Many patients with psychiatric illness have difficulty with medication adherence. Patients with impaired reality testing especially are at risk.

Keck and McElroy evaluated 141 patients who were initially hospitalized for bipolar disorder prospectively over 1 year to assess adherence with medication. During the follow-up period, 71 patients (51%) were partially or totally nonadherent with medication as prescribed. The most commonly cited reason for nonadherence was denial of need.¹

Clinicians and patients face additional challenges due to the deleterious effects of relapse in the setting of both schizophrenia and bipolar disorder. Almost all oral antipsychotic or mood stabilizer medications require a minimum dosing schedule to effectively treat these disorders, and some of these oral medications require regular laboratory monitoring. Moreover, some of the agents can have serious adverse effects (AEs), such as seizure or withdrawal, if stopped abruptly. Social support from family or friends may improve adherence, but many psychiatric outpatients have a smaller social support network than do patients without psychiatric illnesses.²

Long-acting injectable (LAI) antipsychotics have been available for the past 40 years. These medications have provided clinicians with an additional option for patients with schizophrenia or bipolar disorder who are nonadherent to their medication treatment plans or who desire an administration choice that is more convenient than daily oral pills.^3-7 Some clinical practice guidelines recommend considering LAIs as a maintenance treatment for schizophrenia.⁵ Like the rest of the pharmacopoeia, these formulations have AEs, such as extrapyramidal symptoms (EPS), weight gain, and metabolic syndrome.¹ The longer half-life of these drugs may make such effects difficult to reverse.

This article presents a case of the use of depot formulation paliperidone palmitate in an elderly patient with bipolar disorder who was previously on high-dose oral second generation antipsychotics. He developed severe parkinsonism during a protracted hospitalization that ended in death.

Case Presentation

Mr. W was a 68-year-old homeless white male with a history of coronary artery disease status-post coronary artery bypass surgery, obstructive sleep apnea, and bipolar 1 disorder who presented to a large rural VAMC emergency department (ED) as a transfer from an outside hospital (OSH). He originally presented at the OSH for vomiting and diarrhea, but while there, he was placed under involuntary psychiatric commitment. The involuntary commitment form noted him to be tangential and disorganized; he was found walking about the ED without clothes. During the initial psychiatry interview, the clinician noted a disorganized thought process. When asked about circumstances leading to admission, he stated he was “a scuba diver, pilot, actor, submarine commander.” He also reported he had given “seminars to 6,000 people,” he held a psychology degree, and he came from a family that owned part of the island of Kodiak, Alaska. Mr. W stated he had no mental health history and believed psychiatry was witchcraft. He reported having no hallucinations and stated he heard the voice of god. He also reported to have met god multiple times and to have been married to a supermodel.

Mr. W’s chart demonstrated a history of mental illness over 30 years and that he previously was prescribed psychiatric medications. He had multiple inpatient psychiatric admissions with grandiose ideations, disorganized behaviors, and hypersexuality. He had been prescribed quetiapine, divalproex, lithium, carbamazepine, and lorazepam. He was formally diagnosed in the past with bipolar 1 disorder. There also was a family history of psychiatric illness. His mother had received electroconvulsive therapy, and both parents had alcohol substance use disorder.

Mr. W had been homeless for 20 years and had several psychiatric admissions during this period. Mr. W also had chronic difficulty with obtaining food and taking medications as prescribed. Sometimes he would only be able to eat 1 to 2 meals per day. He often changed location and had lived in at least 7 different states. Currently, he was estranged from his family. About 19 years ago, his sister reported that the veteran had told her that he was Jesus Christ, per clinical records. His estranged sister’s statement was corroborated by past psychology consult records citing episodes of the patient hearing god 30 and 26 years before the current admission. His second ex-wife cited inappropriate sexual behavior in front of their children. He had difficulty in school, failed at least 2 grades, and joined the U.S. Navy in tenth grade. A Neurobehavioral Cognitive Status Examination given 19 years ago showed mild impairment on attention and severe impairment in memory.

The physical examination on presentation to the OSH was unremarkable. Mr. W did not cooperate with formal neurocognitive testing, and he consistently made errors during orientation testing. Complete blood count from a OSH ED laboratory test was remarkable for a mild pancytopenia with a leukocyte count of 3,100 cells/mcL, hemoglobin 13.1 g/dL, and hematocrit 38.4%. Red cell distribution width was within normal limits at 13.5%. Stool cultures showed normal fecal flora and no salmonella, shigella, or campylobacter. Thyroid-stimulating hormone (TSH) was slightly elevated at 5.32 U/mL. An electrocardiogram showed a QTc interval of 412 ms. A computerized tomography scan of his head showed no acute intracranial abnormality along with chronic ischemic changes in the brain (Table 1). Presumed cause of his nausea and diarrhea was viral gastroenteritis likely acquired at a homeless shelter.

Once stabilized, Mr. W was admitted to the VA hospital inpatient psychiatry unit under involuntary commitment for acute mania. Risperidone 0.25 mg orally twice a day was started for mood stabilization and psychosis along with trazodone 50 mg orally as needed for insomnia. Despite upward titration and change in frequency of the risperidone dose, Mr. W’s manic episode persisted. He remained on the psychiatric floor for 2 months (Figure). His TSH and free T4 were monitored during his stay, and levothyroxine was started. Risperidone was titrated to 8 mg/d. Mr. W’s Young Mania Rating Scale (YMRS) score decreased from 30 to 24. Mr. W had a mild improvement in irritability and speech rate but little change in elevated mood and delusional content.

He continued to endorse “speaking to god 16 times” even at the highest risperidone dose. The treatment team prescribed dissolvable risperidone tablets secondary to diversion concerns. In addition, the team added benztropine 0.5 mg once a day after observing a stooped posture and decreased arm swing. Mr. W noted risperidone made him “lethargic” and that his “body did not need” it. After 1 month of treatment with risperidone, the treatment team decided to cross taper the veteran from risperidone to a combination of olanzapine and divalproex secondary to inadequate treatment response.

The inpatient team started Mr. W on oral disintegrating tablets of olanzapine 5 mg once a day, and oral divalproex 1,000 mg once a day. An intramuscular backup of olanzapine was made available if oral medication was refused. Divalproex was titrated to 1,250 mg once a day to target a serum level of 61.7 µg/mL, and olanzapine was titrated to 10 mg once a day. After 9 days, the veteran showed moderate improvement in mania symptoms with a YMRS score < 20, indicating the absence of mania. However, the veteran made it very clear that he would stop taking the prescribed medication on discharge. The team elected to initiate a LAI.

The veteran received his first injection of the LAI psychiatric medication paliperidone palmitate 234 mg and a second 156-mg injection of the same medication 1 week later as per loading protocol. He was concurrently on daily oral divalproex 1,250 mg and olanzapine 10 mg. Mr. W continued to note he felt sedated during this period; his sedation worsened after the second injection. He also began to forget the location of his room and developed mumbled speech. His gait deteriorated to where he required a walker 6 days after injection and a wheelchair 3 days later. He became incontinent of urine and feces. Mr. W exhibited masked facies with severe drooling. This eventually progressed to difficulty swallowing. At the advice of speech pathology, he was downgraded to a pureed and nectar-thick liquid diet. He required assistance with meals.

Because of his sedation and parkinsonism symptoms, he was tapered off both olanzapine and divalproex. His last dose of olanzapine was on the date of his first injection and last dose of divalproex was 15 days after the second injection. The benztropine, which was originally given to counteract the effects of risperidone monotherapy, was discontinued over concern of anticholinergic load and sedation. The neurology consultant recommended carbidopa 25 mg and levodopa 100 mg 3 times per day for treatment of parkinsonism symptoms. Mr. W was only able to take 1 dose because of trouble swallowing. Twenty days after his second injection, a rapid response team (local clinical team 1 step below a code team) was called as Mr. W was unusually lethargic and unable to eat. He was then transferred to the medical floor.

While on the medical floor, dobhoff tube access was established for nutrition and to allow administration of carbidopa and levodopa. Mr. W could still speak at this time and was distraught. He stated, “I don’t know why god would do this to me.” Further workup was performed to look for other etiologies of the patient’s change in status. Creatinine kinase testing, lumbar puncture with cerebral spinal fluid (CSF) bacterial culture, CSF cryptococcal testing, and syphilis antigens were all negative. Magnetic resonance imaging of the brain demonstrated diffuse cerebral atrophy with widened cistern and sulci resulting in ex vacuo dilatation.

Neurology thought that the ventriculomegaly did not have features of normal pressure hydrocephalus and was secondary to chronic ischemic demyelination caused by chronic malnutrition. During follow-up visits, the veteran was less and less verbal. It progressed to where he answered questions only in grunts. Eight days after transfer to the medical floor, Mr. W was noted to have his neck locked in a laterally rotated position with clonus of the sternocleidomastoid. Due to concern about possibility of neck dystonia and the poor adherence of the patient with carbidopa and levodopa given orally, the psychiatric team made the recommendation to start benztropine 1 mg given twice a day, delivered via the dobhoff tube to treat both the parkinsonism and dystonia. The following day Mr. W failed a repeat swallow study and was no longer allowed to receive anything orally.

Mild icterus and jaundice were noted on physical examination along with transaminitis and elevated bilirubin. He developed a fever. Thirteen days after transfer to the medical floor, blood cultures revealed Klebsiella septicemia. Benztropine was discontinued at this time because of concern the medication was causing or exacerbating the fever. While being treated for Klebsiella sepsis, the psychiatry team addressed his continued hypophonia, inability to ambulate, masked facies, and neck dystonia with diphenhydramine 50 mg given intramuscular (IM) twice per day.

Mr. W developed several more iatrogenic complications near this time, including urinary tract infection septicemia and acute hypoxic respiratory failure with lung infiltrate on X-ray, requiring ventilator support. His clinical status led to a number of transfers in and out of the medical intensive care unit (MICU). During this time, his parkinsonism symptoms were managed through a combination of carbidopa and levodopa and amantadine. Cervical dystonia was managed with botulism toxin injections. Mr. W spent 6 weeks in the MICU until the decision was made to terminate life support, and he was taken off the ventilator. He died shortly thereafter. Autopsy findings suggested that Mr. W had severe Alzheimer disease.

Discussion

Following the IM injection of paliperidone palmitate, Mr. W had a complicated hospital stay resulting in his demise from sepsis and multiorgan failure. Severe immobilization, rigidity, and dystonia prevented Mr. W from conducting activities of daily living, which resulted in invasive interventions, such as continued foley catheterization. His sepsis was likely secondary to aspiration, catheterization, and eventual ventilation—all iatrogenic complications. Previous estimates in the U.S. have suggested a total of 225,000 deaths per year from iatrogenic causes.⁸

There are several areas of concern. Clearly, Mr. W had severe illness that greatly affected his life. He was estranged from family and had endured a 2-decade period of homelessness. He deserved effective treatment for his psychiatric illness to relieve his suffering. His long period of mental illness without effective treatment very likely biased the initial treatment team toward an aggressive approach.

Fragmented Care

The prolonged hospital stay and multiple complications directly led to fragmentation in Mr. W’s care. He was hospitalized for months on 3 different main services: psychiatry, medicine, and the MICU. Even when he remained on the same service, the primary members of his treatment team changed every few weeks. Many different specialties were consulted and reconsulted. Members of the specialty consult teams changed throughout the hospitalization as well. Given the nature of the local clinical administration, Mr. W likely received the most consistent team members from the attendings on the psychiatry consult-liaison service (who do not rotate) and from a local subspecialty delirium consult team (all members stay consistent except pharmacy residents).

