Failure of fear extinction is a core feature of posttraumatic stress disorder (PTSD).¹ Recently, it was confirmed that the amygdala and the orbitofrontal cortex are crucial for both fear acquisition and fear extinction.² The amygdala was found to have neurons active only during fear acquisition, and other neurons active only during fear extinction.³ In essence, the balance of activity between these 2 neuronal populations determines whether if an incoming stimulus is feared or not feared. This balance is under the influence of several cognitive domains, including memory, reward, and executive function.

In PTSD, the equilibrium is shifted heavily toward fear acquisition. The majority of patients spontaneously regain the capacity for fear extinction over time⁴ or with the help of treatment.^5,6 Nonetheless, some patients with severe PTSD seem unable to recover the ability of fear extinction and remain refractory to both standard and novel psychotherapeutic or psychopharmacologic treatments.⁷ For these patients, direct modulation of the neural activity in the amygdala may permit fear extinction. This article describes the rationale for using deep brain stimulation (DBS) and initial results from the first-ever clinical trial.

Deep Brain Stimulation

Deep brain stimulation involves inserting electrodes in precise cerebral targets and then connecting the leads to a pulse generator (similar to a pacemaker) inserted in a subclavicular pocket. The generator controls the electrical signal (amplitude, pulse width, pulse frequency) delivered to the brain target and can be adjusted with use of a noninvasive programmer. In 1997, the FDA approved DBS for patients with Parkinson disease or essential tremor. Since then, its efficacy in these movement disorders has been confirmed in several studies.^8,9

The mechanism by which the small electrical pulses of DBS influence activity is not clear. Clinically, DBS functionally inhibits the activity of local neurons.¹⁰ One theory describes “frequency jamming,” a concept similar to cardiac overdrive pacing in which the resultant high-frequency neuronal signal is meaningless and discounted by the rest of the brain.¹¹

Over the years, DBS has demonstrated a strong safety profile.¹² The risks of electrode insertion are mitigated with targeting based on high-quality magnetic resonance imaging (MRI) and computed tomography (Figure). Unlike a destructive lesion, DBS is reversible, and the implanted system can be removed in its entirety. Histologic analyses have shown only a small amount of scarring around the electrode tip.¹³ In movement disorder treatment, clinical experience has shown that stimulation-related adverse effects (AEs) are reversible with readjustment of stimulation parameters by external programmer.¹⁴

Novel Applications of DBS

The advantageous safety profile of DBS has permitted its evaluation in the treatment of other conditions thought to have malfunctioning networks at their core—such as intractable epilepsy (in resective surgery noncandidates).^15,16 Although several trials have shown promising results of using DBS for treatment-resistant depression,¹⁷ the results of pivotal sham-controlled trials have been mixed.^18,19 Obsessive-compulsive disorder, on the other hand, received the FDA humanitarian device exemption designation on the basis of positive long-term results.²⁰ In treatment-resistant depression and obsessive-compulsive disorder, functional neuroimaging has identified DBS targets.^21,22 Functional MRI or positron emission tomography (PET) images can be compared at resting state, at symptomatic state, and after treatment response. Nodes hyperactive during a symptomatic state and less active after successful treatment can be targeted with high-frequency DBS to directly reduce the hyperactivity and indirectly modulate or normalize the overall function of the circuit.²³

Given the functional MRI and O15 (oxygen-15) PET evidence of amygdala hyperactivity in patients with PTSD having core symptoms,^24-26 the authors hypothesized that high-frequency DBS targeting of the amygdala would improve PTSD-associated hyperarousal and reexperiencing symptoms in treatment-refractory patients. Indirect data supporting this hypothesis include a correlation between amygdala hyperactivity of increased intensity and symptom severity measured with the Clinician-Administered PTSD Scale (CAPS),²⁷ and a correlation between reduced pretreatment amygdala hyperactivity and successful cognitive-behavioral treatment.^28,29

Preclinical Work

Using a rodent model in which a novel object serves as a cue reminder of foot shocks (traumatic event), the authors tested the hypothesis that amygdala DBS would reduce PTSD-like symptoms.³⁰ When untreated rats were presented with the object in their cage a week after the initial exposure, they immediately buried the object under bedding to avoid being reminded of the shocks. In contrast, rats treated with DBS did not bury the object. In most cases, in fact, they played with it.

The authors also replicated their results but with the addition of rats treated with paroxetine.³¹ Using the same rodent model, they found DBS superior to paroxetine in treating PTSD-like symptoms. This study had a crossover design: DBS and sham DBS. Briefly, 20 rats received an electrode in the amygdala and were exposed to inescapable shocks in the presence of the cue object. The rats were then randomly assigned to a DBS group (10 rats) or a sham-DBS group (10 rats). After 1 week, behavioral testing showed fear extinction in the DBS group and no improvement in the sham-DBS group. Then the groups were switched: The rats originally treated with DBS received no treatment, and the rats that were originally sham-treated underwent DBS. One week later, behavioral testing showed acquisition of fear extinction in all the rats. These results suggested DBS can be effective even when delayed after establishment of fear persistence and PTSD symptoms. These results also showed that DBS effects persist even after therapy discontinuation.

Similarly, other investigators have reported that the role of the amygdala is not limited to fear acquisition; it extends to fear expression. A lesion in the amygdala can prevent fear expression even if the disruption is performed subsequent to fear-conditioning training.³² This finding is important for humans, as DBS would be initiated during the chronic phase of the disorder, after failure of less invasive treatment options, such as pharmacotherapy and psychotherapy.

Early Clinical Experience

The authors have initiated the first ever clinical trial (NCT02091843) evaluating use of DBS for PTSD and are now recruiting patients. Enrollment is limited to 6 combat veterans with disabling PTSD that has not responded to pharmacotherapy and psychotherapy. This VA-funded single-site study, being conducted at the VA Greater Los Angeles Healthcare System (VAGLAHS), was approved by the VAGLAHS Institutional Review Board and the FDA. The authors have published the 2-year trial’s protocol, which includes an active-versus-sham stimulation phase; continuous electroencephalogram monitoring; baseline and posttreatment ¹⁸FDG (fluorodeoxyglucose) PET performed during a resting state vs during investigator-guided exposure to trauma reminders; and extensive psychological and neuropsychological assessments.³³ The literature includes only 1 case report on amygdala DBS.³⁴ The authors of that report used DBS of the basolateral nucleus of the amygdala to treat a teenaged boy with severe autism and found that the therapy was safe.

As of this writing, the authors have recruited and implanted 1 patient and reported on his clinical results (including baseline PET) over the first 8 months of stimulation³⁵ and on the electrophysiologic findings over the first year.³⁶ After experiencing extremely severe combat PTSD refractory to pharmacotherapy and psychotherapy treatments for more than 20 years, the patient treated with DBS is now experiencing substantial symptom relief, and his CAPS score (primary outcome measure) has improved by about 40%. He has tolerated continuous stimulation without any serious DBS-related AEs for up to 16 months. Notably, he has not had a single severe combat nightmare in a year—in stark contrast to nightly combat nightmares during the 20-year period leading to the trial. Furthermore, he has not been having any episodes of severe dissociation, which had been a common disabling problem before the trial. He has taken a second trip out of the country, improved his relationships with family, and made strides (albeit limited) in pursuing additional social interactions.

Avoidance remains a major problem. He recently left his job after 7 years, because he prefers a more nature-oriented rather than people-oriented environment. In addition, his interest in intensive psychotherapy has increased, and he has been considering options for spending more time working on his therapy.

Over 15 months of treatment, the patient’s CAPS total and subscale scores have decreased—his symptoms have improved (Table).²¹ He has had rapid and substantial reductions in recurrence and hyperarousal symptoms but slower improvement in avoidance. Improvements in emotional reactivity would be expected to occur before any change in behavior (eg, avoidance). Patients likely must first recognize changes in emotional reactivity to events before they can engage in a cognitive process to modify learned behavioral responses to those events.

After about 9 months of treatment, all of the study patient’s symptoms were somewhat stabilized, and the authors began making gradual stimulation adjustments to the latest parameters—3.5 V, 60 µs, and 160 Hz for the right electrode and 1.5 V, 60 µs, and 160 Hz for the left electrode—using the contacts in the basolateral nucleus of the amygdala, per postoperative neuroimaging.³⁵ A thin cuts computed tomography (CT) scan of the brain was obtained postoperatively and merged to the preoperative MRI. The CT scan captured the location of the DBS electrode contacts and the MRI superimposition to determine the position of those contacts in the brain.

After 15 to 18 months, when improvement peaked at 48% symptom reduction from baseline, the patient experienced psychiatric decompensation (depression, suicide gesture) not attributable to changes in stimulation settings and not associated with exacerbation of PTSD symptoms. Treatment team members and independent psychiatric consultants attributed the decompensation to the patient’s difficulty in changing a long-standing avoidant behavior routine, owing to severe recurrence and hyperarousal symptoms in the past. His persistent inability to overcome avoidance and isolation, despite core PTSD symptom improvement, had left him feeling worthless.

The patient remains in the study but also is participating in other medication and psychotherapy trials and is making a career change. Periodic decompensations may be part of the treatment course as patients reach a more complex and volatile phase of improvement that requires more intensive cognitive reprocessing. If this proves to be the case with other patients enrolling in the study, intensive psychotherapy that addresses cognitive and emotional PTSD symptoms may be needed once there is improvement in intrusive and hyperarousal symptoms.

Conclusion

Deep brain stimulation has been successful in treating Parkinson disease and essential tremor. Physiologically, DBS seems to inhibit specific brain regions’ dysfunctional activity stemming from a disease process. Deep brain stimulation-induced inhibition of a dysfunctional node improves clinical outcomes in movement disorders.

Given the reversibility and positive safety profile of DBS, new applications are being studied. The authors propose that DBS may benefit patients with severe treatment-refractory PTSD. Their first patient’s core PTSD symptoms have improved significantly, as expected, but as in other psychiatric DBS cases, the seriousness and chronicity of his illness may be complicating the course of recovery. The authors plan to recruit 6 patients for this early-phase safety trial.

Click here to read the digital edition.

Failure of fear extinction is a core feature of posttraumatic stress disorder (PTSD).¹ Recently, it was confirmed that the amygdala and the orbitofrontal cortex are crucial for both fear acquisition and fear extinction.² The amygdala was found to have neurons active only during fear acquisition, and other neurons active only during fear extinction.³ In essence, the balance of activity between these 2 neuronal populations determines whether if an incoming stimulus is feared or not feared. This balance is under the influence of several cognitive domains, including memory, reward, and executive function.

In PTSD, the equilibrium is shifted heavily toward fear acquisition. The majority of patients spontaneously regain the capacity for fear extinction over time⁴ or with the help of treatment.^5,6 Nonetheless, some patients with severe PTSD seem unable to recover the ability of fear extinction and remain refractory to both standard and novel psychotherapeutic or psychopharmacologic treatments.⁷ For these patients, direct modulation of the neural activity in the amygdala may permit fear extinction. This article describes the rationale for using deep brain stimulation (DBS) and initial results from the first-ever clinical trial.

