreported the severity of their migraine symptoms and that a high level of somatization has been found in patients with PNES.

The results of this research project “justify the need for clinicians to assess PNES patients for the presence of migraine and when present, to treat them appropriately for migraine,” according to the researchers.

The study’s authors did not report any conflicts of interest.

Read the study in Seizure (doi: 10.1016/j.seizure.2015.12.006).

[email protected]

Psychogenic nonepileptic seizure (PNES) patients reported having more frequent and longer-lasting migraines than patients diagnosed with epilepsy, in an observational study conducted in the United States.

Researchers questioned 29 patients with epilepsy and 43 PNES patients about their migraines and seizures through the use of standardized questionnaires and a standardized interview. All study participants were found in a clinician database of patients who had been evaluated in the Mayo Clinic epilepsy monitoring unit between 2008 and 2014. Their ages ranged from 20 years to 82 years. Patients who were diagnosed with both PNES and epilepsy were excluded from the research project.

©DKart/iStockphoto

PNES patients reported having significantly more migraine attacks and longer-duration migraines (when untreated) than patients with epilepsy. Specifically, on average, PNES patients said they experienced 6.5 migraine attacks per month and migraines with a length of 39.5 hours, whereas patients with epilepsy said they had, on average, 3.8 migraine attacks per month and migraines lasting 27.3 hours. Another significant difference between the two groups of patients occurred in the numbers of nonvisual migraine aura symptoms reported. While 22 of the PNES patients (78.6%) reported experiencing such symptoms, 7 of the epilepsy patients (46.7%) reported having nonvisual aura symptoms (P = .033).

“Our study adds to the existing literature [on the relationship between PNES and migraine] by detailing specific migraine characteristics in patients with PNES,” wrote Morgan A. Shepard and colleagues. The researchers noted that PNES patients could have overreported the severity of their migraine symptoms and that a high level of somatization has been found in patients with PNES.

The results of this research project “justify the need for clinicians to assess PNES patients for the presence of migraine and when present, to treat them appropriately for migraine,” according to the researchers.

The study’s authors did not report any conflicts of interest.

Read the study in Seizure (doi: 10.1016/j.seizure.2015.12.006).

[email protected]

Cariprazine is a newly approved (September 2015) dopamine D3/D2 receptor partial agonist with higher affinity for the D3 receptor than for D2. The drug is FDA-indicated for treating schizophrenia and bipolar I disorder (BD I)^1,2 (Table 1). In clinical trials, cariprazine alleviated symptoms of schizophrenia and mixed and manic symptoms of BD I, with minimal effect on metabolic parameters, the prolactin level, and cardiac conduction.

Receptor blocking. As a dopamine D3-preferring D3/D2 partial agonist, cariprazine offers an alternative to antipsychotics that preferentially modulate D2 receptors. First-generation (typical) antipsychotics block D2 receptors; atypical antipsychotics block D2 receptors and 5-HT2A receptors. Dopamine partial agonists aripiprazole and brexpiprazole are D2-preferring, with minimal D3 effects. In contrast, cariprazine has a 6-fold to 8-fold higher affinity for D3 receptors than for D2 receptors, and has specificity for the D3 receptor that is 3 to 10 times higher than what aripiprazole has for the D3 receptor^3-5 (Table 2).

Use in schizophrenia. Recommended dosage range is 1.5 to 6 mg/d. In Phase-III clinical trials, dosages of 3 to 9 mg/d produced significant improvement on the Positive and Negative Symptom Scale (PANSS) and on the Clinical Global Impression scale. Higher dosages (6 to 9 mg/d) showed early separation from placebo—by the end of Week 1—but carried a dosage-related risk of AEs, leading the FDA to recommend 6 mg/d as the maximum dosage.^1,6-8

Use in manic or mixed episodes of BD I. Recommended dosage range is 3 to 6 mg/d. In clinical trials, dosages in the range of 3 to 12 mg/d were effective for acute manic or mixed symptoms; significant improvement in the Young Mania Rating Scale (YMRS) score was seen as early as Day 4. Dosages >6 mg/d yielded no additional benefit and were associated with increased risk of AEs.^9-12

Pharmacologic profile, adverse effects. Cariprazine has a pharmacologic profile consistent with the generally favorable metabolic profile and lack of anticholinergic effects seen in clinical trials. In short- and long-term trials, the drug had minimal effects on prolactin, blood pressure, and cardiac conduction.¹³

Across clinical trials for both disorders, akathisia and parkinsonism were among more common AEs of cariprazine. Both AEs were usually mild, resulting in relatively few premature discontinuations from trials. Parkinsonism appeared somewhat dosage-related; akathisia had no clear relationship to dosage.

How it works
The theory behind the use of partial agonists, including cariprazine, is that these agents restore homeostatic balance to neurochemical circuits by:

• decreasing the effects of endogenous neurotransmitters (dopamine tone) in regions of the brain where their transmission is excessive, such as mesolimbic regions in schizophrenia or mania
• simultaneously increasing neurotransmission in regions where transmission of endogenous neurotransmitters is low, such as the prefrontal cortex in schizophrenia
• exerting little effect in regions where neurotransmitter activity is normal, such as the pituitary gland.
• simultaneously

Cariprazine has higher binding affinity for dopamine D3 receptors (Ki 0.085 nM) than for D2L receptors (Ki 0.49 nM) and D2S receptors (Ki 0.69 nM). The drug also has strong affinity for serotonin receptor 5-HT2B; moderate affinity for 5-HT1A; and lower affinity for 5-HT2A, histamine H1, and 5-HT7 receptors. Cariprazine has little or no affinity for adrenergic or cholinergic receptors.¹⁴In patients with schizophrenia, as measured on PET scanning, a dosage of 1.5 mg/d yielded 69% to 75% D2/D3 receptor occupancy. A dosage of 3 mg/d yielded >90% occupancy.