Documentation of clinical reasoning behind treatment decisions was not ideal and occasionally lacking. This led to a tendency to “reinvent the wheel” with Mr. W’s treatment approach every few weeks. It was not until Mr. W had spent a significant amount of time on the medical service that an interdisciplinary treatment team meeting involving medicine, psychiatry, nursing, delirium, and neurology experts occurred. Although the interdisciplinary meeting helped by reviewing the hospital course, agreeing on a likely cause of the symptoms, and creating a treatment plan going forward, Mr. W was not able to recover.

Even when team members were stable, communication in a timely fashion did not always occur. At several points, expert recommendations were delayed by a day or more. Difficulties in treatment implementation were not communicated back to the specialty teams. The most significant example was a delay in recognition when Mr. W could no longer take oral pills secondary to the parkinsonism. Many days passed before an alternative liquid or dissolved medication was recommended on 2 separate occasions.

Subspecialty Consult

Addressing these documentation, communication, and transition challenges is neither easy nor unique to this large rural VA medical center. The authors have attempted to address this in the local system with the creation of a delirium team subspecialty consult service. Team members do not rotate and are able to follow patients throughout their hospital course. At the time of Mr. W’s hospitalization, the team included representatives from nursing, psychiatry, and occasionally pharmacy. Since then, it has expanded to include geriatrics and medicine. In addition to delirium being a marker for complex patients at risk for hospital complications, medical reasons for an extended length of stay could serve as a trigger for a referral to such a team of experts. In Mr. W’s case, that could have led to interdisciplinary consultation up to 2 months before it occurred. This may have led to a much better outcome.

Secondary parkinsonism is most notable with the typical antipychotics. The prevalence can vary between 50% and 75% and may be higher within the elderly population. However, all antipsychotics have a chance of demonstrating EPS. Risperidone has a low incidence at low doses; studies have shown dose-related parkinsonism at doses of 2 to 6 mg/d. Significant risk of parkinsonism is further exacerbated when drug-drug interactions are considered.⁹ Concurrently receiving 2 antipsychotics, olanzapine and paliperidone, initially caused the EPS. The veteran’s cerebral atrophy from significant malnutrition related to chronic homelessness, and the presence of Alzheimer disease only identified postmortem exacerbated this AE. Further complicating the management of the EPS, paliperidone palmitate has a long half-life of 25 to 49 days.⁹ Simply discontinuing the medication did not remove it from Mr. W’s system. Paliperidone would have continued to be present for months.

Conclusion

In this case, aggressive changes in the antipsychotic medications in a short period led to Mr. W effectively having 3 different agents in his system at the same time. This significantly elevated his risk of AEs, including parkinsonism. The clinician must be vigilant to further recognize the initial symptoms of parkinsonism on clinical presentation. Administration of clinical scales, such as the Simpson-Angus Extrapyramidal Side Effect, can help in these situations.¹⁰ Malnutrition and increased age can predispose patients to neurolepticAEs, so treatment teams should exercise caution when administering antipsychotics in such a population. Pharmacokinetic changes in all major organ systems from aging result in higher and more variable drug concentrations. This leads to an increased sensitivity to drugs and AEs.⁹

Given the increasing geriatric patient population in the U.S., treating mania in the elderly will become more common. Providers should carefully consider the risks vs benefit ratio for each individual because a serious adverse reaction may result in detrimental consequences. Even with severe symptoms leading to a bias toward an aggressive approach, it may be better to “start low and go slow.” Early inclusion of interdisciplinary expertise should be sought in complex cases.

Many patients with psychiatric illness have difficulty with medication adherence. Patients with impaired reality testing especially are at risk.

Keck and McElroy evaluated 141 patients who were initially hospitalized for bipolar disorder prospectively over 1 year to assess adherence with medication. During the follow-up period, 71 patients (51%) were partially or totally nonadherent with medication as prescribed. The most commonly cited reason for nonadherence was denial of need.¹

Clinicians and patients face additional challenges due to the deleterious effects of relapse in the setting of both schizophrenia and bipolar disorder. Almost all oral antipsychotic or mood stabilizer medications require a minimum dosing schedule to effectively treat these disorders, and some of these oral medications require regular laboratory monitoring. Moreover, some of the agents can have serious adverse effects (AEs), such as seizure or withdrawal, if stopped abruptly. Social support from family or friends may improve adherence, but many psychiatric outpatients have a smaller social support network than do patients without psychiatric illnesses.²

Long-acting injectable (LAI) antipsychotics have been available for the past 40 years. These medications have provided clinicians with an additional option for patients with schizophrenia or bipolar disorder who are nonadherent to their medication treatment plans or who desire an administration choice that is more convenient than daily oral pills.^3-7 Some clinical practice guidelines recommend considering LAIs as a maintenance treatment for schizophrenia.⁵ Like the rest of the pharmacopoeia, these formulations have AEs, such as extrapyramidal symptoms (EPS), weight gain, and metabolic syndrome.¹ The longer half-life of these drugs may make such effects difficult to reverse.

This article presents a case of the use of depot formulation paliperidone palmitate in an elderly patient with bipolar disorder who was previously on high-dose oral second generation antipsychotics. He developed severe parkinsonism during a protracted hospitalization that ended in death.

Case Presentation

Mr. W was a 68-year-old homeless white male with a history of coronary artery disease status-post coronary artery bypass surgery, obstructive sleep apnea, and bipolar 1 disorder who presented to a large rural VAMC emergency department (ED) as a transfer from an outside hospital (OSH). He originally presented at the OSH for vomiting and diarrhea, but while there, he was placed under involuntary psychiatric commitment. The involuntary commitment form noted him to be tangential and disorganized; he was found walking about the ED without clothes. During the initial psychiatry interview, the clinician noted a disorganized thought process. When asked about circumstances leading to admission, he stated he was “a scuba diver, pilot, actor, submarine commander.” He also reported he had given “seminars to 6,000 people,” he held a psychology degree, and he came from a family that owned part of the island of Kodiak, Alaska. Mr. W stated he had no mental health history and believed psychiatry was witchcraft. He reported having no hallucinations and stated he heard the voice of god. He also reported to have met god multiple times and to have been married to a supermodel.

Mr. W’s chart demonstrated a history of mental illness over 30 years and that he previously was prescribed psychiatric medications. He had multiple inpatient psychiatric admissions with grandiose ideations, disorganized behaviors, and hypersexuality. He had been prescribed quetiapine, divalproex, lithium, carbamazepine, and lorazepam. He was formally diagnosed in the past with bipolar 1 disorder. There also was a family history of psychiatric illness. His mother had received electroconvulsive therapy, and both parents had alcohol substance use disorder.

Mr. W had been homeless for 20 years and had several psychiatric admissions during this period. Mr. W also had chronic difficulty with obtaining food and taking medications as prescribed. Sometimes he would only be able to eat 1 to 2 meals per day. He often changed location and had lived in at least 7 different states. Currently, he was estranged from his family. About 19 years ago, his sister reported that the veteran had told her that he was Jesus Christ, per clinical records. His estranged sister’s statement was corroborated by past psychology consult records citing episodes of the patient hearing god 30 and 26 years before the current admission. His second ex-wife cited inappropriate sexual behavior in front of their children. He had difficulty in school, failed at least 2 grades, and joined the U.S. Navy in tenth grade. A Neurobehavioral Cognitive Status Examination given 19 years ago showed mild impairment on attention and severe impairment in memory.

The physical examination on presentation to the OSH was unremarkable. Mr. W did not cooperate with formal neurocognitive testing, and he consistently made errors during orientation testing. Complete blood count from a OSH ED laboratory test was remarkable for a mild pancytopenia with a leukocyte count of 3,100 cells/mcL, hemoglobin 13.1 g/dL, and hematocrit 38.4%. Red cell distribution width was within normal limits at 13.5%. Stool cultures showed normal fecal flora and no salmonella, shigella, or campylobacter. Thyroid-stimulating hormone (TSH) was slightly elevated at 5.32 U/mL. An electrocardiogram showed a QTc interval of 412 ms. A computerized tomography scan of his head showed no acute intracranial abnormality along with chronic ischemic changes in the brain (Table 1). Presumed cause of his nausea and diarrhea was viral gastroenteritis likely acquired at a homeless shelter.

Once stabilized, Mr. W was admitted to the VA hospital inpatient psychiatry unit under involuntary commitment for acute mania. Risperidone 0.25 mg orally twice a day was started for mood stabilization and psychosis along with trazodone 50 mg orally as needed for insomnia. Despite upward titration and change in frequency of the risperidone dose, Mr. W’s manic episode persisted. He remained on the psychiatric floor for 2 months (Figure). His TSH and free T4 were monitored during his stay, and levothyroxine was started. Risperidone was titrated to 8 mg/d. Mr. W’s Young Mania Rating Scale (YMRS) score decreased from 30 to 24. Mr. W had a mild improvement in irritability and speech rate but little change in elevated mood and delusional content.

He continued to endorse “speaking to god 16 times” even at the highest risperidone dose. The treatment team prescribed dissolvable risperidone tablets secondary to diversion concerns. In addition, the team added benztropine 0.5 mg once a day after observing a stooped posture and decreased arm swing. Mr. W noted risperidone made him “lethargic” and that his “body did not need” it. After 1 month of treatment with risperidone, the treatment team decided to cross taper the veteran from risperidone to a combination of olanzapine and divalproex secondary to inadequate treatment response.

The inpatient team started Mr. W on oral disintegrating tablets of olanzapine 5 mg once a day, and oral divalproex 1,000 mg once a day. An intramuscular backup of olanzapine was made available if oral medication was refused. Divalproex was titrated to 1,250 mg once a day to target a serum level of 61.7 µg/mL, and olanzapine was titrated to 10 mg once a day. After 9 days, the veteran showed moderate improvement in mania symptoms with a YMRS score < 20, indicating the absence of mania. However, the veteran made it very clear that he would stop taking the prescribed medication on discharge. The team elected to initiate a LAI.

The veteran received his first injection of the LAI psychiatric medication paliperidone palmitate 234 mg and a second 156-mg injection of the same medication 1 week later as per loading protocol. He was concurrently on daily oral divalproex 1,250 mg and olanzapine 10 mg. Mr. W continued to note he felt sedated during this period; his sedation worsened after the second injection. He also began to forget the location of his room and developed mumbled speech. His gait deteriorated to where he required a walker 6 days after injection and a wheelchair 3 days later. He became incontinent of urine and feces. Mr. W exhibited masked facies with severe drooling. This eventually progressed to difficulty swallowing. At the advice of speech pathology, he was downgraded to a pureed and nectar-thick liquid diet. He required assistance with meals.

Because of his sedation and parkinsonism symptoms, he was tapered off both olanzapine and divalproex. His last dose of olanzapine was on the date of his first injection and last dose of divalproex was 15 days after the second injection. The benztropine, which was originally given to counteract the effects of risperidone monotherapy, was discontinued over concern of anticholinergic load and sedation. The neurology consultant recommended carbidopa 25 mg and levodopa 100 mg 3 times per day for treatment of parkinsonism symptoms. Mr. W was only able to take 1 dose because of trouble swallowing. Twenty days after his second injection, a rapid response team (local clinical team 1 step below a code team) was called as Mr. W was unusually lethargic and unable to eat. He was then transferred to the medical floor.

While on the medical floor, dobhoff tube access was established for nutrition and to allow administration of carbidopa and levodopa. Mr. W could still speak at this time and was distraught. He stated, “I don’t know why god would do this to me.” Further workup was performed to look for other etiologies of the patient’s change in status. Creatinine kinase testing, lumbar puncture with cerebral spinal fluid (CSF) bacterial culture, CSF cryptococcal testing, and syphilis antigens were all negative. Magnetic resonance imaging of the brain demonstrated diffuse cerebral atrophy with widened cistern and sulci resulting in ex vacuo dilatation.