Deep Brain Stimulation

Deep brain stimulation involves inserting electrodes in precise cerebral targets and then connecting the leads to a pulse generator (similar to a pacemaker) inserted in a subclavicular pocket. The generator controls the electrical signal (amplitude, pulse width, pulse frequency) delivered to the brain target and can be adjusted with use of a noninvasive programmer. In 1997, the FDA approved DBS for patients with Parkinson disease or essential tremor. Since then, its efficacy in these movement disorders has been confirmed in several studies.^8,9

The mechanism by which the small electrical pulses of DBS influence activity is not clear. Clinically, DBS functionally inhibits the activity of local neurons.¹⁰ One theory describes “frequency jamming,” a concept similar to cardiac overdrive pacing in which the resultant high-frequency neuronal signal is meaningless and discounted by the rest of the brain.¹¹

Over the years, DBS has demonstrated a strong safety profile.¹² The risks of electrode insertion are mitigated with targeting based on high-quality magnetic resonance imaging (MRI) and computed tomography (Figure). Unlike a destructive lesion, DBS is reversible, and the implanted system can be removed in its entirety. Histologic analyses have shown only a small amount of scarring around the electrode tip.¹³ In movement disorder treatment, clinical experience has shown that stimulation-related adverse effects (AEs) are reversible with readjustment of stimulation parameters by external programmer.¹⁴

Novel Applications of DBS

The advantageous safety profile of DBS has permitted its evaluation in the treatment of other conditions thought to have malfunctioning networks at their core—such as intractable epilepsy (in resective surgery noncandidates).^15,16 Although several trials have shown promising results of using DBS for treatment-resistant depression,¹⁷ the results of pivotal sham-controlled trials have been mixed.^18,19 Obsessive-compulsive disorder, on the other hand, received the FDA humanitarian device exemption designation on the basis of positive long-term results.²⁰ In treatment-resistant depression and obsessive-compulsive disorder, functional neuroimaging has identified DBS targets.^21,22 Functional MRI or positron emission tomography (PET) images can be compared at resting state, at symptomatic state, and after treatment response. Nodes hyperactive during a symptomatic state and less active after successful treatment can be targeted with high-frequency DBS to directly reduce the hyperactivity and indirectly modulate or normalize the overall function of the circuit.²³

Given the functional MRI and O15 (oxygen-15) PET evidence of amygdala hyperactivity in patients with PTSD having core symptoms,^24-26 the authors hypothesized that high-frequency DBS targeting of the amygdala would improve PTSD-associated hyperarousal and reexperiencing symptoms in treatment-refractory patients. Indirect data supporting this hypothesis include a correlation between amygdala hyperactivity of increased intensity and symptom severity measured with the Clinician-Administered PTSD Scale (CAPS),²⁷ and a correlation between reduced pretreatment amygdala hyperactivity and successful cognitive-behavioral treatment.^28,29

Preclinical Work

Using a rodent model in which a novel object serves as a cue reminder of foot shocks (traumatic event), the authors tested the hypothesis that amygdala DBS would reduce PTSD-like symptoms.³⁰ When untreated rats were presented with the object in their cage a week after the initial exposure, they immediately buried the object under bedding to avoid being reminded of the shocks. In contrast, rats treated with DBS did not bury the object. In most cases, in fact, they played with it.

The authors also replicated their results but with the addition of rats treated with paroxetine.³¹ Using the same rodent model, they found DBS superior to paroxetine in treating PTSD-like symptoms. This study had a crossover design: DBS and sham DBS. Briefly, 20 rats received an electrode in the amygdala and were exposed to inescapable shocks in the presence of the cue object. The rats were then randomly assigned to a DBS group (10 rats) or a sham-DBS group (10 rats). After 1 week, behavioral testing showed fear extinction in the DBS group and no improvement in the sham-DBS group. Then the groups were switched: The rats originally treated with DBS received no treatment, and the rats that were originally sham-treated underwent DBS. One week later, behavioral testing showed acquisition of fear extinction in all the rats. These results suggested DBS can be effective even when delayed after establishment of fear persistence and PTSD symptoms. These results also showed that DBS effects persist even after therapy discontinuation.

Similarly, other investigators have reported that the role of the amygdala is not limited to fear acquisition; it extends to fear expression. A lesion in the amygdala can prevent fear expression even if the disruption is performed subsequent to fear-conditioning training.³² This finding is important for humans, as DBS would be initiated during the chronic phase of the disorder, after failure of less invasive treatment options, such as pharmacotherapy and psychotherapy.

Early Clinical Experience

The authors have initiated the first ever clinical trial (NCT02091843) evaluating use of DBS for PTSD and are now recruiting patients. Enrollment is limited to 6 combat veterans with disabling PTSD that has not responded to pharmacotherapy and psychotherapy. This VA-funded single-site study, being conducted at the VA Greater Los Angeles Healthcare System (VAGLAHS), was approved by the VAGLAHS Institutional Review Board and the FDA. The authors have published the 2-year trial’s protocol, which includes an active-versus-sham stimulation phase; continuous electroencephalogram monitoring; baseline and posttreatment ¹⁸FDG (fluorodeoxyglucose) PET performed during a resting state vs during investigator-guided exposure to trauma reminders; and extensive psychological and neuropsychological assessments.³³ The literature includes only 1 case report on amygdala DBS.³⁴ The authors of that report used DBS of the basolateral nucleus of the amygdala to treat a teenaged boy with severe autism and found that the therapy was safe.

As of this writing, the authors have recruited and implanted 1 patient and reported on his clinical results (including baseline PET) over the first 8 months of stimulation³⁵ and on the electrophysiologic findings over the first year.³⁶ After experiencing extremely severe combat PTSD refractory to pharmacotherapy and psychotherapy treatments for more than 20 years, the patient treated with DBS is now experiencing substantial symptom relief, and his CAPS score (primary outcome measure) has improved by about 40%. He has tolerated continuous stimulation without any serious DBS-related AEs for up to 16 months. Notably, he has not had a single severe combat nightmare in a year—in stark contrast to nightly combat nightmares during the 20-year period leading to the trial. Furthermore, he has not been having any episodes of severe dissociation, which had been a common disabling problem before the trial. He has taken a second trip out of the country, improved his relationships with family, and made strides (albeit limited) in pursuing additional social interactions.

Avoidance remains a major problem. He recently left his job after 7 years, because he prefers a more nature-oriented rather than people-oriented environment. In addition, his interest in intensive psychotherapy has increased, and he has been considering options for spending more time working on his therapy.

Over 15 months of treatment, the patient’s CAPS total and subscale scores have decreased—his symptoms have improved (Table).²¹ He has had rapid and substantial reductions in recurrence and hyperarousal symptoms but slower improvement in avoidance. Improvements in emotional reactivity would be expected to occur before any change in behavior (eg, avoidance). Patients likely must first recognize changes in emotional reactivity to events before they can engage in a cognitive process to modify learned behavioral responses to those events.

After about 9 months of treatment, all of the study patient’s symptoms were somewhat stabilized, and the authors began making gradual stimulation adjustments to the latest parameters—3.5 V, 60 µs, and 160 Hz for the right electrode and 1.5 V, 60 µs, and 160 Hz for the left electrode—using the contacts in the basolateral nucleus of the amygdala, per postoperative neuroimaging.³⁵ A thin cuts computed tomography (CT) scan of the brain was obtained postoperatively and merged to the preoperative MRI. The CT scan captured the location of the DBS electrode contacts and the MRI superimposition to determine the position of those contacts in the brain.

After 15 to 18 months, when improvement peaked at 48% symptom reduction from baseline, the patient experienced psychiatric decompensation (depression, suicide gesture) not attributable to changes in stimulation settings and not associated with exacerbation of PTSD symptoms. Treatment team members and independent psychiatric consultants attributed the decompensation to the patient’s difficulty in changing a long-standing avoidant behavior routine, owing to severe recurrence and hyperarousal symptoms in the past. His persistent inability to overcome avoidance and isolation, despite core PTSD symptom improvement, had left him feeling worthless.

The patient remains in the study but also is participating in other medication and psychotherapy trials and is making a career change. Periodic decompensations may be part of the treatment course as patients reach a more complex and volatile phase of improvement that requires more intensive cognitive reprocessing. If this proves to be the case with other patients enrolling in the study, intensive psychotherapy that addresses cognitive and emotional PTSD symptoms may be needed once there is improvement in intrusive and hyperarousal symptoms.

Conclusion

Deep brain stimulation has been successful in treating Parkinson disease and essential tremor. Physiologically, DBS seems to inhibit specific brain regions’ dysfunctional activity stemming from a disease process. Deep brain stimulation-induced inhibition of a dysfunctional node improves clinical outcomes in movement disorders.

Given the reversibility and positive safety profile of DBS, new applications are being studied. The authors propose that DBS may benefit patients with severe treatment-refractory PTSD. Their first patient’s core PTSD symptoms have improved significantly, as expected, but as in other psychiatric DBS cases, the seriousness and chronicity of his illness may be complicating the course of recovery. The authors plan to recruit 6 patients for this early-phase safety trial.

Click here to read the digital edition.

Failure of fear extinction is a core feature of posttraumatic stress disorder (PTSD).¹ Recently, it was confirmed that the amygdala and the orbitofrontal cortex are crucial for both fear acquisition and fear extinction.² The amygdala was found to have neurons active only during fear acquisition, and other neurons active only during fear extinction.³ In essence, the balance of activity between these 2 neuronal populations determines whether if an incoming stimulus is feared or not feared. This balance is under the influence of several cognitive domains, including memory, reward, and executive function.

In PTSD, the equilibrium is shifted heavily toward fear acquisition. The majority of patients spontaneously regain the capacity for fear extinction over time⁴ or with the help of treatment.^5,6 Nonetheless, some patients with severe PTSD seem unable to recover the ability of fear extinction and remain refractory to both standard and novel psychotherapeutic or psychopharmacologic treatments.⁷ For these patients, direct modulation of the neural activity in the amygdala may permit fear extinction. This article describes the rationale for using deep brain stimulation (DBS) and initial results from the first-ever clinical trial.