Search for an understanding of action continues. The relative contribution of D3 partial agonism, compared with D2 partial agonism, is a subject of ongoing basic scientific and clinical research. D3 is an autoreceptor that (1) controls phasic, but not tonic, activity of dopamine nerve cells and (2) mediates behavioral abnormalities induced by glutamate and N-methyl-D-aspartate receptor antagonists.^5,12 In animal studies, D3-preferring agents have been shown to exert pro-cognitive effects and improve anhedonic symptoms.

Pharmacokinetics
Cariprazine is a once-daily medication with a relatively long half-life that can be taken with or without food. Dosages of 3 to 12 mg/d yield a fairly linear, dose-proportional increase in plasma concentration. The peak serum concentration for cariprazine is 3 to 4 hours under fasting conditions; taking the drug with food causes a slight delay in absorption but does not have a significant effect on the area under the curve. Mean half-life for cariprazine is 2 to 5 days over a dosage range of 1.5 to 12.5 mg/d in otherwise healthy adults with schizophrenia.¹

Cariprazine is metabolized primarily by cytochrome P450 (CYP) 3A4. It is a weak inhibitor of CYP2D6 and CYP3A4.¹ Hepatic metabolism of cariprazine produces 2 active metabolites: desmethyl-cariprazine (DCAR) and didesmethyl-cariprazine (DDCAR), both of which are equipotent to cariprazine. After multiple dose administration, mean cariprazine and DCAR levels reach steady state in 1 to 2 weeks; DDCAR, in 4 to 8 weeks. The systemic exposure and serum levels of DDCAR are roughly 3-fold greater than cariprazine because of the longer elimination half-life of DDCAR.¹

Efficacy in schizophrenia
The efficacy of cariprazine in schizophrenia was established by 3 six-week, randomized, placebo-controlled trials. Two trials were fixed-dosage; a third used 2 flexible dosage ranges. The primary efficacy measure was change from baseline in the total score of the PANSS at the end of Week 6, compared with placebo. In all trials, patients were adults (age 18 to 60) who met DSM-IV-TR criteria for schizophrenia and had a PANSS score between 80 and 120 at screening and baseline.

Study 1 (n = 711) compared dosages of 1.5 mg/d, 3 mg/d, and 4.5 mg/d with placebo.⁷ All cariprazine dosages and an active control (risperdone) were superior to placebo in reducing symptoms of schizophrenia, as measured by the PANSS. The placebo-subtracted differences on PANSS score at 6 weeks for dosages of 1.5 mg/d, 3 mg/d, and 4.5 mg/d were –7.6, –8.8, –10.4, respectively (significant at 95% CI).

Study 2 (n = 151) compared 3 mg/d and 6 mg/d dosages of cariprazine with placebo.¹ Both dosages and an active control (aripiprazole) were superior to placebo in reducing PANSS scores. Placebo-subtracted differences on PANSS score at 6 weeks for dosages of 3 mg/d and 6 mg/day were –6.0, –8.8, respectively (significant at 95% CI).

Study 3 (n = 147) was a fixed-flexible dosage trial comparing cariprazine, 3 to 6 mg/d and 6 to 9 mg/d dosage ranges, to placebo.⁸ Both ranges were superior to placebo in reducing symptoms on PANSS. Placebo-subtracted differences from placebo on PANSS at 6 weeks for cariprazine 3 to 6 or 6 to 9 mg/d were –6.8, –9.9, respectively (significant at 95% CI).

These trials established the efficacy of cariprazine for acute schizophrenia at dosages ranging from 1.5 to 9 mg/d. Although there was a modest trend toward higher efficacy at higher dosages, there was a dose-related increase in certain adverse reactions (extrapyramidal symptoms [EPS]) at dosages >6 mg/d.¹

Efficacy in bipolar disorder
The efficacy of cariprazine for acute treatment of manic or mixed episodes of BD I was established in 3 randomized, placebo-controlled, flexibly dosed 3-week trials. In all trials, patients were adults (age 18 to 65) who met DSM-IV-TR criteria for BD I with manic or mixed episodes and with or without psychotic features (YMRS score, ≥20). The primary efficacy measure in the 3 trials was a change from baseline in the total YMRS score at the end of Week 3, compared with placebo.

Study 1 (n = 492) compared 2 flexibly dosed ranges of cariprazine (3 to 6 mg/d and 6 to 12 mg/d) with placebo.¹⁰ Both dosage ranges were superior to placebo in reducing mixed and manic symptoms, as measured by reduction in the total YMRS score. Placebo-subtracted differences in YMRS scores from placebo at Week 3 for cariprazine 3 to 6 mg/d and 6 to 12 mg/d were –6.1, –5.9, respectively (significant at 95% CI). The higher range offered no additional advantage over the lower range.

Study 2 (n = 235) compared flexibly dosed cariprazine, 3 to 12 mg/d, to placebo.¹¹ Cariprazine was superior to placebo in reducing bipolar symptoms as measured by the YMRS. The difference between cariprazine 3 to 12 mg/d and placebo on the YMRS score at Week 3 was –6.1 (significant at 95% CI).

Study 3 (n = 310) compared flexibly dosed cariprazine, 3 to 12 mg/d, with placebo.¹⁵ Again, cariprazine was superior to placebo in reducing the YMRS score at Week 3: difference, –4.3 (significant at 95% CI).