Neurology thought that the ventriculomegaly did not have features of normal pressure hydrocephalus and was secondary to chronic ischemic demyelination caused by chronic malnutrition. During follow-up visits, the veteran was less and less verbal. It progressed to where he answered questions only in grunts. Eight days after transfer to the medical floor, Mr. W was noted to have his neck locked in a laterally rotated position with clonus of the sternocleidomastoid. Due to concern about possibility of neck dystonia and the poor adherence of the patient with carbidopa and levodopa given orally, the psychiatric team made the recommendation to start benztropine 1 mg given twice a day, delivered via the dobhoff tube to treat both the parkinsonism and dystonia. The following day Mr. W failed a repeat swallow study and was no longer allowed to receive anything orally.

Mild icterus and jaundice were noted on physical examination along with transaminitis and elevated bilirubin. He developed a fever. Thirteen days after transfer to the medical floor, blood cultures revealed Klebsiella septicemia. Benztropine was discontinued at this time because of concern the medication was causing or exacerbating the fever. While being treated for Klebsiella sepsis, the psychiatry team addressed his continued hypophonia, inability to ambulate, masked facies, and neck dystonia with diphenhydramine 50 mg given intramuscular (IM) twice per day.

Mr. W developed several more iatrogenic complications near this time, including urinary tract infection septicemia and acute hypoxic respiratory failure with lung infiltrate on X-ray, requiring ventilator support. His clinical status led to a number of transfers in and out of the medical intensive care unit (MICU). During this time, his parkinsonism symptoms were managed through a combination of carbidopa and levodopa and amantadine. Cervical dystonia was managed with botulism toxin injections. Mr. W spent 6 weeks in the MICU until the decision was made to terminate life support, and he was taken off the ventilator. He died shortly thereafter. Autopsy findings suggested that Mr. W had severe Alzheimer disease.

Discussion

Following the IM injection of paliperidone palmitate, Mr. W had a complicated hospital stay resulting in his demise from sepsis and multiorgan failure. Severe immobilization, rigidity, and dystonia prevented Mr. W from conducting activities of daily living, which resulted in invasive interventions, such as continued foley catheterization. His sepsis was likely secondary to aspiration, catheterization, and eventual ventilation—all iatrogenic complications. Previous estimates in the U.S. have suggested a total of 225,000 deaths per year from iatrogenic causes.⁸

There are several areas of concern. Clearly, Mr. W had severe illness that greatly affected his life. He was estranged from family and had endured a 2-decade period of homelessness. He deserved effective treatment for his psychiatric illness to relieve his suffering. His long period of mental illness without effective treatment very likely biased the initial treatment team toward an aggressive approach.

Fragmented Care

The prolonged hospital stay and multiple complications directly led to fragmentation in Mr. W’s care. He was hospitalized for months on 3 different main services: psychiatry, medicine, and the MICU. Even when he remained on the same service, the primary members of his treatment team changed every few weeks. Many different specialties were consulted and reconsulted. Members of the specialty consult teams changed throughout the hospitalization as well. Given the nature of the local clinical administration, Mr. W likely received the most consistent team members from the attendings on the psychiatry consult-liaison service (who do not rotate) and from a local subspecialty delirium consult team (all members stay consistent except pharmacy residents).

Documentation of clinical reasoning behind treatment decisions was not ideal and occasionally lacking. This led to a tendency to “reinvent the wheel” with Mr. W’s treatment approach every few weeks. It was not until Mr. W had spent a significant amount of time on the medical service that an interdisciplinary treatment team meeting involving medicine, psychiatry, nursing, delirium, and neurology experts occurred. Although the interdisciplinary meeting helped by reviewing the hospital course, agreeing on a likely cause of the symptoms, and creating a treatment plan going forward, Mr. W was not able to recover.

Even when team members were stable, communication in a timely fashion did not always occur. At several points, expert recommendations were delayed by a day or more. Difficulties in treatment implementation were not communicated back to the specialty teams. The most significant example was a delay in recognition when Mr. W could no longer take oral pills secondary to the parkinsonism. Many days passed before an alternative liquid or dissolved medication was recommended on 2 separate occasions.

Subspecialty Consult

Addressing these documentation, communication, and transition challenges is neither easy nor unique to this large rural VA medical center. The authors have attempted to address this in the local system with the creation of a delirium team subspecialty consult service. Team members do not rotate and are able to follow patients throughout their hospital course. At the time of Mr. W’s hospitalization, the team included representatives from nursing, psychiatry, and occasionally pharmacy. Since then, it has expanded to include geriatrics and medicine. In addition to delirium being a marker for complex patients at risk for hospital complications, medical reasons for an extended length of stay could serve as a trigger for a referral to such a team of experts. In Mr. W’s case, that could have led to interdisciplinary consultation up to 2 months before it occurred. This may have led to a much better outcome.

Secondary parkinsonism is most notable with the typical antipychotics. The prevalence can vary between 50% and 75% and may be higher within the elderly population. However, all antipsychotics have a chance of demonstrating EPS. Risperidone has a low incidence at low doses; studies have shown dose-related parkinsonism at doses of 2 to 6 mg/d. Significant risk of parkinsonism is further exacerbated when drug-drug interactions are considered.⁹ Concurrently receiving 2 antipsychotics, olanzapine and paliperidone, initially caused the EPS. The veteran’s cerebral atrophy from significant malnutrition related to chronic homelessness, and the presence of Alzheimer disease only identified postmortem exacerbated this AE. Further complicating the management of the EPS, paliperidone palmitate has a long half-life of 25 to 49 days.⁹ Simply discontinuing the medication did not remove it from Mr. W’s system. Paliperidone would have continued to be present for months.

Conclusion

In this case, aggressive changes in the antipsychotic medications in a short period led to Mr. W effectively having 3 different agents in his system at the same time. This significantly elevated his risk of AEs, including parkinsonism. The clinician must be vigilant to further recognize the initial symptoms of parkinsonism on clinical presentation. Administration of clinical scales, such as the Simpson-Angus Extrapyramidal Side Effect, can help in these situations.¹⁰ Malnutrition and increased age can predispose patients to neurolepticAEs, so treatment teams should exercise caution when administering antipsychotics in such a population. Pharmacokinetic changes in all major organ systems from aging result in higher and more variable drug concentrations. This leads to an increased sensitivity to drugs and AEs.⁹

Given the increasing geriatric patient population in the U.S., treating mania in the elderly will become more common. Providers should carefully consider the risks vs benefit ratio for each individual because a serious adverse reaction may result in detrimental consequences. Even with severe symptoms leading to a bias toward an aggressive approach, it may be better to “start low and go slow.” Early inclusion of interdisciplinary expertise should be sought in complex cases.

Many patients with psychiatric illness have difficulty with medication adherence. Patients with impaired reality testing especially are at risk.

Keck and McElroy evaluated 141 patients who were initially hospitalized for bipolar disorder prospectively over 1 year to assess adherence with medication. During the follow-up period, 71 patients (51%) were partially or totally nonadherent with medication as prescribed. The most commonly cited reason for nonadherence was denial of need.¹

Clinicians and patients face additional challenges due to the deleterious effects of relapse in the setting of both schizophrenia and bipolar disorder. Almost all oral antipsychotic or mood stabilizer medications require a minimum dosing schedule to effectively treat these disorders, and some of these oral medications require regular laboratory monitoring. Moreover, some of the agents can have serious adverse effects (AEs), such as seizure or withdrawal, if stopped abruptly. Social support from family or friends may improve adherence, but many psychiatric outpatients have a smaller social support network than do patients without psychiatric illnesses.²

Long-acting injectable (LAI) antipsychotics have been available for the past 40 years. These medications have provided clinicians with an additional option for patients with schizophrenia or bipolar disorder who are nonadherent to their medication treatment plans or who desire an administration choice that is more convenient than daily oral pills.^3-7 Some clinical practice guidelines recommend considering LAIs as a maintenance treatment for schizophrenia.⁵ Like the rest of the pharmacopoeia, these formulations have AEs, such as extrapyramidal symptoms (EPS), weight gain, and metabolic syndrome.¹ The longer half-life of these drugs may make such effects difficult to reverse.

This article presents a case of the use of depot formulation paliperidone palmitate in an elderly patient with bipolar disorder who was previously on high-dose oral second generation antipsychotics. He developed severe parkinsonism during a protracted hospitalization that ended in death.

Case Presentation

Mr. W was a 68-year-old homeless white male with a history of coronary artery disease status-post coronary artery bypass surgery, obstructive sleep apnea, and bipolar 1 disorder who presented to a large rural VAMC emergency department (ED) as a transfer from an outside hospital (OSH). He originally presented at the OSH for vomiting and diarrhea, but while there, he was placed under involuntary psychiatric commitment. The involuntary commitment form noted him to be tangential and disorganized; he was found walking about the ED without clothes. During the initial psychiatry interview, the clinician noted a disorganized thought process. When asked about circumstances leading to admission, he stated he was “a scuba diver, pilot, actor, submarine commander.” He also reported he had given “seminars to 6,000 people,” he held a psychology degree, and he came from a family that owned part of the island of Kodiak, Alaska. Mr. W stated he had no mental health history and believed psychiatry was witchcraft. He reported having no hallucinations and stated he heard the voice of god. He also reported to have met god multiple times and to have been married to a supermodel.

Mr. W’s chart demonstrated a history of mental illness over 30 years and that he previously was prescribed psychiatric medications. He had multiple inpatient psychiatric admissions with grandiose ideations, disorganized behaviors, and hypersexuality. He had been prescribed quetiapine, divalproex, lithium, carbamazepine, and lorazepam. He was formally diagnosed in the past with bipolar 1 disorder. There also was a family history of psychiatric illness. His mother had received electroconvulsive therapy, and both parents had alcohol substance use disorder.

Mr. W had been homeless for 20 years and had several psychiatric admissions during this period. Mr. W also had chronic difficulty with obtaining food and taking medications as prescribed. Sometimes he would only be able to eat 1 to 2 meals per day. He often changed location and had lived in at least 7 different states. Currently, he was estranged from his family. About 19 years ago, his sister reported that the veteran had told her that he was Jesus Christ, per clinical records. His estranged sister’s statement was corroborated by past psychology consult records citing episodes of the patient hearing god 30 and 26 years before the current admission. His second ex-wife cited inappropriate sexual behavior in front of their children. He had difficulty in school, failed at least 2 grades, and joined the U.S. Navy in tenth grade. A Neurobehavioral Cognitive Status Examination given 19 years ago showed mild impairment on attention and severe impairment in memory.

The physical examination on presentation to the OSH was unremarkable. Mr. W did not cooperate with formal neurocognitive testing, and he consistently made errors during orientation testing. Complete blood count from a OSH ED laboratory test was remarkable for a mild pancytopenia with a leukocyte count of 3,100 cells/mcL, hemoglobin 13.1 g/dL, and hematocrit 38.4%. Red cell distribution width was within normal limits at 13.5%. Stool cultures showed normal fecal flora and no salmonella, shigella, or campylobacter. Thyroid-stimulating hormone (TSH) was slightly elevated at 5.32 U/mL. An electrocardiogram showed a QTc interval of 412 ms. A computerized tomography scan of his head showed no acute intracranial abnormality along with chronic ischemic changes in the brain (Table 1). Presumed cause of his nausea and diarrhea was viral gastroenteritis likely acquired at a homeless shelter.

Once stabilized, Mr. W was admitted to the VA hospital inpatient psychiatry unit under involuntary commitment for acute mania. Risperidone 0.25 mg orally twice a day was started for mood stabilization and psychosis along with trazodone 50 mg orally as needed for insomnia. Despite upward titration and change in frequency of the risperidone dose, Mr. W’s manic episode persisted. He remained on the psychiatric floor for 2 months (Figure). His TSH and free T4 were monitored during his stay, and levothyroxine was started. Risperidone was titrated to 8 mg/d. Mr. W’s Young Mania Rating Scale (YMRS) score decreased from 30 to 24. Mr. W had a mild improvement in irritability and speech rate but little change in elevated mood and delusional content.