Deep Brain Stimulation

Deep brain stimulation involves inserting electrodes in precise cerebral targets and then connecting the leads to a pulse generator (similar to a pacemaker) inserted in a subclavicular pocket. The generator controls the electrical signal (amplitude, pulse width, pulse frequency) delivered to the brain target and can be adjusted with use of a noninvasive programmer. In 1997, the FDA approved DBS for patients with Parkinson disease or essential tremor. Since then, its efficacy in these movement disorders has been confirmed in several studies.^8,9

The mechanism by which the small electrical pulses of DBS influence activity is not clear. Clinically, DBS functionally inhibits the activity of local neurons.¹⁰ One theory describes “frequency jamming,” a concept similar to cardiac overdrive pacing in which the resultant high-frequency neuronal signal is meaningless and discounted by the rest of the brain.¹¹

Over the years, DBS has demonstrated a strong safety profile.¹² The risks of electrode insertion are mitigated with targeting based on high-quality magnetic resonance imaging (MRI) and computed tomography (Figure). Unlike a destructive lesion, DBS is reversible, and the implanted system can be removed in its entirety. Histologic analyses have shown only a small amount of scarring around the electrode tip.¹³ In movement disorder treatment, clinical experience has shown that stimulation-related adverse effects (AEs) are reversible with readjustment of stimulation parameters by external programmer.¹⁴

Novel Applications of DBS

The advantageous safety profile of DBS has permitted its evaluation in the treatment of other conditions thought to have malfunctioning networks at their core—such as intractable epilepsy (in resective surgery noncandidates).^15,16 Although several trials have shown promising results of using DBS for treatment-resistant depression,¹⁷ the results of pivotal sham-controlled trials have been mixed.^18,19 Obsessive-compulsive disorder, on the other hand, received the FDA humanitarian device exemption designation on the basis of positive long-term results.²⁰ In treatment-resistant depression and obsessive-compulsive disorder, functional neuroimaging has identified DBS targets.^21,22 Functional MRI or positron emission tomography (PET) images can be compared at resting state, at symptomatic state, and after treatment response. Nodes hyperactive during a symptomatic state and less active after successful treatment can be targeted with high-frequency DBS to directly reduce the hyperactivity and indirectly modulate or normalize the overall function of the circuit.²³

Given the functional MRI and O15 (oxygen-15) PET evidence of amygdala hyperactivity in patients with PTSD having core symptoms,^24-26 the authors hypothesized that high-frequency DBS targeting of the amygdala would improve PTSD-associated hyperarousal and reexperiencing symptoms in treatment-refractory patients. Indirect data supporting this hypothesis include a correlation between amygdala hyperactivity of increased intensity and symptom severity measured with the Clinician-Administered PTSD Scale (CAPS),²⁷ and a correlation between reduced pretreatment amygdala hyperactivity and successful cognitive-behavioral treatment.^28,29

Preclinical Work

Using a rodent model in which a novel object serves as a cue reminder of foot shocks (traumatic event), the authors tested the hypothesis that amygdala DBS would reduce PTSD-like symptoms.³⁰ When untreated rats were presented with the object in their cage a week after the initial exposure, they immediately buried the object under bedding to avoid being reminded of the shocks. In contrast, rats treated with DBS did not bury the object. In most cases, in fact, they played with it.

The authors also replicated their results but with the addition of rats treated with paroxetine.³¹ Using the same rodent model, they found DBS superior to paroxetine in treating PTSD-like symptoms. This study had a crossover design: DBS and sham DBS. Briefly, 20 rats received an electrode in the amygdala and were exposed to inescapable shocks in the presence of the cue object. The rats were then randomly assigned to a DBS group (10 rats) or a sham-DBS group (10 rats). After 1 week, behavioral testing showed fear extinction in the DBS group and no improvement in the sham-DBS group. Then the groups were switched: The rats originally treated with DBS received no treatment, and the rats that were originally sham-treated underwent DBS. One week later, behavioral testing showed acquisition of fear extinction in all the rats. These results suggested DBS can be effective even when delayed after establishment of fear persistence and PTSD symptoms. These results also showed that DBS effects persist even after therapy discontinuation.

Similarly, other investigators have reported that the role of the amygdala is not limited to fear acquisition; it extends to fear expression. A lesion in the amygdala can prevent fear expression even if the disruption is performed subsequent to fear-conditioning training.³² This finding is important for humans, as DBS would be initiated during the chronic phase of the disorder, after failure of less invasive treatment options, such as pharmacotherapy and psychotherapy.

Early Clinical Experience

The authors have initiated the first ever clinical trial (NCT02091843) evaluating use of DBS for PTSD and are now recruiting patients. Enrollment is limited to 6 combat veterans with disabling PTSD that has not responded to pharmacotherapy and psychotherapy. This VA-funded single-site study, being conducted at the VA Greater Los Angeles Healthcare System (VAGLAHS), was approved by the VAGLAHS Institutional Review Board and the FDA. The authors have published the 2-year trial’s protocol, which includes an active-versus-sham stimulation phase; continuous electroencephalogram monitoring; baseline and posttreatment ¹⁸FDG (fluorodeoxyglucose) PET performed during a resting state vs during investigator-guided exposure to trauma reminders; and extensive psychological and neuropsychological assessments.³³ The literature includes only 1 case report on amygdala DBS.³⁴ The authors of that report used DBS of the basolateral nucleus of the amygdala to treat a teenaged boy with severe autism and found that the therapy was safe.

As of this writing, the authors have recruited and implanted 1 patient and reported on his clinical results (including baseline PET) over the first 8 months of stimulation³⁵ and on the electrophysiologic findings over the first year.³⁶ After experiencing extremely severe combat PTSD refractory to pharmacotherapy and psychotherapy treatments for more than 20 years, the patient treated with DBS is now experiencing substantial symptom relief, and his CAPS score (primary outcome measure) has improved by about 40%. He has tolerated continuous stimulation without any serious DBS-related AEs for up to 16 months. Notably, he has not had a single severe combat nightmare in a year—in stark contrast to nightly combat nightmares during the 20-year period leading to the trial. Furthermore, he has not been having any episodes of severe dissociation, which had been a common disabling problem before the trial. He has taken a second trip out of the country, improved his relationships with family, and made strides (albeit limited) in pursuing additional social interactions.

Avoidance remains a major problem. He recently left his job after 7 years, because he prefers a more nature-oriented rather than people-oriented environment. In addition, his interest in intensive psychotherapy has increased, and he has been considering options for spending more time working on his therapy.

Over 15 months of treatment, the patient’s CAPS total and subscale scores have decreased—his symptoms have improved (Table).²¹ He has had rapid and substantial reductions in recurrence and hyperarousal symptoms but slower improvement in avoidance. Improvements in emotional reactivity would be expected to occur before any change in behavior (eg, avoidance). Patients likely must first recognize changes in emotional reactivity to events before they can engage in a cognitive process to modify learned behavioral responses to those events.

After about 9 months of treatment, all of the study patient’s symptoms were somewhat stabilized, and the authors began making gradual stimulation adjustments to the latest parameters—3.5 V, 60 µs, and 160 Hz for the right electrode and 1.5 V, 60 µs, and 160 Hz for the left electrode—using the contacts in the basolateral nucleus of the amygdala, per postoperative neuroimaging.³⁵ A thin cuts computed tomography (CT) scan of the brain was obtained postoperatively and merged to the preoperative MRI. The CT scan captured the location of the DBS electrode contacts and the MRI superimposition to determine the position of those contacts in the brain.

After 15 to 18 months, when improvement peaked at 48% symptom reduction from baseline, the patient experienced psychiatric decompensation (depression, suicide gesture) not attributable to changes in stimulation settings and not associated with exacerbation of PTSD symptoms. Treatment team members and independent psychiatric consultants attributed the decompensation to the patient’s difficulty in changing a long-standing avoidant behavior routine, owing to severe recurrence and hyperarousal symptoms in the past. His persistent inability to overcome avoidance and isolation, despite core PTSD symptom improvement, had left him feeling worthless.

The patient remains in the study but also is participating in other medication and psychotherapy trials and is making a career change. Periodic decompensations may be part of the treatment course as patients reach a more complex and volatile phase of improvement that requires more intensive cognitive reprocessing. If this proves to be the case with other patients enrolling in the study, intensive psychotherapy that addresses cognitive and emotional PTSD symptoms may be needed once there is improvement in intrusive and hyperarousal symptoms.

Conclusion

Deep brain stimulation has been successful in treating Parkinson disease and essential tremor. Physiologically, DBS seems to inhibit specific brain regions’ dysfunctional activity stemming from a disease process. Deep brain stimulation-induced inhibition of a dysfunctional node improves clinical outcomes in movement disorders.

Given the reversibility and positive safety profile of DBS, new applications are being studied. The authors propose that DBS may benefit patients with severe treatment-refractory PTSD. Their first patient’s core PTSD symptoms have improved significantly, as expected, but as in other psychiatric DBS cases, the seriousness and chronicity of his illness may be complicating the course of recovery. The authors plan to recruit 6 patients for this early-phase safety trial.

Click here to read the digital edition.

Red blood cells

Researchers say they have discovered a mutation associated with hereditary erythrocytosis.

The mutation causes a messenger RNA (mRNA) that is not normally involved in the formation of proteins to be reprogrammed so that it produces erythropoietin (EPO), thereby abnormally increasing red blood cell production.

Radek Skoda, MD, of the University of Basel in Switzerland, and his colleagues described this discovery in NEJM.

The team found the mutation in a family with hereditary erythrocytosis. The researchers studied 10 affected family members spanning 4 generations.

Genome-wide linkage analysis and gene sequencing revealed a heterozygous single-base deletion in exon 2 of EPO (chromosome 7: 100,319,199 GG→G) in all 10 affected family members.

However, the researchers were initially puzzled. This c.32delG mutation should actually lead to a loss of function of the EPO gene because the absence of the base shifts the reading frame of the genetic code, meaning that no more EPO protein can be formed.

Despite this, the concentration of EPO hormone in the patients’ blood measurably increased rather than decreased.

To investigate this, the researchers used CRISPR to engineer cells carrying the c.32delG mutation. In this way, they found a second, hidden mRNA in the EPO gene that is not normally involved in the production of a protein.

The c.32delG mutation also leads to a shift in the reading frame of this second mRNA, with the result that more biologically active EPO hormone is produced.

“The mechanism is intriguing,” Dr Skoda said. “The mutation reprograms the gene product so that it gains a new function and is misused to overproduce EPO.”

Red blood cells

Researchers say they have discovered a mutation associated with hereditary erythrocytosis.

The mutation causes a messenger RNA (mRNA) that is not normally involved in the formation of proteins to be reprogrammed so that it produces erythropoietin (EPO), thereby abnormally increasing red blood cell production.

Radek Skoda, MD, of the University of Basel in Switzerland, and his colleagues described this discovery in NEJM.

The team found the mutation in a family with hereditary erythrocytosis. The researchers studied 10 affected family members spanning 4 generations.

Genome-wide linkage analysis and gene sequencing revealed a heterozygous single-base deletion in exon 2 of EPO (chromosome 7: 100,319,199 GG→G) in all 10 affected family members.

However, the researchers were initially puzzled. This c.32delG mutation should actually lead to a loss of function of the EPO gene because the absence of the base shifts the reading frame of the genetic code, meaning that no more EPO protein can be formed.

Despite this, the concentration of EPO hormone in the patients’ blood measurably increased rather than decreased.

To investigate this, the researchers used CRISPR to engineer cells carrying the c.32delG mutation. In this way, they found a second, hidden mRNA in the EPO gene that is not normally involved in the production of a protein.

The c.32delG mutation also leads to a shift in the reading frame of this second mRNA, with the result that more biologically active EPO hormone is produced.