These trials establish the efficacy of cariprazine in treating acute mania or mixed BD I episodes at dosages ranging from 3 to 12 mg/d. Dosages >6 mg/d did not offer additional benefit over lower dosages, and resulted in a dosage-related increase in EPS at dosages >6 mg/d.¹⁶

Tolerability
Cariprazine generally was well tolerated in short-term trials for schizophrenia and BD I. The only treatment-emergent adverse event reported for at least 1 treatment group in all trials at a rate of ≥10%, and at least twice the rate seen with placebo was akathisia. Adverse events reported at a lower rate than placebo included EPS (particularly parkinsonism), restlessness, headache, insomnia, fatigue, and gastrointestinal distress. The discontinuation rate due to AEs for treatment groups and placebo-treated patients generally was similar. In schizophrenia Study 3, for example, the discontinuation rate due to AEs was 13% for placebo; 14% for cariprazine, 3 to 6 mg/d; and 13% for cariprazine, 6 to 9 mg/d.¹ 48-Week open-label safety study. Patients with schizophrenia received open-label cariprazine for as long as 48 weeks.⁷ Serious adverse events were reported in 12.9%, including 1 death (suicide); exacerbation of symptoms of schizophrenia (4.3%); and psychosis (2.2%). Treatment-emergent adverse events reported in at least 10% of patients included akathisia (14.0%), insomnia (14.0%), and weight gain (11.8%). The mean change in laboratory values, blood pressure, pulse rate, and electrocardiographic parameters was clinically insignificant.

Other studies. In a 16-week, open-label extension study of patients with BD I, the major tolerability issue was akathisia. This AE developed in 37% of patients and led to a 5% withdrawal rate.¹²

In short- and long-term studies for either indication, the effect of the drug on metabolic parameters appears to be small. In studies with active controls, potentially significant weight gain (>7%) was greater for aripiprazole and risperidone than for cariprazine.^6,7 The effect on the prolactin level was minimal. There do not appear to be clinically meaningful changes in laboratory values, vital signs, or QT interval.

Unique clinical issues
Preferential binding. Cariprazine is the third dopamine partial agonist approved for use in the United States; unlike the other 2—aripiprazole and brexpiprazole—cariprazine shows preference for D3 receptors over D2 receptors. The exact clinical impact of a preference for D3 and the drug’s partial agonism of 5-HT1A has not been fully elucidated.

EPS, including akathisia and parkinsonism, were among common adverse events. Both were usually mild, with 0.5% of schizophrenia patients and 2% of BD I patients dropping out of trials because of any type of EPS-related AEs.

Why Rx? On a practical medical level, reasons to prescribe cariprazine likely include:

• minimal effect on prolactin
• relative lack of effect on metabolic parameters, including weight (cariprazine showed less weight gain than risperidone or aripiprazole control arms in trials).

Dosing
The recommended dosage of cariprazine for schizophrenia ranges from 1.5 to 6 mg/d. The recommended starting dosage is 1.5 mg/d, which can be increased to 3 mg on Day 2, with further upward dosage adjustments of 1.5 to 3 mg/d, based on clinical response and tolerability.¹

The recommended dosages of cariprazine for mixed and manic episodes of BD I range from 3 to 6 mg/d. The recommended starting dosage is 1.5 mg/d, which can be increased to 3 mg on Day 2, with further upward dosage adjustments of 1.5 to 3 mg/d, based on clinical response and tolerability.¹

Other key aspects of dosing to keep in mind:

• Because of the long half-life and 2 equipotent active metabolites of cariprazine, any changes made to the dosage will not be reflected fully in the serum level for 2 weeks.
• Administering the drug with food slightly delays, but does not affect, the extent of absorption.
• Because the drug is metabolized primarily by CYP3A4, dosage adjustment is required in the presence of a CYP3A4 inhibitor; the recommended starting dosage of cariprazine is 1.5 mg every other day with a maximum dosage of 3 mg/d when it is administered concomitantly with a strong CYP3A4 inhibitor.
• Because data are not available regarding concomitant use of cariprazine with a strong CYP3A4 inducer, this practice is not recommended.¹
• Because the drug is metabolized primarily by CYP3A4, dosage adjustment is required in the presence of a CYP3A4 Because data are not available regarding concomitant use of cariprazine with a strong CYP3A4

Contraindications
Cariprazine carries a FDA black-box warning of increased mortality in older patients who have dementia-related psychosis, as other atypical antipsychotics do. Clinical trials produced few data about the use of cariprazine in geriatric patients; no data exist about use in the pediatric population.¹

Metabolic, prolactin, and cardiac concerns about cariprazine appeared favorably minor in Phase-III and long-term safety trials. Concomitant use of cariprazine with any strong inducer of CYP3A4 has not been studied, and is not recommended. Dosage reduction is recommended when using cariprazine concomitantly with a CYP3A4 inhibitor.¹

In conclusion
The puzzle in neuropsychiatry has always been to find ways to produce different effects in different brain regions—with a single drug. Cariprazine’s particular binding profile—higher affinity and higher selectivity for D3 receptors than for D2 receptors compared with either aripiprazole or brexpiprazole—may secure a role for it in managing psychosis and mood disorders.

Cariprazine is a newly approved (September 2015) dopamine D3/D2 receptor partial agonist with higher affinity for the D3 receptor than for D2. The drug is FDA-indicated for treating schizophrenia and bipolar I disorder (BD I)^1,2 (Table 1). In clinical trials, cariprazine alleviated symptoms of schizophrenia and mixed and manic symptoms of BD I, with minimal effect on metabolic parameters, the prolactin level, and cardiac conduction.