He continued to endorse “speaking to god 16 times” even at the highest risperidone dose. The treatment team prescribed dissolvable risperidone tablets secondary to diversion concerns. In addition, the team added benztropine 0.5 mg once a day after observing a stooped posture and decreased arm swing. Mr. W noted risperidone made him “lethargic” and that his “body did not need” it. After 1 month of treatment with risperidone, the treatment team decided to cross taper the veteran from risperidone to a combination of olanzapine and divalproex secondary to inadequate treatment response.

The inpatient team started Mr. W on oral disintegrating tablets of olanzapine 5 mg once a day, and oral divalproex 1,000 mg once a day. An intramuscular backup of olanzapine was made available if oral medication was refused. Divalproex was titrated to 1,250 mg once a day to target a serum level of 61.7 µg/mL, and olanzapine was titrated to 10 mg once a day. After 9 days, the veteran showed moderate improvement in mania symptoms with a YMRS score < 20, indicating the absence of mania. However, the veteran made it very clear that he would stop taking the prescribed medication on discharge. The team elected to initiate a LAI.

The veteran received his first injection of the LAI psychiatric medication paliperidone palmitate 234 mg and a second 156-mg injection of the same medication 1 week later as per loading protocol. He was concurrently on daily oral divalproex 1,250 mg and olanzapine 10 mg. Mr. W continued to note he felt sedated during this period; his sedation worsened after the second injection. He also began to forget the location of his room and developed mumbled speech. His gait deteriorated to where he required a walker 6 days after injection and a wheelchair 3 days later. He became incontinent of urine and feces. Mr. W exhibited masked facies with severe drooling. This eventually progressed to difficulty swallowing. At the advice of speech pathology, he was downgraded to a pureed and nectar-thick liquid diet. He required assistance with meals.

Because of his sedation and parkinsonism symptoms, he was tapered off both olanzapine and divalproex. His last dose of olanzapine was on the date of his first injection and last dose of divalproex was 15 days after the second injection. The benztropine, which was originally given to counteract the effects of risperidone monotherapy, was discontinued over concern of anticholinergic load and sedation. The neurology consultant recommended carbidopa 25 mg and levodopa 100 mg 3 times per day for treatment of parkinsonism symptoms. Mr. W was only able to take 1 dose because of trouble swallowing. Twenty days after his second injection, a rapid response team (local clinical team 1 step below a code team) was called as Mr. W was unusually lethargic and unable to eat. He was then transferred to the medical floor.

While on the medical floor, dobhoff tube access was established for nutrition and to allow administration of carbidopa and levodopa. Mr. W could still speak at this time and was distraught. He stated, “I don’t know why god would do this to me.” Further workup was performed to look for other etiologies of the patient’s change in status. Creatinine kinase testing, lumbar puncture with cerebral spinal fluid (CSF) bacterial culture, CSF cryptococcal testing, and syphilis antigens were all negative. Magnetic resonance imaging of the brain demonstrated diffuse cerebral atrophy with widened cistern and sulci resulting in ex vacuo dilatation.

Neurology thought that the ventriculomegaly did not have features of normal pressure hydrocephalus and was secondary to chronic ischemic demyelination caused by chronic malnutrition. During follow-up visits, the veteran was less and less verbal. It progressed to where he answered questions only in grunts. Eight days after transfer to the medical floor, Mr. W was noted to have his neck locked in a laterally rotated position with clonus of the sternocleidomastoid. Due to concern about possibility of neck dystonia and the poor adherence of the patient with carbidopa and levodopa given orally, the psychiatric team made the recommendation to start benztropine 1 mg given twice a day, delivered via the dobhoff tube to treat both the parkinsonism and dystonia. The following day Mr. W failed a repeat swallow study and was no longer allowed to receive anything orally.

Mild icterus and jaundice were noted on physical examination along with transaminitis and elevated bilirubin. He developed a fever. Thirteen days after transfer to the medical floor, blood cultures revealed Klebsiella septicemia. Benztropine was discontinued at this time because of concern the medication was causing or exacerbating the fever. While being treated for Klebsiella sepsis, the psychiatry team addressed his continued hypophonia, inability to ambulate, masked facies, and neck dystonia with diphenhydramine 50 mg given intramuscular (IM) twice per day.

Mr. W developed several more iatrogenic complications near this time, including urinary tract infection septicemia and acute hypoxic respiratory failure with lung infiltrate on X-ray, requiring ventilator support. His clinical status led to a number of transfers in and out of the medical intensive care unit (MICU). During this time, his parkinsonism symptoms were managed through a combination of carbidopa and levodopa and amantadine. Cervical dystonia was managed with botulism toxin injections. Mr. W spent 6 weeks in the MICU until the decision was made to terminate life support, and he was taken off the ventilator. He died shortly thereafter. Autopsy findings suggested that Mr. W had severe Alzheimer disease.

Discussion

Following the IM injection of paliperidone palmitate, Mr. W had a complicated hospital stay resulting in his demise from sepsis and multiorgan failure. Severe immobilization, rigidity, and dystonia prevented Mr. W from conducting activities of daily living, which resulted in invasive interventions, such as continued foley catheterization. His sepsis was likely secondary to aspiration, catheterization, and eventual ventilation—all iatrogenic complications. Previous estimates in the U.S. have suggested a total of 225,000 deaths per year from iatrogenic causes.⁸

There are several areas of concern. Clearly, Mr. W had severe illness that greatly affected his life. He was estranged from family and had endured a 2-decade period of homelessness. He deserved effective treatment for his psychiatric illness to relieve his suffering. His long period of mental illness without effective treatment very likely biased the initial treatment team toward an aggressive approach.

Fragmented Care

The prolonged hospital stay and multiple complications directly led to fragmentation in Mr. W’s care. He was hospitalized for months on 3 different main services: psychiatry, medicine, and the MICU. Even when he remained on the same service, the primary members of his treatment team changed every few weeks. Many different specialties were consulted and reconsulted. Members of the specialty consult teams changed throughout the hospitalization as well. Given the nature of the local clinical administration, Mr. W likely received the most consistent team members from the attendings on the psychiatry consult-liaison service (who do not rotate) and from a local subspecialty delirium consult team (all members stay consistent except pharmacy residents).

Documentation of clinical reasoning behind treatment decisions was not ideal and occasionally lacking. This led to a tendency to “reinvent the wheel” with Mr. W’s treatment approach every few weeks. It was not until Mr. W had spent a significant amount of time on the medical service that an interdisciplinary treatment team meeting involving medicine, psychiatry, nursing, delirium, and neurology experts occurred. Although the interdisciplinary meeting helped by reviewing the hospital course, agreeing on a likely cause of the symptoms, and creating a treatment plan going forward, Mr. W was not able to recover.

Even when team members were stable, communication in a timely fashion did not always occur. At several points, expert recommendations were delayed by a day or more. Difficulties in treatment implementation were not communicated back to the specialty teams. The most significant example was a delay in recognition when Mr. W could no longer take oral pills secondary to the parkinsonism. Many days passed before an alternative liquid or dissolved medication was recommended on 2 separate occasions.

Subspecialty Consult

Addressing these documentation, communication, and transition challenges is neither easy nor unique to this large rural VA medical center. The authors have attempted to address this in the local system with the creation of a delirium team subspecialty consult service. Team members do not rotate and are able to follow patients throughout their hospital course. At the time of Mr. W’s hospitalization, the team included representatives from nursing, psychiatry, and occasionally pharmacy. Since then, it has expanded to include geriatrics and medicine. In addition to delirium being a marker for complex patients at risk for hospital complications, medical reasons for an extended length of stay could serve as a trigger for a referral to such a team of experts. In Mr. W’s case, that could have led to interdisciplinary consultation up to 2 months before it occurred. This may have led to a much better outcome.

Secondary parkinsonism is most notable with the typical antipychotics. The prevalence can vary between 50% and 75% and may be higher within the elderly population. However, all antipsychotics have a chance of demonstrating EPS. Risperidone has a low incidence at low doses; studies have shown dose-related parkinsonism at doses of 2 to 6 mg/d. Significant risk of parkinsonism is further exacerbated when drug-drug interactions are considered.⁹ Concurrently receiving 2 antipsychotics, olanzapine and paliperidone, initially caused the EPS. The veteran’s cerebral atrophy from significant malnutrition related to chronic homelessness, and the presence of Alzheimer disease only identified postmortem exacerbated this AE. Further complicating the management of the EPS, paliperidone palmitate has a long half-life of 25 to 49 days.⁹ Simply discontinuing the medication did not remove it from Mr. W’s system. Paliperidone would have continued to be present for months.

Conclusion

In this case, aggressive changes in the antipsychotic medications in a short period led to Mr. W effectively having 3 different agents in his system at the same time. This significantly elevated his risk of AEs, including parkinsonism. The clinician must be vigilant to further recognize the initial symptoms of parkinsonism on clinical presentation. Administration of clinical scales, such as the Simpson-Angus Extrapyramidal Side Effect, can help in these situations.¹⁰ Malnutrition and increased age can predispose patients to neurolepticAEs, so treatment teams should exercise caution when administering antipsychotics in such a population. Pharmacokinetic changes in all major organ systems from aging result in higher and more variable drug concentrations. This leads to an increased sensitivity to drugs and AEs.⁹

Given the increasing geriatric patient population in the U.S., treating mania in the elderly will become more common. Providers should carefully consider the risks vs benefit ratio for each individual because a serious adverse reaction may result in detrimental consequences. Even with severe symptoms leading to a bias toward an aggressive approach, it may be better to “start low and go slow.” Early inclusion of interdisciplinary expertise should be sought in complex cases.

Photo courtesy of NIH

Primary care may not meet the healthcare needs of cancer survivors in the US, according to research published in JAMA Internal Medicine.

Researchers examined 12 advanced primary care practices selected from a national registry of “workforce innovators” and found that none of these practices had a comprehensive survivorship care program in place.

In addition, there were 3 main barriers to survivorship care—not treating cancer survivors as a distinct population, limitations of electronic health records, and a lack of information and guidance for clinicians.

“This is troubling because these are highly innovative practices that have a national reputation,” said study author Benjamin Crabtree, PhD, of Rutgers Robert Wood Johnson Medical School in New Brunswick, New Jersey.

Dr Crabtree and his colleagues evaluated survivorship care* at the 12 practices, which were based in Colorado, Illinois, Maine, New York, Pennsylvania, and Washington.

Over nearly 2 years, the team spent 10 to 12 days observing each of the practices and interviewing clinicians and administrators.

In this way, the researchers identified 3 main barriers to integrating survivorship care into primary medicine.

Barrier 1

The first barrier was that clinicians did not treat cancer survivors as a distinct population or clinical category.

“There is no diagnosis code for ‘cancer survivor’ that can be entered into the medical record, which is important if you want physicians to pay attention,” Dr Crabtree said.

Some of the clinicians interviewed said their care was comprehensive enough to address the needs of all patients. Other clinicians did not understand what survivorship care entails.

Barrier 2

The second barrier was that electronic health record systems didn’t support survivorship care.

Clinicians reported an inability to identify patients with a history of cancer. Even if a patient’s cancer history was included in his or her record, it might take searching through multiple screens to find the information.

In addition, medical records were sometimes lost as patients changed clinicians over the years, which left it up to patients to report their cancer histories.

Barrier 3

The third barrier was that clinicians did not receive adequate information or guidance for follow-up care of cancer survivors.

Although some of the practices received cancer-related information about their patients, it was considered “inadequate” or “not actionable.”

Clinicians expressed concerns about their knowledge gaps in cancer care and the need to monitor changing information in oncology.