“The mechanism is intriguing,” Dr Skoda said. “The mutation reprograms the gene product so that it gains a new function and is misused to overproduce EPO.”

Red blood cells

Researchers say they have discovered a mutation associated with hereditary erythrocytosis.

The mutation causes a messenger RNA (mRNA) that is not normally involved in the formation of proteins to be reprogrammed so that it produces erythropoietin (EPO), thereby abnormally increasing red blood cell production.

Radek Skoda, MD, of the University of Basel in Switzerland, and his colleagues described this discovery in NEJM.

The team found the mutation in a family with hereditary erythrocytosis. The researchers studied 10 affected family members spanning 4 generations.

Genome-wide linkage analysis and gene sequencing revealed a heterozygous single-base deletion in exon 2 of EPO (chromosome 7: 100,319,199 GG→G) in all 10 affected family members.

However, the researchers were initially puzzled. This c.32delG mutation should actually lead to a loss of function of the EPO gene because the absence of the base shifts the reading frame of the genetic code, meaning that no more EPO protein can be formed.

Despite this, the concentration of EPO hormone in the patients’ blood measurably increased rather than decreased.

To investigate this, the researchers used CRISPR to engineer cells carrying the c.32delG mutation. In this way, they found a second, hidden mRNA in the EPO gene that is not normally involved in the production of a protein.

The c.32delG mutation also leads to a shift in the reading frame of this second mRNA, with the result that more biologically active EPO hormone is produced.

“The mechanism is intriguing,” Dr Skoda said. “The mutation reprograms the gene product so that it gains a new function and is misused to overproduce EPO.”

ORLANDO – In what was hailed as a major advance in preventive cardiology, the ODYSSEY Outcomes trial has shown that adding the PCSK9 inhibitor alirocumab on top of intensive statin therapy reduced major adverse cardiovascular events and all-cause mortality significantly more than placebo plus intensive statin therapy in patients with a recent acute coronary syndrome and an elevated on-statin LDL cholesterol level. 

Bruce Jancin/Frontline Medical News

ODYSSEY Outcomes was a double-blind trial in which 18,924 patients at 1,315 sites in 57 countries were randomized to alirocumab (Praluent) or placebo plus background high-intensity statin therapy starting a median of 2.5 months after an acute coronary syndrome. All participants had to have a baseline LDL cholesterol level of 70 mg/dL or higher despite intensive statin therapy. Alirocumab was titrated to maintain a target LDL of 25-50 mg/dL. An LDL of 15-25 mg/dL was deemed acceptable, but if the level dropped below 15 mg/dL on two consecutive measurements the patient was blindly switched to placebo, as occurred in 7.7% of the alirocumab group. 

The primary study endpoint was a composite outcome comprised of CHD (coronary heart disease) death, nonfatal MI, ischemic stroke, or unstable angina requiring hospitalization. During a median 2.8 years of follow-up, this outcome occurred in 9.5% of the overall population randomized to alirocumab and 11.1% of those on placebo, for a statistically significant and clinically meaningful 15% reduction in relative risk. The CHD death rates in the two study arms were similar; however, the other three components of the primary endpoint occurred significantly less often in the alirocumab group: The risk of nonfatal MI was 14% less (6.6% vs. 7.6%), ischemic stroke was 27% less (1.2 vs. 1.6%), and unstable angina was 39% less (0.4% vs. 0.6%).

All-cause mortality occurred in 3.5% of patients receiving alirocumab and 4.1% on placebo, once again for a statistically significant 15% reduction in risk. This was a major achievement, since even statins haven’t shown a mortality benefit in the post-ACS setting, observed Dr. Steg, cochair of the study. 

The greatest benefits were seen in the 5,629 participants with a baseline LDL of 100 mg/dL or more on high-intensity statin therapy. In this large subgroup at highest baseline risk, alirocumab resulted in an absolute 3.4% risk reduction and a 24% reduction in relative risk of MACE. All-cause mortality decreased by an absolute 1.7%, translating to a 29% relative risk reduction. The number-needed-to-treat (NNT) for the duration of the study in order to prevent one additional MACE event in this group was 29, with an NNT to prevent one additional death of 60, added Dr. Steg, professor of cardiology at the University of Paris and chief of cardiology at Bichat Hospital. 

“The risk/benefit for alirocumab is extraordinarily favorable. There was almost no risk over the course of the trial. There was no increase in neurocognitive disorders, new-onset or worsening diabetes, cataracts, or hemorrhagic stroke,” the cardiologist said. 
Indeed, the sole adverse event that occurred more frequently in the alirocumab group was mild local injection site reactions, which occurred in 3.8% of the alirocumab group and 2.1% of controls. 

There was a tendency for LDL to creep upward in both the alirocumab and placebo arms over the course of follow-up. Dr. Steg attributed this to down-titration or cessation of alirocumab as per protocol along with the inability of a substantial proportion of patients to tolerate intensive statin therapy. Most study participants had never been on a statin until their ACS. 

A year ago at ACC 2017, other investigators presented the results of FOURIER, a large clinical outcomes trial of evolocumab (Repatha), another PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor. FOURIER also showed a 15% relative risk reduction in major adverse cardiovascular events, but unlike in ODYSSEY Outcomes, there was no significant impact upon mortality. Dr. Steg attributed this to several key differences between the two trials.

The post-ACS population of ODYSSEY Outcomes was on average higher-risk than FOURIER participants, who had stable atherosclerotic cardiovascular disease. The background statin therapy was more intensive in ODYSSEY, and the average follow-up was close to 8 months longer, too. 

Bruce Jancin/Frontline Medical News

The study population is representative of an enormous number of patients seen in clinical practice, added Dr. Fuster, professor of medicine and physician-in-chief at Mount Sinai Hospital in New York. He estimated that one-third of patients who experience ACS can’t subsequently get their LDL down to the 70 mg/dL range on statin therapy, generally because of drug intolerance. 
He voiced a concern: “Up until now, the feasibility and affordability of using this type of drug has been extremely difficult. I hope this particular study is a trigger – a catalyzer – for making this drug much more available to people who need it.” 

The study met with an enthusiastic audience reception. Prior to presentation of the results at the meeting’s opening session, 79% of the audience of more than 4,000 in the main arena indicated they either don’t prescribe PCSK9 inhibitors or do so only a handful of times per year.

Immediately after seeing the data, 62% of the audience said their practice will change as a result of the study findings. 

ODYSSEY Outcomes was funded by Sanofi and Regeneron Pharmaceuticals. Dr. Steg reported serving as a consultant to and receiving research grants from those pharmaceutical companies and numerous others. 

[email protected] 
SOURCE: Steg GP. 

ORLANDO – In what was hailed as a major advance in preventive cardiology, the ODYSSEY Outcomes trial has shown that adding the PCSK9 inhibitor alirocumab on top of intensive statin therapy reduced major adverse cardiovascular events and all-cause mortality significantly more than placebo plus intensive statin therapy in patients with a recent acute coronary syndrome and an elevated on-statin LDL cholesterol level. 

Bruce Jancin/Frontline Medical News

ODYSSEY Outcomes was a double-blind trial in which 18,924 patients at 1,315 sites in 57 countries were randomized to alirocumab (Praluent) or placebo plus background high-intensity statin therapy starting a median of 2.5 months after an acute coronary syndrome. All participants had to have a baseline LDL cholesterol level of 70 mg/dL or higher despite intensive statin therapy. Alirocumab was titrated to maintain a target LDL of 25-50 mg/dL. An LDL of 15-25 mg/dL was deemed acceptable, but if the level dropped below 15 mg/dL on two consecutive measurements the patient was blindly switched to placebo, as occurred in 7.7% of the alirocumab group. 

The primary study endpoint was a composite outcome comprised of CHD (coronary heart disease) death, nonfatal MI, ischemic stroke, or unstable angina requiring hospitalization. During a median 2.8 years of follow-up, this outcome occurred in 9.5% of the overall population randomized to alirocumab and 11.1% of those on placebo, for a statistically significant and clinically meaningful 15% reduction in relative risk. The CHD death rates in the two study arms were similar; however, the other three components of the primary endpoint occurred significantly less often in the alirocumab group: The risk of nonfatal MI was 14% less (6.6% vs. 7.6%), ischemic stroke was 27% less (1.2 vs. 1.6%), and unstable angina was 39% less (0.4% vs. 0.6%).

All-cause mortality occurred in 3.5% of patients receiving alirocumab and 4.1% on placebo, once again for a statistically significant 15% reduction in risk. This was a major achievement, since even statins haven’t shown a mortality benefit in the post-ACS setting, observed Dr. Steg, cochair of the study. 

The greatest benefits were seen in the 5,629 participants with a baseline LDL of 100 mg/dL or more on high-intensity statin therapy. In this large subgroup at highest baseline risk, alirocumab resulted in an absolute 3.4% risk reduction and a 24% reduction in relative risk of MACE. All-cause mortality decreased by an absolute 1.7%, translating to a 29% relative risk reduction. The number-needed-to-treat (NNT) for the duration of the study in order to prevent one additional MACE event in this group was 29, with an NNT to prevent one additional death of 60, added Dr. Steg, professor of cardiology at the University of Paris and chief of cardiology at Bichat Hospital. 

“The risk/benefit for alirocumab is extraordinarily favorable. There was almost no risk over the course of the trial. There was no increase in neurocognitive disorders, new-onset or worsening diabetes, cataracts, or hemorrhagic stroke,” the cardiologist said. 
Indeed, the sole adverse event that occurred more frequently in the alirocumab group was mild local injection site reactions, which occurred in 3.8% of the alirocumab group and 2.1% of controls. 

There was a tendency for LDL to creep upward in both the alirocumab and placebo arms over the course of follow-up. Dr. Steg attributed this to down-titration or cessation of alirocumab as per protocol along with the inability of a substantial proportion of patients to tolerate intensive statin therapy. Most study participants had never been on a statin until their ACS. 

A year ago at ACC 2017, other investigators presented the results of FOURIER, a large clinical outcomes trial of evolocumab (Repatha), another PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor. FOURIER also showed a 15% relative risk reduction in major adverse cardiovascular events, but unlike in ODYSSEY Outcomes, there was no significant impact upon mortality. Dr. Steg attributed this to several key differences between the two trials.

The post-ACS population of ODYSSEY Outcomes was on average higher-risk than FOURIER participants, who had stable atherosclerotic cardiovascular disease. The background statin therapy was more intensive in ODYSSEY, and the average follow-up was close to 8 months longer, too. 

Bruce Jancin/Frontline Medical News

The study population is representative of an enormous number of patients seen in clinical practice, added Dr. Fuster, professor of medicine and physician-in-chief at Mount Sinai Hospital in New York. He estimated that one-third of patients who experience ACS can’t subsequently get their LDL down to the 70 mg/dL range on statin therapy, generally because of drug intolerance. 
He voiced a concern: “Up until now, the feasibility and affordability of using this type of drug has been extremely difficult. I hope this particular study is a trigger – a catalyzer – for making this drug much more available to people who need it.” 