Receptor blocking. As a dopamine D3-preferring D3/D2 partial agonist, cariprazine offers an alternative to antipsychotics that preferentially modulate D2 receptors. First-generation (typical) antipsychotics block D2 receptors; atypical antipsychotics block D2 receptors and 5-HT2A receptors. Dopamine partial agonists aripiprazole and brexpiprazole are D2-preferring, with minimal D3 effects. In contrast, cariprazine has a 6-fold to 8-fold higher affinity for D3 receptors than for D2 receptors, and has specificity for the D3 receptor that is 3 to 10 times higher than what aripiprazole has for the D3 receptor^3-5 (Table 2).

Use in schizophrenia. Recommended dosage range is 1.5 to 6 mg/d. In Phase-III clinical trials, dosages of 3 to 9 mg/d produced significant improvement on the Positive and Negative Symptom Scale (PANSS) and on the Clinical Global Impression scale. Higher dosages (6 to 9 mg/d) showed early separation from placebo—by the end of Week 1—but carried a dosage-related risk of AEs, leading the FDA to recommend 6 mg/d as the maximum dosage.^1,6-8

Use in manic or mixed episodes of BD I. Recommended dosage range is 3 to 6 mg/d. In clinical trials, dosages in the range of 3 to 12 mg/d were effective for acute manic or mixed symptoms; significant improvement in the Young Mania Rating Scale (YMRS) score was seen as early as Day 4. Dosages >6 mg/d yielded no additional benefit and were associated with increased risk of AEs.^9-12

Pharmacologic profile, adverse effects. Cariprazine has a pharmacologic profile consistent with the generally favorable metabolic profile and lack of anticholinergic effects seen in clinical trials. In short- and long-term trials, the drug had minimal effects on prolactin, blood pressure, and cardiac conduction.¹³

Across clinical trials for both disorders, akathisia and parkinsonism were among more common AEs of cariprazine. Both AEs were usually mild, resulting in relatively few premature discontinuations from trials. Parkinsonism appeared somewhat dosage-related; akathisia had no clear relationship to dosage.

How it works
The theory behind the use of partial agonists, including cariprazine, is that these agents restore homeostatic balance to neurochemical circuits by:

• decreasing the effects of endogenous neurotransmitters (dopamine tone) in regions of the brain where their transmission is excessive, such as mesolimbic regions in schizophrenia or mania
• simultaneously increasing neurotransmission in regions where transmission of endogenous neurotransmitters is low, such as the prefrontal cortex in schizophrenia
• exerting little effect in regions where neurotransmitter activity is normal, such as the pituitary gland.
• simultaneously

Cariprazine has higher binding affinity for dopamine D3 receptors (Ki 0.085 nM) than for D2L receptors (Ki 0.49 nM) and D2S receptors (Ki 0.69 nM). The drug also has strong affinity for serotonin receptor 5-HT2B; moderate affinity for 5-HT1A; and lower affinity for 5-HT2A, histamine H1, and 5-HT7 receptors. Cariprazine has little or no affinity for adrenergic or cholinergic receptors.¹⁴In patients with schizophrenia, as measured on PET scanning, a dosage of 1.5 mg/d yielded 69% to 75% D2/D3 receptor occupancy. A dosage of 3 mg/d yielded >90% occupancy.

Search for an understanding of action continues. The relative contribution of D3 partial agonism, compared with D2 partial agonism, is a subject of ongoing basic scientific and clinical research. D3 is an autoreceptor that (1) controls phasic, but not tonic, activity of dopamine nerve cells and (2) mediates behavioral abnormalities induced by glutamate and N-methyl-D-aspartate receptor antagonists.^5,12 In animal studies, D3-preferring agents have been shown to exert pro-cognitive effects and improve anhedonic symptoms.

Pharmacokinetics
Cariprazine is a once-daily medication with a relatively long half-life that can be taken with or without food. Dosages of 3 to 12 mg/d yield a fairly linear, dose-proportional increase in plasma concentration. The peak serum concentration for cariprazine is 3 to 4 hours under fasting conditions; taking the drug with food causes a slight delay in absorption but does not have a significant effect on the area under the curve. Mean half-life for cariprazine is 2 to 5 days over a dosage range of 1.5 to 12.5 mg/d in otherwise healthy adults with schizophrenia.¹

Cariprazine is metabolized primarily by cytochrome P450 (CYP) 3A4. It is a weak inhibitor of CYP2D6 and CYP3A4.¹ Hepatic metabolism of cariprazine produces 2 active metabolites: desmethyl-cariprazine (DCAR) and didesmethyl-cariprazine (DDCAR), both of which are equipotent to cariprazine. After multiple dose administration, mean cariprazine and DCAR levels reach steady state in 1 to 2 weeks; DDCAR, in 4 to 8 weeks. The systemic exposure and serum levels of DDCAR are roughly 3-fold greater than cariprazine because of the longer elimination half-life of DDCAR.¹

Efficacy in schizophrenia
The efficacy of cariprazine in schizophrenia was established by 3 six-week, randomized, placebo-controlled trials. Two trials were fixed-dosage; a third used 2 flexible dosage ranges. The primary efficacy measure was change from baseline in the total score of the PANSS at the end of Week 6, compared with placebo. In all trials, patients were adults (age 18 to 60) who met DSM-IV-TR criteria for schizophrenia and had a PANSS score between 80 and 120 at screening and baseline.