“There is nothing in the residency curriculum about cancer survivorship,” Dr Crabtree said. “There is also nothing in Continuing Medical Education courses. It’s just not there.”

Dr Crabtree and his colleagues believe these barriers must be addressed so that comprehensive cancer survivorship services can move to the forefront of primary care.

* Survivorship care includes checking for cancer recurrence, monitoring long-term effects of radiation and chemotherapy, and assessing a patient’s psychological well-being.

Photo courtesy of NIH

Primary care may not meet the healthcare needs of cancer survivors in the US, according to research published in JAMA Internal Medicine.

Researchers examined 12 advanced primary care practices selected from a national registry of “workforce innovators” and found that none of these practices had a comprehensive survivorship care program in place.

In addition, there were 3 main barriers to survivorship care—not treating cancer survivors as a distinct population, limitations of electronic health records, and a lack of information and guidance for clinicians.

“This is troubling because these are highly innovative practices that have a national reputation,” said study author Benjamin Crabtree, PhD, of Rutgers Robert Wood Johnson Medical School in New Brunswick, New Jersey.

Dr Crabtree and his colleagues evaluated survivorship care* at the 12 practices, which were based in Colorado, Illinois, Maine, New York, Pennsylvania, and Washington.

Over nearly 2 years, the team spent 10 to 12 days observing each of the practices and interviewing clinicians and administrators.

In this way, the researchers identified 3 main barriers to integrating survivorship care into primary medicine.

Barrier 1

The first barrier was that clinicians did not treat cancer survivors as a distinct population or clinical category.

“There is no diagnosis code for ‘cancer survivor’ that can be entered into the medical record, which is important if you want physicians to pay attention,” Dr Crabtree said.

Some of the clinicians interviewed said their care was comprehensive enough to address the needs of all patients. Other clinicians did not understand what survivorship care entails.

Barrier 2

The second barrier was that electronic health record systems didn’t support survivorship care.

Clinicians reported an inability to identify patients with a history of cancer. Even if a patient’s cancer history was included in his or her record, it might take searching through multiple screens to find the information.

In addition, medical records were sometimes lost as patients changed clinicians over the years, which left it up to patients to report their cancer histories.

Barrier 3

The third barrier was that clinicians did not receive adequate information or guidance for follow-up care of cancer survivors.

Although some of the practices received cancer-related information about their patients, it was considered “inadequate” or “not actionable.”

Clinicians expressed concerns about their knowledge gaps in cancer care and the need to monitor changing information in oncology.

“There is nothing in the residency curriculum about cancer survivorship,” Dr Crabtree said. “There is also nothing in Continuing Medical Education courses. It’s just not there.”

Dr Crabtree and his colleagues believe these barriers must be addressed so that comprehensive cancer survivorship services can move to the forefront of primary care.

* Survivorship care includes checking for cancer recurrence, monitoring long-term effects of radiation and chemotherapy, and assessing a patient’s psychological well-being.

Photo courtesy of NIH

Primary care may not meet the healthcare needs of cancer survivors in the US, according to research published in JAMA Internal Medicine.

Researchers examined 12 advanced primary care practices selected from a national registry of “workforce innovators” and found that none of these practices had a comprehensive survivorship care program in place.

In addition, there were 3 main barriers to survivorship care—not treating cancer survivors as a distinct population, limitations of electronic health records, and a lack of information and guidance for clinicians.

“This is troubling because these are highly innovative practices that have a national reputation,” said study author Benjamin Crabtree, PhD, of Rutgers Robert Wood Johnson Medical School in New Brunswick, New Jersey.

Dr Crabtree and his colleagues evaluated survivorship care* at the 12 practices, which were based in Colorado, Illinois, Maine, New York, Pennsylvania, and Washington.

Over nearly 2 years, the team spent 10 to 12 days observing each of the practices and interviewing clinicians and administrators.

In this way, the researchers identified 3 main barriers to integrating survivorship care into primary medicine.

Barrier 1

The first barrier was that clinicians did not treat cancer survivors as a distinct population or clinical category.

“There is no diagnosis code for ‘cancer survivor’ that can be entered into the medical record, which is important if you want physicians to pay attention,” Dr Crabtree said.

Some of the clinicians interviewed said their care was comprehensive enough to address the needs of all patients. Other clinicians did not understand what survivorship care entails.

Barrier 2

The second barrier was that electronic health record systems didn’t support survivorship care.

Clinicians reported an inability to identify patients with a history of cancer. Even if a patient’s cancer history was included in his or her record, it might take searching through multiple screens to find the information.

In addition, medical records were sometimes lost as patients changed clinicians over the years, which left it up to patients to report their cancer histories.

Barrier 3

The third barrier was that clinicians did not receive adequate information or guidance for follow-up care of cancer survivors.

Although some of the practices received cancer-related information about their patients, it was considered “inadequate” or “not actionable.”

Clinicians expressed concerns about their knowledge gaps in cancer care and the need to monitor changing information in oncology.

“There is nothing in the residency curriculum about cancer survivorship,” Dr Crabtree said. “There is also nothing in Continuing Medical Education courses. It’s just not there.”

Dr Crabtree and his colleagues believe these barriers must be addressed so that comprehensive cancer survivorship services can move to the forefront of primary care.

* Survivorship care includes checking for cancer recurrence, monitoring long-term effects of radiation and chemotherapy, and assessing a patient’s psychological well-being.

This past August, President Trump, with the advice and consent of the United States Senate, nominated Indiana Health Commissioner Jerome M. Adams, MD, MPH, as the nation’s 20th Surgeon General (SG). As the country’s “doctor,” the SG has access to the best available scientific information to advise Americans of ways to improve their health and decrease risk for illness and injury. Overseen by the Office of the Assistant Secretary for Health, the Office of the Surgeon General has no budget or line authority. As a political appointee, the SG ranks three levels below a presidential cabinet member and reports to an assistant health secretary.¹

The SG nominally oversees the US Public Health Service Commissioned Corps, an exclusive group of more than 6,700 public health professionals working throughout the federal government with the mission to protect, promote, and advance the health of our nation.² In 2010, under the Affordable Care Act, the SG was designated as Chair of the National Prevention Council, which coordinates and leads 20 executive departments encouraging prevention, wellness, and health promotion activities.

Past SGs, during their time in office, have quietly gone about their duties, although some have used their platform to raise awareness of specific public health concerns. C. Everett Koop (a Reagan appointee) is among the most-remembered SGs, thanks in part to his use of the media to promote his causes, specifically smoking cessation and AIDS prevention. Newly appointed Dr. Adams, an anesthesiologist by training, is known for his focus on the opioid epidemic, tobacco use, and infant mortality.

As we’ve seen over the years, the limitations of the SG’s role equate to a mixed bag of “results.” For every C. Everett Koop (whether you agree with his views or not, he was prolific!), there are several SGs who came and went from office without making a blip on the public’s radar. Since health care remains at the forefront of our national conversation, the burning question is: If you were a consultant to the SG, which health issues would you prioritize?

I posed this question to 30 of my PA and NP colleagues. While certainly not an official survey—rather, a straw poll—I was nonetheless surprised by the overlap in responses. Here are some of the highlights.

Substance abuse/opioid crisis. Globally, one in every eight deaths result from the use of tobacco, alcohol, and other drugs. According to Humphreys et al, the implications of addiction are clear: It will do massive and increasing damage to humanity if not addressed emergently and at the source.³ But to do so, we must understand the root cause. Neuroscientific research has shown that repeated addictive drug use can rewire the brain’s motivational and reward circuits and influence decision-making.³

This is evidenced by the startling fact that every day, an average of 91 Americans die of opioid overdose.³ In March, the Director-General of the World Health Organization called for more scientifically informed public policies regarding addiction.⁴ The President’s Commission on Combating Drug Addiction and the Opioid Crisis released a preliminary report in August recommending next steps, which included the declaration of a federal state of emergency.⁵

Mental health. As you may recall from my December 2016 editorial, mental health is a forgotten facet of primary care—and one that is imperative to address.⁶ Only 43% of family physicians in this country provide mental health care; furthermore, half of Americans with mental health conditions go without essential care, and those with intellectual and developmental disabilities are significantly underserved.⁶ Perhaps increased efforts to attend to mental health in primary care will subsequently reduce addiction and substance abuse rates, resulting in a physically and mentally healthier America.

Oral health. Dr. Koop was known for his quote, “You can’t be healthy without good oral health.” Unfortunately, the major challenge expressed in Oral Health in America: A Report of the Surgeon General—“not all Americans have achieved the same level of oral health and well-being”—is as relevant today as it was when the report was released in 2000.⁷ We must therefore accelerate efforts toward achieving this goal. We must also address the need for a more diverse and well-distributed oral health workforce.

The CDC Division of Oral Health has made oral health an integral component of public health programs, with a goal of eliminating disparities and improving oral health for all. Continued investment in research, such as that undertaken by the National Institute of Dental and Craniofacial Research Centers for Research to Reduce Disparities in Oral Health, is critical.⁸ Lastly, we must continue to expand initiatives to prevent tobacco use and promote better dietary choices.

Obesity. Literature on the health consequences of obesity in both adults and children has increased exponentially in recent decades, due to the condition’s alarming prevalence in the US and other industrialized countries. The CDC reports significant racial and ethnic disparities in obesity, specifically among Hispanics/Latinos compared to non-Hispanic whites. Because obesity significantly contributes to acute and chronic diseases and has a direct relationship to morbidity and mortality, public health officials should target health prevention messages and interventions to those populations with the greatest need.⁹

Kidney disease. An estimated 31 million people in the US have chronic kidney disease (CKD), and it is the eighth leading cause of death in this country. Shockingly, 9 out of 10 people who have stage 3 CKD are not even aware they have it.¹⁰ The cost of CKD in the US is extortionate; research in this area is horrifically underfunded compared to that for other chronic diseases. The entire NIH budget for CKD is $31 billion, while the expense to the patient population is $32 billion—and every five minutes, someone’s kidneys fail.¹¹

The seemingly obvious question is, what can we do to prevent CKD? As far back as 1948, SG Thomas Parran Jr. advocated for preventive and curative services.¹² Alas, I recently came across an excellent poem by Joseph Malins (circa 1855) that speaks volumes about prevention versus cure (see box).

Environmental threats/emerging viruses. Particular attention should be paid to newly identified infectious agents, both locally and internationally, to prevent public health problems—for example, the Zika virus epidemic. In 1896, William Osler said, “Humanity has but three great enemies: infection, famine, and war; of these, by far the greatest, by far the most terrible is infection.”¹³ We know the factors that contribute to the emergence of new infections: the evolution of pathogenic infectious agents (microbial adaptation and change), development of drug resistance, and vector resistance to pesticides. Other important factors include climate and changing ecosystems, economic development and land use (eg, urbanization, deforestation), and technology and industry (eg, food processing and handling).¹⁴

Access to health care. Last but certainly not least, every respondent emphasized that we need to prioritize access to health care and eliminate socioeconomic disparities. But when we recognize that these disparities exist across all populations, we see that this is not an easy task. Lack of health insurance, lack of financial resources, irregular sources of care, legal obstacles, structural barriers, lack of health care providers, language barriers, socioeconomic disparity, and age are all contributing factors that are also obstacles.¹⁵ But in order for any of the previously discussed changes in health care to be influential, they must be accessible.

And so I open the floor to you, colleagues: What do you think should be done to improve access to health care? What are your pressing public health issues? Share your thoughts with me at [email protected].