The study met with an enthusiastic audience reception. Prior to presentation of the results at the meeting’s opening session, 79% of the audience of more than 4,000 in the main arena indicated they either don’t prescribe PCSK9 inhibitors or do so only a handful of times per year.

Immediately after seeing the data, 62% of the audience said their practice will change as a result of the study findings. 

ODYSSEY Outcomes was funded by Sanofi and Regeneron Pharmaceuticals. Dr. Steg reported serving as a consultant to and receiving research grants from those pharmaceutical companies and numerous others. 

[email protected] 
SOURCE: Steg GP. 

ORLANDO – In what was hailed as a major advance in preventive cardiology, the ODYSSEY Outcomes trial has shown that adding the PCSK9 inhibitor alirocumab on top of intensive statin therapy reduced major adverse cardiovascular events and all-cause mortality significantly more than placebo plus intensive statin therapy in patients with a recent acute coronary syndrome and an elevated on-statin LDL cholesterol level. 

Bruce Jancin/Frontline Medical News

ODYSSEY Outcomes was a double-blind trial in which 18,924 patients at 1,315 sites in 57 countries were randomized to alirocumab (Praluent) or placebo plus background high-intensity statin therapy starting a median of 2.5 months after an acute coronary syndrome. All participants had to have a baseline LDL cholesterol level of 70 mg/dL or higher despite intensive statin therapy. Alirocumab was titrated to maintain a target LDL of 25-50 mg/dL. An LDL of 15-25 mg/dL was deemed acceptable, but if the level dropped below 15 mg/dL on two consecutive measurements the patient was blindly switched to placebo, as occurred in 7.7% of the alirocumab group. 

The primary study endpoint was a composite outcome comprised of CHD (coronary heart disease) death, nonfatal MI, ischemic stroke, or unstable angina requiring hospitalization. During a median 2.8 years of follow-up, this outcome occurred in 9.5% of the overall population randomized to alirocumab and 11.1% of those on placebo, for a statistically significant and clinically meaningful 15% reduction in relative risk. The CHD death rates in the two study arms were similar; however, the other three components of the primary endpoint occurred significantly less often in the alirocumab group: The risk of nonfatal MI was 14% less (6.6% vs. 7.6%), ischemic stroke was 27% less (1.2 vs. 1.6%), and unstable angina was 39% less (0.4% vs. 0.6%).

All-cause mortality occurred in 3.5% of patients receiving alirocumab and 4.1% on placebo, once again for a statistically significant 15% reduction in risk. This was a major achievement, since even statins haven’t shown a mortality benefit in the post-ACS setting, observed Dr. Steg, cochair of the study. 

The greatest benefits were seen in the 5,629 participants with a baseline LDL of 100 mg/dL or more on high-intensity statin therapy. In this large subgroup at highest baseline risk, alirocumab resulted in an absolute 3.4% risk reduction and a 24% reduction in relative risk of MACE. All-cause mortality decreased by an absolute 1.7%, translating to a 29% relative risk reduction. The number-needed-to-treat (NNT) for the duration of the study in order to prevent one additional MACE event in this group was 29, with an NNT to prevent one additional death of 60, added Dr. Steg, professor of cardiology at the University of Paris and chief of cardiology at Bichat Hospital. 

“The risk/benefit for alirocumab is extraordinarily favorable. There was almost no risk over the course of the trial. There was no increase in neurocognitive disorders, new-onset or worsening diabetes, cataracts, or hemorrhagic stroke,” the cardiologist said. 
Indeed, the sole adverse event that occurred more frequently in the alirocumab group was mild local injection site reactions, which occurred in 3.8% of the alirocumab group and 2.1% of controls. 

There was a tendency for LDL to creep upward in both the alirocumab and placebo arms over the course of follow-up. Dr. Steg attributed this to down-titration or cessation of alirocumab as per protocol along with the inability of a substantial proportion of patients to tolerate intensive statin therapy. Most study participants had never been on a statin until their ACS. 

A year ago at ACC 2017, other investigators presented the results of FOURIER, a large clinical outcomes trial of evolocumab (Repatha), another PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor. FOURIER also showed a 15% relative risk reduction in major adverse cardiovascular events, but unlike in ODYSSEY Outcomes, there was no significant impact upon mortality. Dr. Steg attributed this to several key differences between the two trials.

The post-ACS population of ODYSSEY Outcomes was on average higher-risk than FOURIER participants, who had stable atherosclerotic cardiovascular disease. The background statin therapy was more intensive in ODYSSEY, and the average follow-up was close to 8 months longer, too. 

Bruce Jancin/Frontline Medical News

The study population is representative of an enormous number of patients seen in clinical practice, added Dr. Fuster, professor of medicine and physician-in-chief at Mount Sinai Hospital in New York. He estimated that one-third of patients who experience ACS can’t subsequently get their LDL down to the 70 mg/dL range on statin therapy, generally because of drug intolerance. 
He voiced a concern: “Up until now, the feasibility and affordability of using this type of drug has been extremely difficult. I hope this particular study is a trigger – a catalyzer – for making this drug much more available to people who need it.” 

The study met with an enthusiastic audience reception. Prior to presentation of the results at the meeting’s opening session, 79% of the audience of more than 4,000 in the main arena indicated they either don’t prescribe PCSK9 inhibitors or do so only a handful of times per year.

Immediately after seeing the data, 62% of the audience said their practice will change as a result of the study findings. 

ODYSSEY Outcomes was funded by Sanofi and Regeneron Pharmaceuticals. Dr. Steg reported serving as a consultant to and receiving research grants from those pharmaceutical companies and numerous others. 

[email protected] 
SOURCE: Steg GP. 

ORLANDO – The ODYSSEY Outcomes trial proves the point that LDL-cholesterol reduction with PCSK9 inhibitors can reduce not only cardiovascular events, but all-cause mortality, Prakash Deedwania, MD, said in an interview at the annual meeting of the American College of Cardiology.

That mortality reduction builds on the FOURIER trial results, which showed last year that evolocumab significantly reduced cardiovascular events in patients with stable atherosclerotic cardiovascular disease who were still at residual risk based on elevated LDL cholesterol levels said Dr. Deedwania, professor of medicine at the University of California, San Francisco, in Fresno, who was not involved with ODYSSEY Outcomes.

However, one finding about mortality in ODYSSEY Outcomes was disappointing: LDL levels increase slightly over time in both the treatment and placebo groups.

Source: Deedwania P ACC 18.




 

ORLANDO – The ODYSSEY Outcomes trial proves the point that LDL-cholesterol reduction with PCSK9 inhibitors can reduce not only cardiovascular events, but all-cause mortality, Prakash Deedwania, MD, said in an interview at the annual meeting of the American College of Cardiology.

That mortality reduction builds on the FOURIER trial results, which showed last year that evolocumab significantly reduced cardiovascular events in patients with stable atherosclerotic cardiovascular disease who were still at residual risk based on elevated LDL cholesterol levels said Dr. Deedwania, professor of medicine at the University of California, San Francisco, in Fresno, who was not involved with ODYSSEY Outcomes.

However, one finding about mortality in ODYSSEY Outcomes was disappointing: LDL levels increase slightly over time in both the treatment and placebo groups.

Source: Deedwania P ACC 18.




 

ORLANDO – The ODYSSEY Outcomes trial proves the point that LDL-cholesterol reduction with PCSK9 inhibitors can reduce not only cardiovascular events, but all-cause mortality, Prakash Deedwania, MD, said in an interview at the annual meeting of the American College of Cardiology.

That mortality reduction builds on the FOURIER trial results, which showed last year that evolocumab significantly reduced cardiovascular events in patients with stable atherosclerotic cardiovascular disease who were still at residual risk based on elevated LDL cholesterol levels said Dr. Deedwania, professor of medicine at the University of California, San Francisco, in Fresno, who was not involved with ODYSSEY Outcomes.

However, one finding about mortality in ODYSSEY Outcomes was disappointing: LDL levels increase slightly over time in both the treatment and placebo groups.

Source: Deedwania P ACC 18.




 

ORLANDO – Although the VEST study results showed that a wearable cardioverter defibrillator cut all-cause mortality in at-risk, post-MI patients, the findings failed to show a statistically significant reduction in sudden death or death from ventricular tachycardia. This suggests better targeting of the device is needed, commented Dhanunjaya Lakkireddy, MD, in a video interview at the annual meeting of the American College of Cardiology.

The Vest Prevention of Early Sudden Death Trial (VEST) randomized 2,302 patients within the first 7 days following an acute MI who also had a left ventricular ejection fraction of 35% or less to either 90 days of treatment with a wearable cardioverter defibrillator (WCD) or usual care. After a median of 84 days, the results showed no statistically significant reduction from WCD use in the primary endpoint of sudden death or death from ventricular tachyarrhythmias, but a statistically significant reduction in the secondary endpoint of all-cause death: 3.1% in the patients randomized to WCD use and 4.9% among the control patients, reported Jeffrey Olgin, MD, chief of cardiology at the University of California, San Francisco.

The results suggest that a more robust benefit might occur in post-MI, low ejection fraction patients who undergo additional selection based on having frequent premature ventricular contractions and nonsustained ventricular tachycardia, suggested Dr. Lakkireddy, professor of medicine and director of the Center for Excellence in AF and Complex Arrhythmias at the University of Kansas Medical Center in Kansas City.

VEST was sponsored by Zoll, a company that markets a WCD. Dr. Lakkireddy had no relevant disclosures.
[email protected]

On Twitter @mitchelzoler

Source: Olgin J and Lakkireddy D ACC 18.

ORLANDO – Although the VEST study results showed that a wearable cardioverter defibrillator cut all-cause mortality in at-risk, post-MI patients, the findings failed to show a statistically significant reduction in sudden death or death from ventricular tachycardia. This suggests better targeting of the device is needed, commented Dhanunjaya Lakkireddy, MD, in a video interview at the annual meeting of the American College of Cardiology.

The Vest Prevention of Early Sudden Death Trial (VEST) randomized 2,302 patients within the first 7 days following an acute MI who also had a left ventricular ejection fraction of 35% or less to either 90 days of treatment with a wearable cardioverter defibrillator (WCD) or usual care. After a median of 84 days, the results showed no statistically significant reduction from WCD use in the primary endpoint of sudden death or death from ventricular tachyarrhythmias, but a statistically significant reduction in the secondary endpoint of all-cause death: 3.1% in the patients randomized to WCD use and 4.9% among the control patients, reported Jeffrey Olgin, MD, chief of cardiology at the University of California, San Francisco.

The results suggest that a more robust benefit might occur in post-MI, low ejection fraction patients who undergo additional selection based on having frequent premature ventricular contractions and nonsustained ventricular tachycardia, suggested Dr. Lakkireddy, professor of medicine and director of the Center for Excellence in AF and Complex Arrhythmias at the University of Kansas Medical Center in Kansas City.