Study 1 (n = 711) compared dosages of 1.5 mg/d, 3 mg/d, and 4.5 mg/d with placebo.⁷ All cariprazine dosages and an active control (risperdone) were superior to placebo in reducing symptoms of schizophrenia, as measured by the PANSS. The placebo-subtracted differences on PANSS score at 6 weeks for dosages of 1.5 mg/d, 3 mg/d, and 4.5 mg/d were –7.6, –8.8, –10.4, respectively (significant at 95% CI).

Study 2 (n = 151) compared 3 mg/d and 6 mg/d dosages of cariprazine with placebo.¹ Both dosages and an active control (aripiprazole) were superior to placebo in reducing PANSS scores. Placebo-subtracted differences on PANSS score at 6 weeks for dosages of 3 mg/d and 6 mg/day were –6.0, –8.8, respectively (significant at 95% CI).

Study 3 (n = 147) was a fixed-flexible dosage trial comparing cariprazine, 3 to 6 mg/d and 6 to 9 mg/d dosage ranges, to placebo.⁸ Both ranges were superior to placebo in reducing symptoms on PANSS. Placebo-subtracted differences from placebo on PANSS at 6 weeks for cariprazine 3 to 6 or 6 to 9 mg/d were –6.8, –9.9, respectively (significant at 95% CI).

These trials established the efficacy of cariprazine for acute schizophrenia at dosages ranging from 1.5 to 9 mg/d. Although there was a modest trend toward higher efficacy at higher dosages, there was a dose-related increase in certain adverse reactions (extrapyramidal symptoms [EPS]) at dosages >6 mg/d.¹

Efficacy in bipolar disorder
The efficacy of cariprazine for acute treatment of manic or mixed episodes of BD I was established in 3 randomized, placebo-controlled, flexibly dosed 3-week trials. In all trials, patients were adults (age 18 to 65) who met DSM-IV-TR criteria for BD I with manic or mixed episodes and with or without psychotic features (YMRS score, ≥20). The primary efficacy measure in the 3 trials was a change from baseline in the total YMRS score at the end of Week 3, compared with placebo.

Study 1 (n = 492) compared 2 flexibly dosed ranges of cariprazine (3 to 6 mg/d and 6 to 12 mg/d) with placebo.¹⁰ Both dosage ranges were superior to placebo in reducing mixed and manic symptoms, as measured by reduction in the total YMRS score. Placebo-subtracted differences in YMRS scores from placebo at Week 3 for cariprazine 3 to 6 mg/d and 6 to 12 mg/d were –6.1, –5.9, respectively (significant at 95% CI). The higher range offered no additional advantage over the lower range.

Study 2 (n = 235) compared flexibly dosed cariprazine, 3 to 12 mg/d, to placebo.¹¹ Cariprazine was superior to placebo in reducing bipolar symptoms as measured by the YMRS. The difference between cariprazine 3 to 12 mg/d and placebo on the YMRS score at Week 3 was –6.1 (significant at 95% CI).

Study 3 (n = 310) compared flexibly dosed cariprazine, 3 to 12 mg/d, with placebo.¹⁵ Again, cariprazine was superior to placebo in reducing the YMRS score at Week 3: difference, –4.3 (significant at 95% CI).

These trials establish the efficacy of cariprazine in treating acute mania or mixed BD I episodes at dosages ranging from 3 to 12 mg/d. Dosages >6 mg/d did not offer additional benefit over lower dosages, and resulted in a dosage-related increase in EPS at dosages >6 mg/d.¹⁶

Tolerability
Cariprazine generally was well tolerated in short-term trials for schizophrenia and BD I. The only treatment-emergent adverse event reported for at least 1 treatment group in all trials at a rate of ≥10%, and at least twice the rate seen with placebo was akathisia. Adverse events reported at a lower rate than placebo included EPS (particularly parkinsonism), restlessness, headache, insomnia, fatigue, and gastrointestinal distress. The discontinuation rate due to AEs for treatment groups and placebo-treated patients generally was similar. In schizophrenia Study 3, for example, the discontinuation rate due to AEs was 13% for placebo; 14% for cariprazine, 3 to 6 mg/d; and 13% for cariprazine, 6 to 9 mg/d.¹ 48-Week open-label safety study. Patients with schizophrenia received open-label cariprazine for as long as 48 weeks.⁷ Serious adverse events were reported in 12.9%, including 1 death (suicide); exacerbation of symptoms of schizophrenia (4.3%); and psychosis (2.2%). Treatment-emergent adverse events reported in at least 10% of patients included akathisia (14.0%), insomnia (14.0%), and weight gain (11.8%). The mean change in laboratory values, blood pressure, pulse rate, and electrocardiographic parameters was clinically insignificant.

Other studies. In a 16-week, open-label extension study of patients with BD I, the major tolerability issue was akathisia. This AE developed in 37% of patients and led to a 5% withdrawal rate.¹²

In short- and long-term studies for either indication, the effect of the drug on metabolic parameters appears to be small. In studies with active controls, potentially significant weight gain (>7%) was greater for aripiprazole and risperidone than for cariprazine.^6,7 The effect on the prolactin level was minimal. There do not appear to be clinically meaningful changes in laboratory values, vital signs, or QT interval.

Unique clinical issues
Preferential binding. Cariprazine is the third dopamine partial agonist approved for use in the United States; unlike the other 2—aripiprazole and brexpiprazole—cariprazine shows preference for D3 receptors over D2 receptors. The exact clinical impact of a preference for D3 and the drug’s partial agonism of 5-HT1A has not been fully elucidated.

EPS, including akathisia and parkinsonism, were among common adverse events. Both were usually mild, with 0.5% of schizophrenia patients and 2% of BD I patients dropping out of trials because of any type of EPS-related AEs.