This past August, President Trump, with the advice and consent of the United States Senate, nominated Indiana Health Commissioner Jerome M. Adams, MD, MPH, as the nation’s 20th Surgeon General (SG). As the country’s “doctor,” the SG has access to the best available scientific information to advise Americans of ways to improve their health and decrease risk for illness and injury. Overseen by the Office of the Assistant Secretary for Health, the Office of the Surgeon General has no budget or line authority. As a political appointee, the SG ranks three levels below a presidential cabinet member and reports to an assistant health secretary.¹

The SG nominally oversees the US Public Health Service Commissioned Corps, an exclusive group of more than 6,700 public health professionals working throughout the federal government with the mission to protect, promote, and advance the health of our nation.² In 2010, under the Affordable Care Act, the SG was designated as Chair of the National Prevention Council, which coordinates and leads 20 executive departments encouraging prevention, wellness, and health promotion activities.

Past SGs, during their time in office, have quietly gone about their duties, although some have used their platform to raise awareness of specific public health concerns. C. Everett Koop (a Reagan appointee) is among the most-remembered SGs, thanks in part to his use of the media to promote his causes, specifically smoking cessation and AIDS prevention. Newly appointed Dr. Adams, an anesthesiologist by training, is known for his focus on the opioid epidemic, tobacco use, and infant mortality.

As we’ve seen over the years, the limitations of the SG’s role equate to a mixed bag of “results.” For every C. Everett Koop (whether you agree with his views or not, he was prolific!), there are several SGs who came and went from office without making a blip on the public’s radar. Since health care remains at the forefront of our national conversation, the burning question is: If you were a consultant to the SG, which health issues would you prioritize?

I posed this question to 30 of my PA and NP colleagues. While certainly not an official survey—rather, a straw poll—I was nonetheless surprised by the overlap in responses. Here are some of the highlights.

Substance abuse/opioid crisis. Globally, one in every eight deaths result from the use of tobacco, alcohol, and other drugs. According to Humphreys et al, the implications of addiction are clear: It will do massive and increasing damage to humanity if not addressed emergently and at the source.³ But to do so, we must understand the root cause. Neuroscientific research has shown that repeated addictive drug use can rewire the brain’s motivational and reward circuits and influence decision-making.³

This is evidenced by the startling fact that every day, an average of 91 Americans die of opioid overdose.³ In March, the Director-General of the World Health Organization called for more scientifically informed public policies regarding addiction.⁴ The President’s Commission on Combating Drug Addiction and the Opioid Crisis released a preliminary report in August recommending next steps, which included the declaration of a federal state of emergency.⁵

Mental health. As you may recall from my December 2016 editorial, mental health is a forgotten facet of primary care—and one that is imperative to address.⁶ Only 43% of family physicians in this country provide mental health care; furthermore, half of Americans with mental health conditions go without essential care, and those with intellectual and developmental disabilities are significantly underserved.⁶ Perhaps increased efforts to attend to mental health in primary care will subsequently reduce addiction and substance abuse rates, resulting in a physically and mentally healthier America.

Oral health. Dr. Koop was known for his quote, “You can’t be healthy without good oral health.” Unfortunately, the major challenge expressed in Oral Health in America: A Report of the Surgeon General—“not all Americans have achieved the same level of oral health and well-being”—is as relevant today as it was when the report was released in 2000.⁷ We must therefore accelerate efforts toward achieving this goal. We must also address the need for a more diverse and well-distributed oral health workforce.

The CDC Division of Oral Health has made oral health an integral component of public health programs, with a goal of eliminating disparities and improving oral health for all. Continued investment in research, such as that undertaken by the National Institute of Dental and Craniofacial Research Centers for Research to Reduce Disparities in Oral Health, is critical.⁸ Lastly, we must continue to expand initiatives to prevent tobacco use and promote better dietary choices.

Obesity. Literature on the health consequences of obesity in both adults and children has increased exponentially in recent decades, due to the condition’s alarming prevalence in the US and other industrialized countries. The CDC reports significant racial and ethnic disparities in obesity, specifically among Hispanics/Latinos compared to non-Hispanic whites. Because obesity significantly contributes to acute and chronic diseases and has a direct relationship to morbidity and mortality, public health officials should target health prevention messages and interventions to those populations with the greatest need.⁹

Kidney disease. An estimated 31 million people in the US have chronic kidney disease (CKD), and it is the eighth leading cause of death in this country. Shockingly, 9 out of 10 people who have stage 3 CKD are not even aware they have it.¹⁰ The cost of CKD in the US is extortionate; research in this area is horrifically underfunded compared to that for other chronic diseases. The entire NIH budget for CKD is $31 billion, while the expense to the patient population is $32 billion—and every five minutes, someone’s kidneys fail.¹¹

The seemingly obvious question is, what can we do to prevent CKD? As far back as 1948, SG Thomas Parran Jr. advocated for preventive and curative services.¹² Alas, I recently came across an excellent poem by Joseph Malins (circa 1855) that speaks volumes about prevention versus cure (see box).

Environmental threats/emerging viruses. Particular attention should be paid to newly identified infectious agents, both locally and internationally, to prevent public health problems—for example, the Zika virus epidemic. In 1896, William Osler said, “Humanity has but three great enemies: infection, famine, and war; of these, by far the greatest, by far the most terrible is infection.”¹³ We know the factors that contribute to the emergence of new infections: the evolution of pathogenic infectious agents (microbial adaptation and change), development of drug resistance, and vector resistance to pesticides. Other important factors include climate and changing ecosystems, economic development and land use (eg, urbanization, deforestation), and technology and industry (eg, food processing and handling).¹⁴

Access to health care. Last but certainly not least, every respondent emphasized that we need to prioritize access to health care and eliminate socioeconomic disparities. But when we recognize that these disparities exist across all populations, we see that this is not an easy task. Lack of health insurance, lack of financial resources, irregular sources of care, legal obstacles, structural barriers, lack of health care providers, language barriers, socioeconomic disparity, and age are all contributing factors that are also obstacles.¹⁵ But in order for any of the previously discussed changes in health care to be influential, they must be accessible.

And so I open the floor to you, colleagues: What do you think should be done to improve access to health care? What are your pressing public health issues? Share your thoughts with me at [email protected].

This past August, President Trump, with the advice and consent of the United States Senate, nominated Indiana Health Commissioner Jerome M. Adams, MD, MPH, as the nation’s 20th Surgeon General (SG). As the country’s “doctor,” the SG has access to the best available scientific information to advise Americans of ways to improve their health and decrease risk for illness and injury. Overseen by the Office of the Assistant Secretary for Health, the Office of the Surgeon General has no budget or line authority. As a political appointee, the SG ranks three levels below a presidential cabinet member and reports to an assistant health secretary.¹

The SG nominally oversees the US Public Health Service Commissioned Corps, an exclusive group of more than 6,700 public health professionals working throughout the federal government with the mission to protect, promote, and advance the health of our nation.² In 2010, under the Affordable Care Act, the SG was designated as Chair of the National Prevention Council, which coordinates and leads 20 executive departments encouraging prevention, wellness, and health promotion activities.

Past SGs, during their time in office, have quietly gone about their duties, although some have used their platform to raise awareness of specific public health concerns. C. Everett Koop (a Reagan appointee) is among the most-remembered SGs, thanks in part to his use of the media to promote his causes, specifically smoking cessation and AIDS prevention. Newly appointed Dr. Adams, an anesthesiologist by training, is known for his focus on the opioid epidemic, tobacco use, and infant mortality.

As we’ve seen over the years, the limitations of the SG’s role equate to a mixed bag of “results.” For every C. Everett Koop (whether you agree with his views or not, he was prolific!), there are several SGs who came and went from office without making a blip on the public’s radar. Since health care remains at the forefront of our national conversation, the burning question is: If you were a consultant to the SG, which health issues would you prioritize?

I posed this question to 30 of my PA and NP colleagues. While certainly not an official survey—rather, a straw poll—I was nonetheless surprised by the overlap in responses. Here are some of the highlights.

Substance abuse/opioid crisis. Globally, one in every eight deaths result from the use of tobacco, alcohol, and other drugs. According to Humphreys et al, the implications of addiction are clear: It will do massive and increasing damage to humanity if not addressed emergently and at the source.³ But to do so, we must understand the root cause. Neuroscientific research has shown that repeated addictive drug use can rewire the brain’s motivational and reward circuits and influence decision-making.³

This is evidenced by the startling fact that every day, an average of 91 Americans die of opioid overdose.³ In March, the Director-General of the World Health Organization called for more scientifically informed public policies regarding addiction.⁴ The President’s Commission on Combating Drug Addiction and the Opioid Crisis released a preliminary report in August recommending next steps, which included the declaration of a federal state of emergency.⁵

Mental health. As you may recall from my December 2016 editorial, mental health is a forgotten facet of primary care—and one that is imperative to address.⁶ Only 43% of family physicians in this country provide mental health care; furthermore, half of Americans with mental health conditions go without essential care, and those with intellectual and developmental disabilities are significantly underserved.⁶ Perhaps increased efforts to attend to mental health in primary care will subsequently reduce addiction and substance abuse rates, resulting in a physically and mentally healthier America.

Oral health. Dr. Koop was known for his quote, “You can’t be healthy without good oral health.” Unfortunately, the major challenge expressed in Oral Health in America: A Report of the Surgeon General—“not all Americans have achieved the same level of oral health and well-being”—is as relevant today as it was when the report was released in 2000.⁷ We must therefore accelerate efforts toward achieving this goal. We must also address the need for a more diverse and well-distributed oral health workforce.

The CDC Division of Oral Health has made oral health an integral component of public health programs, with a goal of eliminating disparities and improving oral health for all. Continued investment in research, such as that undertaken by the National Institute of Dental and Craniofacial Research Centers for Research to Reduce Disparities in Oral Health, is critical.⁸ Lastly, we must continue to expand initiatives to prevent tobacco use and promote better dietary choices.

Obesity. Literature on the health consequences of obesity in both adults and children has increased exponentially in recent decades, due to the condition’s alarming prevalence in the US and other industrialized countries. The CDC reports significant racial and ethnic disparities in obesity, specifically among Hispanics/Latinos compared to non-Hispanic whites. Because obesity significantly contributes to acute and chronic diseases and has a direct relationship to morbidity and mortality, public health officials should target health prevention messages and interventions to those populations with the greatest need.⁹

Kidney disease. An estimated 31 million people in the US have chronic kidney disease (CKD), and it is the eighth leading cause of death in this country. Shockingly, 9 out of 10 people who have stage 3 CKD are not even aware they have it.¹⁰ The cost of CKD in the US is extortionate; research in this area is horrifically underfunded compared to that for other chronic diseases. The entire NIH budget for CKD is $31 billion, while the expense to the patient population is $32 billion—and every five minutes, someone’s kidneys fail.¹¹

The seemingly obvious question is, what can we do to prevent CKD? As far back as 1948, SG Thomas Parran Jr. advocated for preventive and curative services.¹² Alas, I recently came across an excellent poem by Joseph Malins (circa 1855) that speaks volumes about prevention versus cure (see box).

Environmental threats/emerging viruses. Particular attention should be paid to newly identified infectious agents, both locally and internationally, to prevent public health problems—for example, the Zika virus epidemic. In 1896, William Osler said, “Humanity has but three great enemies: infection, famine, and war; of these, by far the greatest, by far the most terrible is infection.”¹³ We know the factors that contribute to the emergence of new infections: the evolution of pathogenic infectious agents (microbial adaptation and change), development of drug resistance, and vector resistance to pesticides. Other important factors include climate and changing ecosystems, economic development and land use (eg, urbanization, deforestation), and technology and industry (eg, food processing and handling).¹⁴

Access to health care. Last but certainly not least, every respondent emphasized that we need to prioritize access to health care and eliminate socioeconomic disparities. But when we recognize that these disparities exist across all populations, we see that this is not an easy task. Lack of health insurance, lack of financial resources, irregular sources of care, legal obstacles, structural barriers, lack of health care providers, language barriers, socioeconomic disparity, and age are all contributing factors that are also obstacles.¹⁵ But in order for any of the previously discussed changes in health care to be influential, they must be accessible.