VEST was sponsored by Zoll, a company that markets a WCD. Dr. Lakkireddy had no relevant disclosures.
[email protected]

On Twitter @mitchelzoler

Source: Olgin J and Lakkireddy D ACC 18.

ORLANDO – Although the VEST study results showed that a wearable cardioverter defibrillator cut all-cause mortality in at-risk, post-MI patients, the findings failed to show a statistically significant reduction in sudden death or death from ventricular tachycardia. This suggests better targeting of the device is needed, commented Dhanunjaya Lakkireddy, MD, in a video interview at the annual meeting of the American College of Cardiology.

The Vest Prevention of Early Sudden Death Trial (VEST) randomized 2,302 patients within the first 7 days following an acute MI who also had a left ventricular ejection fraction of 35% or less to either 90 days of treatment with a wearable cardioverter defibrillator (WCD) or usual care. After a median of 84 days, the results showed no statistically significant reduction from WCD use in the primary endpoint of sudden death or death from ventricular tachyarrhythmias, but a statistically significant reduction in the secondary endpoint of all-cause death: 3.1% in the patients randomized to WCD use and 4.9% among the control patients, reported Jeffrey Olgin, MD, chief of cardiology at the University of California, San Francisco.

The results suggest that a more robust benefit might occur in post-MI, low ejection fraction patients who undergo additional selection based on having frequent premature ventricular contractions and nonsustained ventricular tachycardia, suggested Dr. Lakkireddy, professor of medicine and director of the Center for Excellence in AF and Complex Arrhythmias at the University of Kansas Medical Center in Kansas City.

VEST was sponsored by Zoll, a company that markets a WCD. Dr. Lakkireddy had no relevant disclosures.
[email protected]

On Twitter @mitchelzoler

Source: Olgin J and Lakkireddy D ACC 18.

ORLANDO – The excellent showing of alirocumab in post–acute coronary syndrome patients in the landmark ODYSSEY Outcomes trial should set the stage for broader use of the PCSK9-inhibitor in certain high-risk patients, Gabriel Steg, MD, said in a video interview at the annual meeting of the American College of Cardiology.

The findings from the 3-year trial are threefold: First, the trial met its primary goal, significantly lower major adverse cardiovascular events and 15% lower mortality in alirocumab-treated patients compared with those on placebo; second, the effect was greater in patients who started with an LDL level above 100 mg/dL; and third, alirocumab was remarkably safe, said Dr. Steg, director of the coronary care unit of Bichat Hospital in Paris.

“We now have good reason to target a lower LDL range of at least less than 50 mg/dL, and possibly even lower, using PCSK9 inhibitors to get the benefits we’re seeing in the trial applied to broader groups of patients,” he added.

SOURCE: Steg G ACC 18.

ORLANDO – The excellent showing of alirocumab in post–acute coronary syndrome patients in the landmark ODYSSEY Outcomes trial should set the stage for broader use of the PCSK9-inhibitor in certain high-risk patients, Gabriel Steg, MD, said in a video interview at the annual meeting of the American College of Cardiology.

The findings from the 3-year trial are threefold: First, the trial met its primary goal, significantly lower major adverse cardiovascular events and 15% lower mortality in alirocumab-treated patients compared with those on placebo; second, the effect was greater in patients who started with an LDL level above 100 mg/dL; and third, alirocumab was remarkably safe, said Dr. Steg, director of the coronary care unit of Bichat Hospital in Paris.

“We now have good reason to target a lower LDL range of at least less than 50 mg/dL, and possibly even lower, using PCSK9 inhibitors to get the benefits we’re seeing in the trial applied to broader groups of patients,” he added.

SOURCE: Steg G ACC 18.

ORLANDO – The excellent showing of alirocumab in post–acute coronary syndrome patients in the landmark ODYSSEY Outcomes trial should set the stage for broader use of the PCSK9-inhibitor in certain high-risk patients, Gabriel Steg, MD, said in a video interview at the annual meeting of the American College of Cardiology.

The findings from the 3-year trial are threefold: First, the trial met its primary goal, significantly lower major adverse cardiovascular events and 15% lower mortality in alirocumab-treated patients compared with those on placebo; second, the effect was greater in patients who started with an LDL level above 100 mg/dL; and third, alirocumab was remarkably safe, said Dr. Steg, director of the coronary care unit of Bichat Hospital in Paris.

“We now have good reason to target a lower LDL range of at least less than 50 mg/dL, and possibly even lower, using PCSK9 inhibitors to get the benefits we’re seeing in the trial applied to broader groups of patients,” he added.

SOURCE: Steg G ACC 18.

ORLANDO – Reviewing patient charts for asthma risk factors using natural language processing can be done 8 times faster than reviewing the charts by hand, and with high levels of accuracy, researchers reported here.

Thomas R. Collins/Frontline Medical News

Natural language processing (NLP) is a kind of artificial intelligence in which computers are “trained” through a reiterative process to understand human language.

Researchers at Mayo Clinic previously have shown that a program created in-house can successfully and quickly determine patients’ asthma status. In this study, they turned to assessment of asthma risk factors, Chung-Il Wi, MD, assistant professor of pediatrics at Mayo said in a presentation at the joint congress of the American Academy of Allergy, Asthma and Immunology and the World Asthma Organization.

They used a convenience sample of 177 patient charts to train the NLP system. The system extracted – from key terms and sentences in the electronic health record (EHR) – data such as breastfeeding history and history of atopic conditions such as allergic rhinitis, eczema, and food allergy. From parent charts, the system extracted terms related to family history of asthma and other atopic conditions. The performance of the NLP algorithm was assessed by comparison with results of a manual chart review in a test cohort of 220 patient charts.

SOURCE: Wi C AAAAI/WAO Joint Congress 2018 abstract 637.

ORLANDO – Reviewing patient charts for asthma risk factors using natural language processing can be done 8 times faster than reviewing the charts by hand, and with high levels of accuracy, researchers reported here.

Thomas R. Collins/Frontline Medical News

Natural language processing (NLP) is a kind of artificial intelligence in which computers are “trained” through a reiterative process to understand human language.

Researchers at Mayo Clinic previously have shown that a program created in-house can successfully and quickly determine patients’ asthma status. In this study, they turned to assessment of asthma risk factors, Chung-Il Wi, MD, assistant professor of pediatrics at Mayo said in a presentation at the joint congress of the American Academy of Allergy, Asthma and Immunology and the World Asthma Organization.

They used a convenience sample of 177 patient charts to train the NLP system. The system extracted – from key terms and sentences in the electronic health record (EHR) – data such as breastfeeding history and history of atopic conditions such as allergic rhinitis, eczema, and food allergy. From parent charts, the system extracted terms related to family history of asthma and other atopic conditions. The performance of the NLP algorithm was assessed by comparison with results of a manual chart review in a test cohort of 220 patient charts.

SOURCE: Wi C AAAAI/WAO Joint Congress 2018 abstract 637.

ORLANDO – Reviewing patient charts for asthma risk factors using natural language processing can be done 8 times faster than reviewing the charts by hand, and with high levels of accuracy, researchers reported here.

Thomas R. Collins/Frontline Medical News

Natural language processing (NLP) is a kind of artificial intelligence in which computers are “trained” through a reiterative process to understand human language.

Researchers at Mayo Clinic previously have shown that a program created in-house can successfully and quickly determine patients’ asthma status. In this study, they turned to assessment of asthma risk factors, Chung-Il Wi, MD, assistant professor of pediatrics at Mayo said in a presentation at the joint congress of the American Academy of Allergy, Asthma and Immunology and the World Asthma Organization.

They used a convenience sample of 177 patient charts to train the NLP system. The system extracted – from key terms and sentences in the electronic health record (EHR) – data such as breastfeeding history and history of atopic conditions such as allergic rhinitis, eczema, and food allergy. From parent charts, the system extracted terms related to family history of asthma and other atopic conditions. The performance of the NLP algorithm was assessed by comparison with results of a manual chart review in a test cohort of 220 patient charts.

SOURCE: Wi C AAAAI/WAO Joint Congress 2018 abstract 637.

Photo by Rhoda Baer

Researchers have developed a new method to measure social networks of adolescent and young adult (AYA) cancer survivors.

This method indicated that AYA cancer survivors often have stronger social networks than their non-cancer peers.

However, the strength of the social network varied by diagnosis, with the lymphoma and leukemia survivors having the greatest support.

These findings were published in Cancer.

“Cancer survivors need healthy social connections, and, to the best of our knowledge, this is the first published study to quantify social networks of adolescent and young adult cancer survivors compared to their peers,” said study author I-Chan Huang, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.

“The study introduces a method we developed and validated for evaluating social networks of these cancer survivors.”

The method, called the functional social network index (FSNI), measures marital status, contact frequency with friends and relatives, and available resources for health support/advice, which includes emotional support, tangible support, physical activity advice, and weight management advice.

The researchers compared the FSNI to a pair of traditional social network indices—density and betweenness centrality.

Density represents the ratio of the existing relationships/connections within a network to all possible relationships/connections. And betweenness centrality represents the ratio of the existing shortest paths between 2 friends/relatives of the study participants to the shortest possible paths between 2 friends/relatives.

Subjects

The researchers used the 3 social network indices to analyze 102 AYA cancer survivors, ages 18 to 30, and 102 young adults with no cancer history who were matched to the survivors by age, sex, and race.

Subjects were recruited from a commercial national Internet survey panel. They reported detailed social connection information with up to 25 friends and relatives.

The cancer survivors were between 15 and 30 years old when their cancer was diagnosed, and all had completed treatment at least 5 years prior.

Results

Neither the density index nor the betweenness centrality index demonstrated significant differences between cancer survivors and controls (all P values were less than 0.05).

However, according to the FSNI, cancer survivors had more available resources for emotional support (beta [b]=3.02; P=0.003), tangible support (b=4.17; P<0.001), physical activity advice (b=3.94; P<0.001), and weight management advice (b=4.10; P<0.001).

“This makes sense,” Dr Huang said. “Because of their cancer, survivors often have strong networks of physicians, friends, and relatives to provide advice and support.”

However, the FSNI showed the strength of cancer survivors’ support network varied by diagnosis.

Lymphoma survivors ranked highest on the FSNI (b=2.765; P=0.02), followed by survivors of leukemia (b=2.542; P=0.03) and solid tumors (b=2.178; P=0.047), with central nervous system malignancies as the reference.

The researchers also found a higher FSNI was associated with better coping skills, including using emotional support (b=0.08; P=0.04), using instrumental support (b=0.12; P<0.001), venting of emotions (b=0.10; P=0.004), positive reframing (b=0.12; P=0.003), planning for the future (b=0.08; P=0.03), participating in religious activities (b=0.16; P<0.001), and less denial (b=0.10; P=0.01) and destructive behavior (b=0.08; P=0.04).

The researchers said long-term follow-up is needed to understand how social networks and social support may change over time.

“Adolescents and young adult cancer survivors are in a transitory stage of independence from parents,” Dr Huang said. “While this study suggests that survivors often report strong social connections, our previous studies have reported that childhood cancer survivors are more likely than their peers to struggle mentally and physically and report issues like distress and loneliness.”