Why Rx? On a practical medical level, reasons to prescribe cariprazine likely include:

• minimal effect on prolactin
• relative lack of effect on metabolic parameters, including weight (cariprazine showed less weight gain than risperidone or aripiprazole control arms in trials).

Dosing
The recommended dosage of cariprazine for schizophrenia ranges from 1.5 to 6 mg/d. The recommended starting dosage is 1.5 mg/d, which can be increased to 3 mg on Day 2, with further upward dosage adjustments of 1.5 to 3 mg/d, based on clinical response and tolerability.¹

The recommended dosages of cariprazine for mixed and manic episodes of BD I range from 3 to 6 mg/d. The recommended starting dosage is 1.5 mg/d, which can be increased to 3 mg on Day 2, with further upward dosage adjustments of 1.5 to 3 mg/d, based on clinical response and tolerability.¹

Other key aspects of dosing to keep in mind:

• Because of the long half-life and 2 equipotent active metabolites of cariprazine, any changes made to the dosage will not be reflected fully in the serum level for 2 weeks.
• Administering the drug with food slightly delays, but does not affect, the extent of absorption.
• Because the drug is metabolized primarily by CYP3A4, dosage adjustment is required in the presence of a CYP3A4 inhibitor; the recommended starting dosage of cariprazine is 1.5 mg every other day with a maximum dosage of 3 mg/d when it is administered concomitantly with a strong CYP3A4 inhibitor.
• Because data are not available regarding concomitant use of cariprazine with a strong CYP3A4 inducer, this practice is not recommended.¹
• Because the drug is metabolized primarily by CYP3A4, dosage adjustment is required in the presence of a CYP3A4 Because data are not available regarding concomitant use of cariprazine with a strong CYP3A4

Contraindications
Cariprazine carries a FDA black-box warning of increased mortality in older patients who have dementia-related psychosis, as other atypical antipsychotics do. Clinical trials produced few data about the use of cariprazine in geriatric patients; no data exist about use in the pediatric population.¹

Metabolic, prolactin, and cardiac concerns about cariprazine appeared favorably minor in Phase-III and long-term safety trials. Concomitant use of cariprazine with any strong inducer of CYP3A4 has not been studied, and is not recommended. Dosage reduction is recommended when using cariprazine concomitantly with a CYP3A4 inhibitor.¹

In conclusion
The puzzle in neuropsychiatry has always been to find ways to produce different effects in different brain regions—with a single drug. Cariprazine’s particular binding profile—higher affinity and higher selectivity for D3 receptors than for D2 receptors compared with either aripiprazole or brexpiprazole—may secure a role for it in managing psychosis and mood disorders.

Cariprazine is a newly approved (September 2015) dopamine D3/D2 receptor partial agonist with higher affinity for the D3 receptor than for D2. The drug is FDA-indicated for treating schizophrenia and bipolar I disorder (BD I)^1,2 (Table 1). In clinical trials, cariprazine alleviated symptoms of schizophrenia and mixed and manic symptoms of BD I, with minimal effect on metabolic parameters, the prolactin level, and cardiac conduction.

Receptor blocking. As a dopamine D3-preferring D3/D2 partial agonist, cariprazine offers an alternative to antipsychotics that preferentially modulate D2 receptors. First-generation (typical) antipsychotics block D2 receptors; atypical antipsychotics block D2 receptors and 5-HT2A receptors. Dopamine partial agonists aripiprazole and brexpiprazole are D2-preferring, with minimal D3 effects. In contrast, cariprazine has a 6-fold to 8-fold higher affinity for D3 receptors than for D2 receptors, and has specificity for the D3 receptor that is 3 to 10 times higher than what aripiprazole has for the D3 receptor^3-5 (Table 2).

Use in schizophrenia. Recommended dosage range is 1.5 to 6 mg/d. In Phase-III clinical trials, dosages of 3 to 9 mg/d produced significant improvement on the Positive and Negative Symptom Scale (PANSS) and on the Clinical Global Impression scale. Higher dosages (6 to 9 mg/d) showed early separation from placebo—by the end of Week 1—but carried a dosage-related risk of AEs, leading the FDA to recommend 6 mg/d as the maximum dosage.^1,6-8

Use in manic or mixed episodes of BD I. Recommended dosage range is 3 to 6 mg/d. In clinical trials, dosages in the range of 3 to 12 mg/d were effective for acute manic or mixed symptoms; significant improvement in the Young Mania Rating Scale (YMRS) score was seen as early as Day 4. Dosages >6 mg/d yielded no additional benefit and were associated with increased risk of AEs.^9-12

Pharmacologic profile, adverse effects. Cariprazine has a pharmacologic profile consistent with the generally favorable metabolic profile and lack of anticholinergic effects seen in clinical trials. In short- and long-term trials, the drug had minimal effects on prolactin, blood pressure, and cardiac conduction.¹³

Across clinical trials for both disorders, akathisia and parkinsonism were among more common AEs of cariprazine. Both AEs were usually mild, resulting in relatively few premature discontinuations from trials. Parkinsonism appeared somewhat dosage-related; akathisia had no clear relationship to dosage.