And so I open the floor to you, colleagues: What do you think should be done to improve access to health care? What are your pressing public health issues? Share your thoughts with me at [email protected].

Even after several years on the market, only about half of cancer drug indications recently approved by the European Medicines Agency (EMA) had conclusive evidence that they can extend or improve quality of life, according to results of a retrospective cohort study.

With a median of 5.4 years of follow-up, significant improvements in overall survival or quality of life had been published for 35 of 68 (51%) cancer drug indications approved by the EMA, according to the report by Courtney Davis, MD, senior lecturer in the department of global health and social medicine, King’s College London, United Kingdom, and colleagues.

Furthermore, not all survival benefits were clinically meaningful, according to an analysis published in the report.

The dearth of evidence for survival or quality-of-life benefits has “negative implications” for both patients and public health, Dr. Davis and colleagues said in their article (BMJ 2017 Oct 5. doi:10.1136/bmj.j4530).

“When expensive drugs that lack clinically meaningful benefits are approved and paid for within publicly funded healthcare systems, individual patients can be harmed, important societal resources wasted, and the delivery of equitable and affordable care undermined,” they wrote.

Dr. Davis and associates systematically evaluated the evidence base for regulatory and scientific reports on 48 cancer drugs approved for 68 indications by the EMA between 2009-2013. Of those indications, 17 were for hematologic malignancies and 51 were for solid tumors.

Only 18 of 68 indications (26%) were supported by pivotal studies that had a primary outcome of overall survival, according to the investigators. That was an important finding for the investigators, who wrote that that EMA commonly accepts use of surrogate measures of drug benefit despite their own statements that overall survival is the “most persuasive outcome” in studies of new oncology drugs.

“To a large extent, regulatory evidence standards determine the clinical value of … new oncology drugs,” Dr. Davis and co-authors wrote. “Our study suggests these standards are failing to incentivize drug development that best meets the needs of patients, clinicians, and healthcare systems.”

The investigators also assessed the clinical value of reported improvements using the European Society for Medical Oncology-Magnitude of Clinical Benefit Scale (ESMO-MCBS). According to investigators, only 11 of the 23 drugs used to treat solid tumors (48%) reached the threshold for a meaningful survival benefit.

This report in BMJ echoes findings of an earlier study by Chul Kim, MD, and colleagues looking at cancer drugs approved by the U.S. Food and Drug Administration (FDA) between 2008 and 2012 (JAMA Intern Med. 2015;175(12):1992-4).

Dr. Kim, of the medical oncology service, National Cancer Institute, National Institutes of Health, Bethesda, Md., and colleagues found that 36 of 54 FDA approvals (67%) occurred with no evidence of survival or quality of life benefit. After a median of 4.4 years of follow-up, only 5 of those 36 (14%) had additional randomized study data that showed an improvement in overall survival, according to the published report.

The study was supported by Health Action International, which did not have a role in study design or data collection, analysis, or interpretation. The authors did not give financial disclosures.

Even after several years on the market, only about half of cancer drug indications recently approved by the European Medicines Agency (EMA) had conclusive evidence that they can extend or improve quality of life, according to results of a retrospective cohort study.

With a median of 5.4 years of follow-up, significant improvements in overall survival or quality of life had been published for 35 of 68 (51%) cancer drug indications approved by the EMA, according to the report by Courtney Davis, MD, senior lecturer in the department of global health and social medicine, King’s College London, United Kingdom, and colleagues.

Furthermore, not all survival benefits were clinically meaningful, according to an analysis published in the report.

The dearth of evidence for survival or quality-of-life benefits has “negative implications” for both patients and public health, Dr. Davis and colleagues said in their article (BMJ 2017 Oct 5. doi:10.1136/bmj.j4530).

“When expensive drugs that lack clinically meaningful benefits are approved and paid for within publicly funded healthcare systems, individual patients can be harmed, important societal resources wasted, and the delivery of equitable and affordable care undermined,” they wrote.

Dr. Davis and associates systematically evaluated the evidence base for regulatory and scientific reports on 48 cancer drugs approved for 68 indications by the EMA between 2009-2013. Of those indications, 17 were for hematologic malignancies and 51 were for solid tumors.

Only 18 of 68 indications (26%) were supported by pivotal studies that had a primary outcome of overall survival, according to the investigators. That was an important finding for the investigators, who wrote that that EMA commonly accepts use of surrogate measures of drug benefit despite their own statements that overall survival is the “most persuasive outcome” in studies of new oncology drugs.

“To a large extent, regulatory evidence standards determine the clinical value of … new oncology drugs,” Dr. Davis and co-authors wrote. “Our study suggests these standards are failing to incentivize drug development that best meets the needs of patients, clinicians, and healthcare systems.”

The investigators also assessed the clinical value of reported improvements using the European Society for Medical Oncology-Magnitude of Clinical Benefit Scale (ESMO-MCBS). According to investigators, only 11 of the 23 drugs used to treat solid tumors (48%) reached the threshold for a meaningful survival benefit.

This report in BMJ echoes findings of an earlier study by Chul Kim, MD, and colleagues looking at cancer drugs approved by the U.S. Food and Drug Administration (FDA) between 2008 and 2012 (JAMA Intern Med. 2015;175(12):1992-4).

Dr. Kim, of the medical oncology service, National Cancer Institute, National Institutes of Health, Bethesda, Md., and colleagues found that 36 of 54 FDA approvals (67%) occurred with no evidence of survival or quality of life benefit. After a median of 4.4 years of follow-up, only 5 of those 36 (14%) had additional randomized study data that showed an improvement in overall survival, according to the published report.

The study was supported by Health Action International, which did not have a role in study design or data collection, analysis, or interpretation. The authors did not give financial disclosures.

Even after several years on the market, only about half of cancer drug indications recently approved by the European Medicines Agency (EMA) had conclusive evidence that they can extend or improve quality of life, according to results of a retrospective cohort study.

With a median of 5.4 years of follow-up, significant improvements in overall survival or quality of life had been published for 35 of 68 (51%) cancer drug indications approved by the EMA, according to the report by Courtney Davis, MD, senior lecturer in the department of global health and social medicine, King’s College London, United Kingdom, and colleagues.

Furthermore, not all survival benefits were clinically meaningful, according to an analysis published in the report.

The dearth of evidence for survival or quality-of-life benefits has “negative implications” for both patients and public health, Dr. Davis and colleagues said in their article (BMJ 2017 Oct 5. doi:10.1136/bmj.j4530).

“When expensive drugs that lack clinically meaningful benefits are approved and paid for within publicly funded healthcare systems, individual patients can be harmed, important societal resources wasted, and the delivery of equitable and affordable care undermined,” they wrote.

Dr. Davis and associates systematically evaluated the evidence base for regulatory and scientific reports on 48 cancer drugs approved for 68 indications by the EMA between 2009-2013. Of those indications, 17 were for hematologic malignancies and 51 were for solid tumors.

Only 18 of 68 indications (26%) were supported by pivotal studies that had a primary outcome of overall survival, according to the investigators. That was an important finding for the investigators, who wrote that that EMA commonly accepts use of surrogate measures of drug benefit despite their own statements that overall survival is the “most persuasive outcome” in studies of new oncology drugs.

“To a large extent, regulatory evidence standards determine the clinical value of … new oncology drugs,” Dr. Davis and co-authors wrote. “Our study suggests these standards are failing to incentivize drug development that best meets the needs of patients, clinicians, and healthcare systems.”

The investigators also assessed the clinical value of reported improvements using the European Society for Medical Oncology-Magnitude of Clinical Benefit Scale (ESMO-MCBS). According to investigators, only 11 of the 23 drugs used to treat solid tumors (48%) reached the threshold for a meaningful survival benefit.

This report in BMJ echoes findings of an earlier study by Chul Kim, MD, and colleagues looking at cancer drugs approved by the U.S. Food and Drug Administration (FDA) between 2008 and 2012 (JAMA Intern Med. 2015;175(12):1992-4).

Dr. Kim, of the medical oncology service, National Cancer Institute, National Institutes of Health, Bethesda, Md., and colleagues found that 36 of 54 FDA approvals (67%) occurred with no evidence of survival or quality of life benefit. After a median of 4.4 years of follow-up, only 5 of those 36 (14%) had additional randomized study data that showed an improvement in overall survival, according to the published report.

The study was supported by Health Action International, which did not have a role in study design or data collection, analysis, or interpretation. The authors did not give financial disclosures.

LISBON – The investigational glucagon-like peptide (GLP)-1 receptor agonist semaglutide added to standard care for type 2 diabetes mellitus (T2DM) resulted in clinically significant weight loss over 2 years in the SUSTAIN-6 phase 3 trial.

Participants treated with semaglutide in the study lost an average of 3.6 to 4.9 kg, depending on the dose they were given (0.5 mg or 1.0 mg), which was significantly (P less than .0001) more than those who were randomized to matching placebos (-0.7 mg and -0.5 mg).

Sara Freeman/Frontline Medical News

LISBON – The investigational glucagon-like peptide (GLP)-1 receptor agonist semaglutide added to standard care for type 2 diabetes mellitus (T2DM) resulted in clinically significant weight loss over 2 years in the SUSTAIN-6 phase 3 trial.

Participants treated with semaglutide in the study lost an average of 3.6 to 4.9 kg, depending on the dose they were given (0.5 mg or 1.0 mg), which was significantly (P less than .0001) more than those who were randomized to matching placebos (-0.7 mg and -0.5 mg).

Sara Freeman/Frontline Medical News

LISBON – The investigational glucagon-like peptide (GLP)-1 receptor agonist semaglutide added to standard care for type 2 diabetes mellitus (T2DM) resulted in clinically significant weight loss over 2 years in the SUSTAIN-6 phase 3 trial.

Participants treated with semaglutide in the study lost an average of 3.6 to 4.9 kg, depending on the dose they were given (0.5 mg or 1.0 mg), which was significantly (P less than .0001) more than those who were randomized to matching placebos (-0.7 mg and -0.5 mg).

Sara Freeman/Frontline Medical News

BARCELONA – How low to go in treating hypertension is a topic of considerable recent controversy. Now the HOPE-3 trial investigators have weighed in, reporting that optimal outcomes in their landmark randomized trial were seen with an achieved, on-treatment systolic blood pressure of 130-140 mm Hg and a diastolic blood pressure of 75-80 mm Hg, Eva M. Lonn, MD, reported at the annual congress of the European Society of Cardiology.

Those results stand in glaring contrast to the findings of the much-discussed SPRINT trial, in which hypertensive patients fared best with an on-treatment SBP driven below 120 mm Hg (N Engl J Med. 2015 Nov 26; 373:2103-16).

Bruce Jancin/Frontline Medical News

[email protected]

BARCELONA – How low to go in treating hypertension is a topic of considerable recent controversy. Now the HOPE-3 trial investigators have weighed in, reporting that optimal outcomes in their landmark randomized trial were seen with an achieved, on-treatment systolic blood pressure of 130-140 mm Hg and a diastolic blood pressure of 75-80 mm Hg, Eva M. Lonn, MD, reported at the annual congress of the European Society of Cardiology.

Those results stand in glaring contrast to the findings of the much-discussed SPRINT trial, in which hypertensive patients fared best with an on-treatment SBP driven below 120 mm Hg (N Engl J Med. 2015 Nov 26; 373:2103-16).

Bruce Jancin/Frontline Medical News

[email protected]

BARCELONA – How low to go in treating hypertension is a topic of considerable recent controversy. Now the HOPE-3 trial investigators have weighed in, reporting that optimal outcomes in their landmark randomized trial were seen with an achieved, on-treatment systolic blood pressure of 130-140 mm Hg and a diastolic blood pressure of 75-80 mm Hg, Eva M. Lonn, MD, reported at the annual congress of the European Society of Cardiology.