Dr Huang and his colleagues are working to streamline the FSNI to make it easier for healthcare providers to assess support available to cancer survivors of any age.

Meanwhile, researchers are working to better understand how social connections affect health outcomes in order to design interventions to foster those connections.

“A lack of social connections with friends and relatives is associated with poor quality of life, risky health behaviors, chronic health conditions, and premature death,” Dr Huang said. “Once we identify the mechanism between social connections and health outcomes, we can start designing interventions to use social networks to improve health outcomes of cancer survivors.”

Photo by Rhoda Baer

Researchers have developed a new method to measure social networks of adolescent and young adult (AYA) cancer survivors.

This method indicated that AYA cancer survivors often have stronger social networks than their non-cancer peers.

However, the strength of the social network varied by diagnosis, with the lymphoma and leukemia survivors having the greatest support.

These findings were published in Cancer.

“Cancer survivors need healthy social connections, and, to the best of our knowledge, this is the first published study to quantify social networks of adolescent and young adult cancer survivors compared to their peers,” said study author I-Chan Huang, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.

“The study introduces a method we developed and validated for evaluating social networks of these cancer survivors.”

The method, called the functional social network index (FSNI), measures marital status, contact frequency with friends and relatives, and available resources for health support/advice, which includes emotional support, tangible support, physical activity advice, and weight management advice.

The researchers compared the FSNI to a pair of traditional social network indices—density and betweenness centrality.

Density represents the ratio of the existing relationships/connections within a network to all possible relationships/connections. And betweenness centrality represents the ratio of the existing shortest paths between 2 friends/relatives of the study participants to the shortest possible paths between 2 friends/relatives.

Subjects

The researchers used the 3 social network indices to analyze 102 AYA cancer survivors, ages 18 to 30, and 102 young adults with no cancer history who were matched to the survivors by age, sex, and race.

Subjects were recruited from a commercial national Internet survey panel. They reported detailed social connection information with up to 25 friends and relatives.

The cancer survivors were between 15 and 30 years old when their cancer was diagnosed, and all had completed treatment at least 5 years prior.

Results

Neither the density index nor the betweenness centrality index demonstrated significant differences between cancer survivors and controls (all P values were less than 0.05).

However, according to the FSNI, cancer survivors had more available resources for emotional support (beta [b]=3.02; P=0.003), tangible support (b=4.17; P<0.001), physical activity advice (b=3.94; P<0.001), and weight management advice (b=4.10; P<0.001).

“This makes sense,” Dr Huang said. “Because of their cancer, survivors often have strong networks of physicians, friends, and relatives to provide advice and support.”

However, the FSNI showed the strength of cancer survivors’ support network varied by diagnosis.

Lymphoma survivors ranked highest on the FSNI (b=2.765; P=0.02), followed by survivors of leukemia (b=2.542; P=0.03) and solid tumors (b=2.178; P=0.047), with central nervous system malignancies as the reference.

The researchers also found a higher FSNI was associated with better coping skills, including using emotional support (b=0.08; P=0.04), using instrumental support (b=0.12; P<0.001), venting of emotions (b=0.10; P=0.004), positive reframing (b=0.12; P=0.003), planning for the future (b=0.08; P=0.03), participating in religious activities (b=0.16; P<0.001), and less denial (b=0.10; P=0.01) and destructive behavior (b=0.08; P=0.04).

The researchers said long-term follow-up is needed to understand how social networks and social support may change over time.

“Adolescents and young adult cancer survivors are in a transitory stage of independence from parents,” Dr Huang said. “While this study suggests that survivors often report strong social connections, our previous studies have reported that childhood cancer survivors are more likely than their peers to struggle mentally and physically and report issues like distress and loneliness.”

Dr Huang and his colleagues are working to streamline the FSNI to make it easier for healthcare providers to assess support available to cancer survivors of any age.

Meanwhile, researchers are working to better understand how social connections affect health outcomes in order to design interventions to foster those connections.

“A lack of social connections with friends and relatives is associated with poor quality of life, risky health behaviors, chronic health conditions, and premature death,” Dr Huang said. “Once we identify the mechanism between social connections and health outcomes, we can start designing interventions to use social networks to improve health outcomes of cancer survivors.”

Photo by Rhoda Baer

Researchers have developed a new method to measure social networks of adolescent and young adult (AYA) cancer survivors.

This method indicated that AYA cancer survivors often have stronger social networks than their non-cancer peers.

However, the strength of the social network varied by diagnosis, with the lymphoma and leukemia survivors having the greatest support.

These findings were published in Cancer.

“Cancer survivors need healthy social connections, and, to the best of our knowledge, this is the first published study to quantify social networks of adolescent and young adult cancer survivors compared to their peers,” said study author I-Chan Huang, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.

“The study introduces a method we developed and validated for evaluating social networks of these cancer survivors.”

The method, called the functional social network index (FSNI), measures marital status, contact frequency with friends and relatives, and available resources for health support/advice, which includes emotional support, tangible support, physical activity advice, and weight management advice.

The researchers compared the FSNI to a pair of traditional social network indices—density and betweenness centrality.

Density represents the ratio of the existing relationships/connections within a network to all possible relationships/connections. And betweenness centrality represents the ratio of the existing shortest paths between 2 friends/relatives of the study participants to the shortest possible paths between 2 friends/relatives.

Subjects

The researchers used the 3 social network indices to analyze 102 AYA cancer survivors, ages 18 to 30, and 102 young adults with no cancer history who were matched to the survivors by age, sex, and race.

Subjects were recruited from a commercial national Internet survey panel. They reported detailed social connection information with up to 25 friends and relatives.

The cancer survivors were between 15 and 30 years old when their cancer was diagnosed, and all had completed treatment at least 5 years prior.

Results

Neither the density index nor the betweenness centrality index demonstrated significant differences between cancer survivors and controls (all P values were less than 0.05).

However, according to the FSNI, cancer survivors had more available resources for emotional support (beta [b]=3.02; P=0.003), tangible support (b=4.17; P<0.001), physical activity advice (b=3.94; P<0.001), and weight management advice (b=4.10; P<0.001).

“This makes sense,” Dr Huang said. “Because of their cancer, survivors often have strong networks of physicians, friends, and relatives to provide advice and support.”

However, the FSNI showed the strength of cancer survivors’ support network varied by diagnosis.

Lymphoma survivors ranked highest on the FSNI (b=2.765; P=0.02), followed by survivors of leukemia (b=2.542; P=0.03) and solid tumors (b=2.178; P=0.047), with central nervous system malignancies as the reference.

The researchers also found a higher FSNI was associated with better coping skills, including using emotional support (b=0.08; P=0.04), using instrumental support (b=0.12; P<0.001), venting of emotions (b=0.10; P=0.004), positive reframing (b=0.12; P=0.003), planning for the future (b=0.08; P=0.03), participating in religious activities (b=0.16; P<0.001), and less denial (b=0.10; P=0.01) and destructive behavior (b=0.08; P=0.04).

The researchers said long-term follow-up is needed to understand how social networks and social support may change over time.

“Adolescents and young adult cancer survivors are in a transitory stage of independence from parents,” Dr Huang said. “While this study suggests that survivors often report strong social connections, our previous studies have reported that childhood cancer survivors are more likely than their peers to struggle mentally and physically and report issues like distress and loneliness.”

Dr Huang and his colleagues are working to streamline the FSNI to make it easier for healthcare providers to assess support available to cancer survivors of any age.

Meanwhile, researchers are working to better understand how social connections affect health outcomes in order to design interventions to foster those connections.

“A lack of social connections with friends and relatives is associated with poor quality of life, risky health behaviors, chronic health conditions, and premature death,” Dr Huang said. “Once we identify the mechanism between social connections and health outcomes, we can start designing interventions to use social networks to improve health outcomes of cancer survivors.”

YUBA CITY, Calif. – When Landon Morris was diagnosed with hemophilia shortly after birth, his mother, Jessica Morris, was devastated. “It was like having your dreams – all the dreams you imagined for your child – just kind of disappear,” she recalled.

Hemophilia, a rare bleeding disorder caused by a gene mutation that prevents blood from clotting properly, is typically passed from mother to son. Ms. Morris’ grandfather had it, and she remembered hearing how painful it was. “It was almost like he was bubble-wrapped,” she said. “He was coddled, because his mom didn’t want him to get hurt.”

But Landon’s life turned out much different than she expected.

“He’s wild. He’s probably sometimes the roughest of them all,” she said, as she watched the 6-year-old race around a park. “He leads a totally normal life. He plays T-ball. He’ll start soccer in the fall. He runs and jumps and wrestles with his brothers.” That’s due almost entirely to his medication – the kind that wasn’t available in his grandfather’s day. For the Morris family, this type of drug – broadly known as clotting factor – is a miracle, helping Landon’s blood clot normally. And its cost is almost entirely covered by his father’s federal employee health plan.

Vying for patients

The market for hemophilia medicines in the United States is flooded with 28 different drugs, with another 21 drugs in development. Because blood factor drugs are biological products – in this case, a protein – there are no cheaper copies, called biosimilars, available. Not only do prices rise steadily as each new product comes on the market, demand is growing – and pushing costs upward – as more and more clotting factor is used to prevent bleeding episodes, not just to treat them.

Yet competition has not brought prices down in the way someone “operating at the level of undergrad Econ 101 would expect,” said Jerry Avorn, MD, a professor of medicine at Harvard Medical School, Boston, who studies prescription drug costs.

The problem is that companies have no incentive to lower prices. Patients generally don’t push back because insurers pay the bulk of the cost. And insurers tend not to object because the market for the drugs – expensive as they are – is small and the patients are especially vulnerable.

Pushing back on costs

In Europe, hemophilia drugs cost less than half what they cost in the United States. That’s because payers – usually governments – request bids and pick products based on cost and quality.

Without pushback from insurers in the United States, “the price of any drug in the U.S. is whatever the market will bear as seen by the manufacturer,” said Dr. Avorn of Harvard.

Recently, a few insurance companies have quietly started to push back on costs. Bayer’s Mr. O’Leary said several insurers have approached the company and demanded rebates in exchange for offering the drug to their customers. Mr. O’Leary would not discuss the details because he said the contracts are confidential.

State Medicaid programs, which provide health insurance to low-income Americans and cover about half of hemophilia patients, already receive significant rebates from hemophilia drug manufacturers.

Michelle Rice, a senior vice president at the National Hemophilia Foundation, said she has been working with several insurers to help them manage costs safely. “We understand the need to control costs, but they can’t impede access to the product a patient needs,” she said.

It is not yet clear whether such efforts will work, let alone spread.

Kaiser Health News is a nonprofit news service covering health issues. It is an editorially independent program of the Kaiser Family Foundation that is not affiliated with Kaiser Permanente. KHN’s coverage of prescription drug development, costs, and pricing is supported by the Laura and John Arnold Foundation.