How it works
The theory behind the use of partial agonists, including cariprazine, is that these agents restore homeostatic balance to neurochemical circuits by:

• decreasing the effects of endogenous neurotransmitters (dopamine tone) in regions of the brain where their transmission is excessive, such as mesolimbic regions in schizophrenia or mania
• simultaneously increasing neurotransmission in regions where transmission of endogenous neurotransmitters is low, such as the prefrontal cortex in schizophrenia
• exerting little effect in regions where neurotransmitter activity is normal, such as the pituitary gland.
• simultaneously

Cariprazine has higher binding affinity for dopamine D3 receptors (Ki 0.085 nM) than for D2L receptors (Ki 0.49 nM) and D2S receptors (Ki 0.69 nM). The drug also has strong affinity for serotonin receptor 5-HT2B; moderate affinity for 5-HT1A; and lower affinity for 5-HT2A, histamine H1, and 5-HT7 receptors. Cariprazine has little or no affinity for adrenergic or cholinergic receptors.¹⁴In patients with schizophrenia, as measured on PET scanning, a dosage of 1.5 mg/d yielded 69% to 75% D2/D3 receptor occupancy. A dosage of 3 mg/d yielded >90% occupancy.

Search for an understanding of action continues. The relative contribution of D3 partial agonism, compared with D2 partial agonism, is a subject of ongoing basic scientific and clinical research. D3 is an autoreceptor that (1) controls phasic, but not tonic, activity of dopamine nerve cells and (2) mediates behavioral abnormalities induced by glutamate and N-methyl-D-aspartate receptor antagonists.^5,12 In animal studies, D3-preferring agents have been shown to exert pro-cognitive effects and improve anhedonic symptoms.

Pharmacokinetics
Cariprazine is a once-daily medication with a relatively long half-life that can be taken with or without food. Dosages of 3 to 12 mg/d yield a fairly linear, dose-proportional increase in plasma concentration. The peak serum concentration for cariprazine is 3 to 4 hours under fasting conditions; taking the drug with food causes a slight delay in absorption but does not have a significant effect on the area under the curve. Mean half-life for cariprazine is 2 to 5 days over a dosage range of 1.5 to 12.5 mg/d in otherwise healthy adults with schizophrenia.¹

Cariprazine is metabolized primarily by cytochrome P450 (CYP) 3A4. It is a weak inhibitor of CYP2D6 and CYP3A4.¹ Hepatic metabolism of cariprazine produces 2 active metabolites: desmethyl-cariprazine (DCAR) and didesmethyl-cariprazine (DDCAR), both of which are equipotent to cariprazine. After multiple dose administration, mean cariprazine and DCAR levels reach steady state in 1 to 2 weeks; DDCAR, in 4 to 8 weeks. The systemic exposure and serum levels of DDCAR are roughly 3-fold greater than cariprazine because of the longer elimination half-life of DDCAR.¹

Efficacy in schizophrenia
The efficacy of cariprazine in schizophrenia was established by 3 six-week, randomized, placebo-controlled trials. Two trials were fixed-dosage; a third used 2 flexible dosage ranges. The primary efficacy measure was change from baseline in the total score of the PANSS at the end of Week 6, compared with placebo. In all trials, patients were adults (age 18 to 60) who met DSM-IV-TR criteria for schizophrenia and had a PANSS score between 80 and 120 at screening and baseline.

Study 1 (n = 711) compared dosages of 1.5 mg/d, 3 mg/d, and 4.5 mg/d with placebo.⁷ All cariprazine dosages and an active control (risperdone) were superior to placebo in reducing symptoms of schizophrenia, as measured by the PANSS. The placebo-subtracted differences on PANSS score at 6 weeks for dosages of 1.5 mg/d, 3 mg/d, and 4.5 mg/d were –7.6, –8.8, –10.4, respectively (significant at 95% CI).

Study 2 (n = 151) compared 3 mg/d and 6 mg/d dosages of cariprazine with placebo.¹ Both dosages and an active control (aripiprazole) were superior to placebo in reducing PANSS scores. Placebo-subtracted differences on PANSS score at 6 weeks for dosages of 3 mg/d and 6 mg/day were –6.0, –8.8, respectively (significant at 95% CI).

Study 3 (n = 147) was a fixed-flexible dosage trial comparing cariprazine, 3 to 6 mg/d and 6 to 9 mg/d dosage ranges, to placebo.⁸ Both ranges were superior to placebo in reducing symptoms on PANSS. Placebo-subtracted differences from placebo on PANSS at 6 weeks for cariprazine 3 to 6 or 6 to 9 mg/d were –6.8, –9.9, respectively (significant at 95% CI).

These trials established the efficacy of cariprazine for acute schizophrenia at dosages ranging from 1.5 to 9 mg/d. Although there was a modest trend toward higher efficacy at higher dosages, there was a dose-related increase in certain adverse reactions (extrapyramidal symptoms [EPS]) at dosages >6 mg/d.¹

Efficacy in bipolar disorder
The efficacy of cariprazine for acute treatment of manic or mixed episodes of BD I was established in 3 randomized, placebo-controlled, flexibly dosed 3-week trials. In all trials, patients were adults (age 18 to 65) who met DSM-IV-TR criteria for BD I with manic or mixed episodes and with or without psychotic features (YMRS score, ≥20). The primary efficacy measure in the 3 trials was a change from baseline in the total YMRS score at the end of Week 3, compared with placebo.

Study 1 (n = 492) compared 2 flexibly dosed ranges of cariprazine (3 to 6 mg/d and 6 to 12 mg/d) with placebo.¹⁰ Both dosage ranges were superior to placebo in reducing mixed and manic symptoms, as measured by reduction in the total YMRS score. Placebo-subtracted differences in YMRS scores from placebo at Week 3 for cariprazine 3 to 6 mg/d and 6 to 12 mg/d were –6.1, –5.9, respectively (significant at 95% CI). The higher range offered no additional advantage over the lower range.