Those results stand in glaring contrast to the findings of the much-discussed SPRINT trial, in which hypertensive patients fared best with an on-treatment SBP driven below 120 mm Hg (N Engl J Med. 2015 Nov 26; 373:2103-16).

Bruce Jancin/Frontline Medical News

[email protected]

Infestation with Demodex mites was significantly more common in patients with rosacea compared with healthy controls, based on data from a meta-analysis of 1,513 adults with rosacea. The findings were published in the September issue of the Journal of the American Academy of Dermatology.

The cause of rosacea remains unclear and differs within subgroups, but previous studies have suggested an association between rosacea and the presence of Demodex mites, wrote Yin-Shuo Chang, MD, and Yu-Chen Huang, MD, both of Taipei Medical University, Taiwan (J Am Acad Dermatol. 2017; 77[3]:441-7).

M. Sand, et al/Head &amp; face medicine/ISSN 1746-160X/CC BY 2.0

Courtesy RegionalDerm.com

Infestation with Demodex mites was significantly more common in patients with rosacea compared with healthy controls, based on data from a meta-analysis of 1,513 adults with rosacea. The findings were published in the September issue of the Journal of the American Academy of Dermatology.

The cause of rosacea remains unclear and differs within subgroups, but previous studies have suggested an association between rosacea and the presence of Demodex mites, wrote Yin-Shuo Chang, MD, and Yu-Chen Huang, MD, both of Taipei Medical University, Taiwan (J Am Acad Dermatol. 2017; 77[3]:441-7).

M. Sand, et al/Head &amp; face medicine/ISSN 1746-160X/CC BY 2.0

Courtesy RegionalDerm.com

Infestation with Demodex mites was significantly more common in patients with rosacea compared with healthy controls, based on data from a meta-analysis of 1,513 adults with rosacea. The findings were published in the September issue of the Journal of the American Academy of Dermatology.

The cause of rosacea remains unclear and differs within subgroups, but previous studies have suggested an association between rosacea and the presence of Demodex mites, wrote Yin-Shuo Chang, MD, and Yu-Chen Huang, MD, both of Taipei Medical University, Taiwan (J Am Acad Dermatol. 2017; 77[3]:441-7).

M. Sand, et al/Head &amp; face medicine/ISSN 1746-160X/CC BY 2.0

Courtesy RegionalDerm.com

SAN DIEGO – Patients who were successfully treated for methicillin-resistant Staphylococcus aureus infections were about four times more likely to become recolonized if their homes contained MRSA, according to the results of a longitudinal household study.

“Many of these homes were contaminated with a classic community strain,” Meghan Frost Davis, DVM, PhD, MPH, said during an oral presentation at an annual meeting on infectious disease. “We need to think about interventions in the home environment to improve our ability to achieve successful decolonization.”

Amy Karon/Frontline Medical News

SAN DIEGO – Patients who were successfully treated for methicillin-resistant Staphylococcus aureus infections were about four times more likely to become recolonized if their homes contained MRSA, according to the results of a longitudinal household study.

“Many of these homes were contaminated with a classic community strain,” Meghan Frost Davis, DVM, PhD, MPH, said during an oral presentation at an annual meeting on infectious disease. “We need to think about interventions in the home environment to improve our ability to achieve successful decolonization.”

Amy Karon/Frontline Medical News

SAN DIEGO – Patients who were successfully treated for methicillin-resistant Staphylococcus aureus infections were about four times more likely to become recolonized if their homes contained MRSA, according to the results of a longitudinal household study.

“Many of these homes were contaminated with a classic community strain,” Meghan Frost Davis, DVM, PhD, MPH, said during an oral presentation at an annual meeting on infectious disease. “We need to think about interventions in the home environment to improve our ability to achieve successful decolonization.”

Amy Karon/Frontline Medical News

Micrograph showing MDS

The European Commission has granted orphan designation to asunercept (APG101) for the treatment of myelodysplastic syndromes (MDS).

Asunercept is a fully human fusion protein that consists of the extracellular domain of the CD95 receptor and the Fc domain of an IgG1 antibody.

Asunercept binds to the CD95 ligand and blocks activation of the CD95 receptor.

Excessive stimulation of the CD95 receptor on hematopoietic precursors inhibits erythropoiesis in MDS patients.

As a result, the patients develop transfusion-dependent anemia that is refractory to erythropoiesis-stimulating agents (ESAs).

Treatment with asunercept, by inhibiting the CD95 system, stimulates the production of red blood cells and decreases transfusion dependency.

Asunercept has been evaluated in a phase 1 trial, the results of which were presented at the 2016 ASH Annual Meeting.

The trial enrolled 20 patients with low- to intermediate-risk MDS. All patients had anemia resulting in a high transfusion burden, had hemoglobin levels of less than 10 g/dL, and were refractory to ESAs.

Patients received once-weekly asunercept infusions for 12 weeks. Eight of the 20 patients (40%) experienced a reduction in transfusion frequency for 6 months.

Asunercept was considered generally well tolerated, with no grade 3 or higher treatment-related adverse events reported. The most common treatment-emergent adverse events were peripheral edema (n=6), urinary tract infection (n=4), and oral herpes (n=3).

One patient developed acute myeloid leukemia, and 1 patient died from sepsis due to pre-existing neutropenia.

“We are highly encouraged by the data from our clinical phase 1 trial with asunercept in these patients and are currently preparing to initiate a clinical phase 2 proof-of-concept trial to further evaluate the efficacy of asunercept in MDS,” said Harald Fricke, chief medical officer of Apogenix AG, the company developing asunercept.

About orphan designation

Orphan designation provides regulatory and financial incentives for companies to develop and market therapies that treat life-threatening or chronically debilitating conditions affecting no more than 5 in 10,000 people in the European Union, and where no satisfactory treatment is available.

Orphan designation provides a 10-year period of marketing exclusivity if the drug receives regulatory approval.

The designation also provides incentives for companies seeking protocol assistance from the European Medicines Agency during the product development phase and direct access to the centralized authorization procedure.

Micrograph showing MDS

The European Commission has granted orphan designation to asunercept (APG101) for the treatment of myelodysplastic syndromes (MDS).

Asunercept is a fully human fusion protein that consists of the extracellular domain of the CD95 receptor and the Fc domain of an IgG1 antibody.

Asunercept binds to the CD95 ligand and blocks activation of the CD95 receptor.

Excessive stimulation of the CD95 receptor on hematopoietic precursors inhibits erythropoiesis in MDS patients.

As a result, the patients develop transfusion-dependent anemia that is refractory to erythropoiesis-stimulating agents (ESAs).

Treatment with asunercept, by inhibiting the CD95 system, stimulates the production of red blood cells and decreases transfusion dependency.

Asunercept has been evaluated in a phase 1 trial, the results of which were presented at the 2016 ASH Annual Meeting.

The trial enrolled 20 patients with low- to intermediate-risk MDS. All patients had anemia resulting in a high transfusion burden, had hemoglobin levels of less than 10 g/dL, and were refractory to ESAs.

Patients received once-weekly asunercept infusions for 12 weeks. Eight of the 20 patients (40%) experienced a reduction in transfusion frequency for 6 months.

Asunercept was considered generally well tolerated, with no grade 3 or higher treatment-related adverse events reported. The most common treatment-emergent adverse events were peripheral edema (n=6), urinary tract infection (n=4), and oral herpes (n=3).

One patient developed acute myeloid leukemia, and 1 patient died from sepsis due to pre-existing neutropenia.

“We are highly encouraged by the data from our clinical phase 1 trial with asunercept in these patients and are currently preparing to initiate a clinical phase 2 proof-of-concept trial to further evaluate the efficacy of asunercept in MDS,” said Harald Fricke, chief medical officer of Apogenix AG, the company developing asunercept.

About orphan designation

Orphan designation provides regulatory and financial incentives for companies to develop and market therapies that treat life-threatening or chronically debilitating conditions affecting no more than 5 in 10,000 people in the European Union, and where no satisfactory treatment is available.

Orphan designation provides a 10-year period of marketing exclusivity if the drug receives regulatory approval.

The designation also provides incentives for companies seeking protocol assistance from the European Medicines Agency during the product development phase and direct access to the centralized authorization procedure.

Micrograph showing MDS

The European Commission has granted orphan designation to asunercept (APG101) for the treatment of myelodysplastic syndromes (MDS).

Asunercept is a fully human fusion protein that consists of the extracellular domain of the CD95 receptor and the Fc domain of an IgG1 antibody.

Asunercept binds to the CD95 ligand and blocks activation of the CD95 receptor.

Excessive stimulation of the CD95 receptor on hematopoietic precursors inhibits erythropoiesis in MDS patients.

As a result, the patients develop transfusion-dependent anemia that is refractory to erythropoiesis-stimulating agents (ESAs).

Treatment with asunercept, by inhibiting the CD95 system, stimulates the production of red blood cells and decreases transfusion dependency.

Asunercept has been evaluated in a phase 1 trial, the results of which were presented at the 2016 ASH Annual Meeting.

The trial enrolled 20 patients with low- to intermediate-risk MDS. All patients had anemia resulting in a high transfusion burden, had hemoglobin levels of less than 10 g/dL, and were refractory to ESAs.

Patients received once-weekly asunercept infusions for 12 weeks. Eight of the 20 patients (40%) experienced a reduction in transfusion frequency for 6 months.

Asunercept was considered generally well tolerated, with no grade 3 or higher treatment-related adverse events reported. The most common treatment-emergent adverse events were peripheral edema (n=6), urinary tract infection (n=4), and oral herpes (n=3).

One patient developed acute myeloid leukemia, and 1 patient died from sepsis due to pre-existing neutropenia.

“We are highly encouraged by the data from our clinical phase 1 trial with asunercept in these patients and are currently preparing to initiate a clinical phase 2 proof-of-concept trial to further evaluate the efficacy of asunercept in MDS,” said Harald Fricke, chief medical officer of Apogenix AG, the company developing asunercept.

About orphan designation

Orphan designation provides regulatory and financial incentives for companies to develop and market therapies that treat life-threatening or chronically debilitating conditions affecting no more than 5 in 10,000 people in the European Union, and where no satisfactory treatment is available.

Orphan designation provides a 10-year period of marketing exclusivity if the drug receives regulatory approval.

The designation also provides incentives for companies seeking protocol assistance from the European Medicines Agency during the product development phase and direct access to the centralized authorization procedure.

SAN DIEGO – Recent sexual risk behavior and partnership type may be important predictors of pre-exposure prophylaxis in men who have sex with men, results from a 48-week study suggest.

“We know from other studies including iPrEX, the Partners PrEP, and the Demo project that individuals who report higher risk behaviors are more likely to be adherent to pre-exposure prophylaxis (PrEP),” lead study author Jill Blumenthal, MD, said in an interview in advance of an annual scientific meeting on infectious diseases.

[email protected]

SAN DIEGO – Recent sexual risk behavior and partnership type may be important predictors of pre-exposure prophylaxis in men who have sex with men, results from a 48-week study suggest.

“We know from other studies including iPrEX, the Partners PrEP, and the Demo project that individuals who report higher risk behaviors are more likely to be adherent to pre-exposure prophylaxis (PrEP),” lead study author Jill Blumenthal, MD, said in an interview in advance of an annual scientific meeting on infectious diseases.

[email protected]

SAN DIEGO – Recent sexual risk behavior and partnership type may be important predictors of pre-exposure prophylaxis in men who have sex with men, results from a 48-week study suggest.

“We know from other studies including iPrEX, the Partners PrEP, and the Demo project that individuals who report higher risk behaviors are more likely to be adherent to pre-exposure prophylaxis (PrEP),” lead study author Jill Blumenthal, MD, said in an interview in advance of an annual scientific meeting on infectious diseases.

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