YUBA CITY, Calif. – When Landon Morris was diagnosed with hemophilia shortly after birth, his mother, Jessica Morris, was devastated. “It was like having your dreams – all the dreams you imagined for your child – just kind of disappear,” she recalled.

Hemophilia, a rare bleeding disorder caused by a gene mutation that prevents blood from clotting properly, is typically passed from mother to son. Ms. Morris’ grandfather had it, and she remembered hearing how painful it was. “It was almost like he was bubble-wrapped,” she said. “He was coddled, because his mom didn’t want him to get hurt.”

But Landon’s life turned out much different than she expected.

“He’s wild. He’s probably sometimes the roughest of them all,” she said, as she watched the 6-year-old race around a park. “He leads a totally normal life. He plays T-ball. He’ll start soccer in the fall. He runs and jumps and wrestles with his brothers.” That’s due almost entirely to his medication – the kind that wasn’t available in his grandfather’s day. For the Morris family, this type of drug – broadly known as clotting factor – is a miracle, helping Landon’s blood clot normally. And its cost is almost entirely covered by his father’s federal employee health plan.

Vying for patients

The market for hemophilia medicines in the United States is flooded with 28 different drugs, with another 21 drugs in development. Because blood factor drugs are biological products – in this case, a protein – there are no cheaper copies, called biosimilars, available. Not only do prices rise steadily as each new product comes on the market, demand is growing – and pushing costs upward – as more and more clotting factor is used to prevent bleeding episodes, not just to treat them.

Yet competition has not brought prices down in the way someone “operating at the level of undergrad Econ 101 would expect,” said Jerry Avorn, MD, a professor of medicine at Harvard Medical School, Boston, who studies prescription drug costs.

The problem is that companies have no incentive to lower prices. Patients generally don’t push back because insurers pay the bulk of the cost. And insurers tend not to object because the market for the drugs – expensive as they are – is small and the patients are especially vulnerable.

Pushing back on costs

In Europe, hemophilia drugs cost less than half what they cost in the United States. That’s because payers – usually governments – request bids and pick products based on cost and quality.

Without pushback from insurers in the United States, “the price of any drug in the U.S. is whatever the market will bear as seen by the manufacturer,” said Dr. Avorn of Harvard.

Recently, a few insurance companies have quietly started to push back on costs. Bayer’s Mr. O’Leary said several insurers have approached the company and demanded rebates in exchange for offering the drug to their customers. Mr. O’Leary would not discuss the details because he said the contracts are confidential.

State Medicaid programs, which provide health insurance to low-income Americans and cover about half of hemophilia patients, already receive significant rebates from hemophilia drug manufacturers.

Michelle Rice, a senior vice president at the National Hemophilia Foundation, said she has been working with several insurers to help them manage costs safely. “We understand the need to control costs, but they can’t impede access to the product a patient needs,” she said.

It is not yet clear whether such efforts will work, let alone spread.

Kaiser Health News is a nonprofit news service covering health issues. It is an editorially independent program of the Kaiser Family Foundation that is not affiliated with Kaiser Permanente. KHN’s coverage of prescription drug development, costs, and pricing is supported by the Laura and John Arnold Foundation.

YUBA CITY, Calif. – When Landon Morris was diagnosed with hemophilia shortly after birth, his mother, Jessica Morris, was devastated. “It was like having your dreams – all the dreams you imagined for your child – just kind of disappear,” she recalled.

Hemophilia, a rare bleeding disorder caused by a gene mutation that prevents blood from clotting properly, is typically passed from mother to son. Ms. Morris’ grandfather had it, and she remembered hearing how painful it was. “It was almost like he was bubble-wrapped,” she said. “He was coddled, because his mom didn’t want him to get hurt.”

But Landon’s life turned out much different than she expected.

“He’s wild. He’s probably sometimes the roughest of them all,” she said, as she watched the 6-year-old race around a park. “He leads a totally normal life. He plays T-ball. He’ll start soccer in the fall. He runs and jumps and wrestles with his brothers.” That’s due almost entirely to his medication – the kind that wasn’t available in his grandfather’s day. For the Morris family, this type of drug – broadly known as clotting factor – is a miracle, helping Landon’s blood clot normally. And its cost is almost entirely covered by his father’s federal employee health plan.

Vying for patients

The market for hemophilia medicines in the United States is flooded with 28 different drugs, with another 21 drugs in development. Because blood factor drugs are biological products – in this case, a protein – there are no cheaper copies, called biosimilars, available. Not only do prices rise steadily as each new product comes on the market, demand is growing – and pushing costs upward – as more and more clotting factor is used to prevent bleeding episodes, not just to treat them.

Yet competition has not brought prices down in the way someone “operating at the level of undergrad Econ 101 would expect,” said Jerry Avorn, MD, a professor of medicine at Harvard Medical School, Boston, who studies prescription drug costs.

The problem is that companies have no incentive to lower prices. Patients generally don’t push back because insurers pay the bulk of the cost. And insurers tend not to object because the market for the drugs – expensive as they are – is small and the patients are especially vulnerable.

Pushing back on costs

In Europe, hemophilia drugs cost less than half what they cost in the United States. That’s because payers – usually governments – request bids and pick products based on cost and quality.

Without pushback from insurers in the United States, “the price of any drug in the U.S. is whatever the market will bear as seen by the manufacturer,” said Dr. Avorn of Harvard.

Recently, a few insurance companies have quietly started to push back on costs. Bayer’s Mr. O’Leary said several insurers have approached the company and demanded rebates in exchange for offering the drug to their customers. Mr. O’Leary would not discuss the details because he said the contracts are confidential.

State Medicaid programs, which provide health insurance to low-income Americans and cover about half of hemophilia patients, already receive significant rebates from hemophilia drug manufacturers.

Michelle Rice, a senior vice president at the National Hemophilia Foundation, said she has been working with several insurers to help them manage costs safely. “We understand the need to control costs, but they can’t impede access to the product a patient needs,” she said.

It is not yet clear whether such efforts will work, let alone spread.

Kaiser Health News is a nonprofit news service covering health issues. It is an editorially independent program of the Kaiser Family Foundation that is not affiliated with Kaiser Permanente. KHN’s coverage of prescription drug development, costs, and pricing is supported by the Laura and John Arnold Foundation.

LAS VEGAS – Even if you do not believe in medical cannabis, be open to patients who ask you if it might benefit them, Kevin P. Hill, MD, advised.

“Being willing to talk to your patient about it is important,” said Dr. Hill, of the division of addiction psychiatry at Beth Israel Deaconess Medical Center, Boston, said at an annual psychopharmacology update held by the Nevada Psychiatric Association. “Because what will happen is, they’ll say, ‘Look. I need medical marijuana to treat my anxiety.’ Then you can say, ‘Well, I have treatments that work for anxiety that we haven’t tried.’ Maybe you can get them into treatment because of that conversation.”

In his opinion, the appropriate candidate for medical cannabis is someone with a debilitating condition who has failed multiple first- and second-line treatments. “The policy of medical cannabis is ahead of the science,” he noted. “It’s not a good place to be, but now the question becomes: How do we give people what they want while addressing the risks? I think we need to do a better job of that. We can provide a service to patients and colleagues by being informed and thoughtful on the topic.”

Food and Drug Administration–approved cannabinoids to date are dronabinol (Marinol) and nabilone (Cesamet). These agents are approved for nausea and vomiting associated with chemotherapy and for appetite stimulation in wasting illnesses such as AIDS. “Your patients may come to you and say, ‘I think I need medical cannabis for condition X,’ ” said Dr. Hill, who authored the book “Marijuana: The Unbiased Truth About the World’s Most Popular Weed” (Center City, Minn.: Hazelden Publishing, 2015). “Maybe the cannabis plant can outperform the two approved agents that we have. I think we have to be open to that possibility. Maybe they offer some things that dronabinol and nabilone don’t.”

LAS VEGAS – Even if you do not believe in medical cannabis, be open to patients who ask you if it might benefit them, Kevin P. Hill, MD, advised.

“Being willing to talk to your patient about it is important,” said Dr. Hill, of the division of addiction psychiatry at Beth Israel Deaconess Medical Center, Boston, said at an annual psychopharmacology update held by the Nevada Psychiatric Association. “Because what will happen is, they’ll say, ‘Look. I need medical marijuana to treat my anxiety.’ Then you can say, ‘Well, I have treatments that work for anxiety that we haven’t tried.’ Maybe you can get them into treatment because of that conversation.”

In his opinion, the appropriate candidate for medical cannabis is someone with a debilitating condition who has failed multiple first- and second-line treatments. “The policy of medical cannabis is ahead of the science,” he noted. “It’s not a good place to be, but now the question becomes: How do we give people what they want while addressing the risks? I think we need to do a better job of that. We can provide a service to patients and colleagues by being informed and thoughtful on the topic.”

Food and Drug Administration–approved cannabinoids to date are dronabinol (Marinol) and nabilone (Cesamet). These agents are approved for nausea and vomiting associated with chemotherapy and for appetite stimulation in wasting illnesses such as AIDS. “Your patients may come to you and say, ‘I think I need medical cannabis for condition X,’ ” said Dr. Hill, who authored the book “Marijuana: The Unbiased Truth About the World’s Most Popular Weed” (Center City, Minn.: Hazelden Publishing, 2015). “Maybe the cannabis plant can outperform the two approved agents that we have. I think we have to be open to that possibility. Maybe they offer some things that dronabinol and nabilone don’t.”

LAS VEGAS – Even if you do not believe in medical cannabis, be open to patients who ask you if it might benefit them, Kevin P. Hill, MD, advised.

“Being willing to talk to your patient about it is important,” said Dr. Hill, of the division of addiction psychiatry at Beth Israel Deaconess Medical Center, Boston, said at an annual psychopharmacology update held by the Nevada Psychiatric Association. “Because what will happen is, they’ll say, ‘Look. I need medical marijuana to treat my anxiety.’ Then you can say, ‘Well, I have treatments that work for anxiety that we haven’t tried.’ Maybe you can get them into treatment because of that conversation.”

In his opinion, the appropriate candidate for medical cannabis is someone with a debilitating condition who has failed multiple first- and second-line treatments. “The policy of medical cannabis is ahead of the science,” he noted. “It’s not a good place to be, but now the question becomes: How do we give people what they want while addressing the risks? I think we need to do a better job of that. We can provide a service to patients and colleagues by being informed and thoughtful on the topic.”

Food and Drug Administration–approved cannabinoids to date are dronabinol (Marinol) and nabilone (Cesamet). These agents are approved for nausea and vomiting associated with chemotherapy and for appetite stimulation in wasting illnesses such as AIDS. “Your patients may come to you and say, ‘I think I need medical cannabis for condition X,’ ” said Dr. Hill, who authored the book “Marijuana: The Unbiased Truth About the World’s Most Popular Weed” (Center City, Minn.: Hazelden Publishing, 2015). “Maybe the cannabis plant can outperform the two approved agents that we have. I think we have to be open to that possibility. Maybe they offer some things that dronabinol and nabilone don’t.”