Study 2 (n = 235) compared flexibly dosed cariprazine, 3 to 12 mg/d, to placebo.¹¹ Cariprazine was superior to placebo in reducing bipolar symptoms as measured by the YMRS. The difference between cariprazine 3 to 12 mg/d and placebo on the YMRS score at Week 3 was –6.1 (significant at 95% CI).

Study 3 (n = 310) compared flexibly dosed cariprazine, 3 to 12 mg/d, with placebo.¹⁵ Again, cariprazine was superior to placebo in reducing the YMRS score at Week 3: difference, –4.3 (significant at 95% CI).

These trials establish the efficacy of cariprazine in treating acute mania or mixed BD I episodes at dosages ranging from 3 to 12 mg/d. Dosages >6 mg/d did not offer additional benefit over lower dosages, and resulted in a dosage-related increase in EPS at dosages >6 mg/d.¹⁶

Tolerability
Cariprazine generally was well tolerated in short-term trials for schizophrenia and BD I. The only treatment-emergent adverse event reported for at least 1 treatment group in all trials at a rate of ≥10%, and at least twice the rate seen with placebo was akathisia. Adverse events reported at a lower rate than placebo included EPS (particularly parkinsonism), restlessness, headache, insomnia, fatigue, and gastrointestinal distress. The discontinuation rate due to AEs for treatment groups and placebo-treated patients generally was similar. In schizophrenia Study 3, for example, the discontinuation rate due to AEs was 13% for placebo; 14% for cariprazine, 3 to 6 mg/d; and 13% for cariprazine, 6 to 9 mg/d.¹ 48-Week open-label safety study. Patients with schizophrenia received open-label cariprazine for as long as 48 weeks.⁷ Serious adverse events were reported in 12.9%, including 1 death (suicide); exacerbation of symptoms of schizophrenia (4.3%); and psychosis (2.2%). Treatment-emergent adverse events reported in at least 10% of patients included akathisia (14.0%), insomnia (14.0%), and weight gain (11.8%). The mean change in laboratory values, blood pressure, pulse rate, and electrocardiographic parameters was clinically insignificant.

Other studies. In a 16-week, open-label extension study of patients with BD I, the major tolerability issue was akathisia. This AE developed in 37% of patients and led to a 5% withdrawal rate.¹²

In short- and long-term studies for either indication, the effect of the drug on metabolic parameters appears to be small. In studies with active controls, potentially significant weight gain (>7%) was greater for aripiprazole and risperidone than for cariprazine.^6,7 The effect on the prolactin level was minimal. There do not appear to be clinically meaningful changes in laboratory values, vital signs, or QT interval.

Unique clinical issues
Preferential binding. Cariprazine is the third dopamine partial agonist approved for use in the United States; unlike the other 2—aripiprazole and brexpiprazole—cariprazine shows preference for D3 receptors over D2 receptors. The exact clinical impact of a preference for D3 and the drug’s partial agonism of 5-HT1A has not been fully elucidated.

EPS, including akathisia and parkinsonism, were among common adverse events. Both were usually mild, with 0.5% of schizophrenia patients and 2% of BD I patients dropping out of trials because of any type of EPS-related AEs.

Why Rx? On a practical medical level, reasons to prescribe cariprazine likely include:

• minimal effect on prolactin
• relative lack of effect on metabolic parameters, including weight (cariprazine showed less weight gain than risperidone or aripiprazole control arms in trials).

Dosing
The recommended dosage of cariprazine for schizophrenia ranges from 1.5 to 6 mg/d. The recommended starting dosage is 1.5 mg/d, which can be increased to 3 mg on Day 2, with further upward dosage adjustments of 1.5 to 3 mg/d, based on clinical response and tolerability.¹

The recommended dosages of cariprazine for mixed and manic episodes of BD I range from 3 to 6 mg/d. The recommended starting dosage is 1.5 mg/d, which can be increased to 3 mg on Day 2, with further upward dosage adjustments of 1.5 to 3 mg/d, based on clinical response and tolerability.¹

Other key aspects of dosing to keep in mind:

• Because of the long half-life and 2 equipotent active metabolites of cariprazine, any changes made to the dosage will not be reflected fully in the serum level for 2 weeks.
• Administering the drug with food slightly delays, but does not affect, the extent of absorption.
• Because the drug is metabolized primarily by CYP3A4, dosage adjustment is required in the presence of a CYP3A4 inhibitor; the recommended starting dosage of cariprazine is 1.5 mg every other day with a maximum dosage of 3 mg/d when it is administered concomitantly with a strong CYP3A4 inhibitor.
• Because data are not available regarding concomitant use of cariprazine with a strong CYP3A4 inducer, this practice is not recommended.¹
• Because the drug is metabolized primarily by CYP3A4, dosage adjustment is required in the presence of a CYP3A4 Because data are not available regarding concomitant use of cariprazine with a strong CYP3A4

Contraindications
Cariprazine carries a FDA black-box warning of increased mortality in older patients who have dementia-related psychosis, as other atypical antipsychotics do. Clinical trials produced few data about the use of cariprazine in geriatric patients; no data exist about use in the pediatric population.¹

Metabolic, prolactin, and cardiac concerns about cariprazine appeared favorably minor in Phase-III and long-term safety trials. Concomitant use of cariprazine with any strong inducer of CYP3A4 has not been studied, and is not recommended. Dosage reduction is recommended when using cariprazine concomitantly with a CYP3A4 inhibitor.¹

In conclusion
The puzzle in neuropsychiatry has always been to find ways to produce different effects in different brain regions—with a single drug. Cariprazine’s particular binding profile—higher affinity and higher selectivity for D3 receptors than for D2 receptors compared with either aripiprazole or brexpiprazole—may secure a role for it in managing psychosis and mood disorders.