A crescendo of paranoid fear sharply increases the likelihood that a person will kill his (her) misperceived persecutor. Persecutory delusions are more likely to lead to homicide than any other psychiatric symptom.1 If people define a delusional situation as real, the situation is real in its consequences.

Based on my experience performing more than 100 insanity evaluations of paranoid persons charged with murder, I have identified 4 paranoid motives for homicide.

Self-defense. The most common paranoid motive for murder is the misperceived need to defend one’s self.

A steel worker believed that there was a conspiracy to kill him. His wife insisted that he go to a hospital emergency room for an evaluation. He then concluded that his wife was in on the conspiracy and stabbed her to death.

Defense of one’s manhood. Homosexual panic occurs in men who think of themselves as heterosexual.

A man with paranoid schizophrenia developed a delusion that his former high school football coach was having the entire team rape him at night. He shot the coach 6 times in front of 22 witnesses.

Defense of one’s children. A parent may kill to save her (his) children’s souls.

A deeply religious woman developed persecutory delusions that her 9-year-old son and 3-year-old daughter were going to be kidnapped and forced to make child pornography. To save her children’s souls, she stabbed her children more than 100 times.

Defense of the world. Homicide may be seen as a way to protect all humankind.

A woman developed a delusion that her father was Satan and would kill her. She believed that if she could kill her father (Satan) and his family she would save herself and bring about world peace. After killing her father, she thrust the sharp end of a tire iron into her grandmother’s umbilicus and vagina because those body parts were involved in “birthing Satan.”

Questioning to determine risk
I have found that, when evaluating a paranoid, delusional person for potential violence, it is better to present that person with a hypothetical question about encountering his perceived persecutor than with a generic question about homicidality.² For example, a delusional person who reports that he was afraid of being killed by the Mafia could be asked, “If you were walking down an alley and encountered a man dressed like a Mafia hit man with a bulge in his jacket, what would you do?” One interviewee might reply, “The Mafia has so much power there is nothing I could do.” Another might answer, “As soon as I got close enough I would blow his head off with my .357 Magnum.” Although both people would be reporting honestly that they have no homicidal ideas, the latter has a much lower threshold for killing in misperceived self-defense.

Summing up
Persecutory delusions are more likely than any other psychiatric symptom to lead a psychotic person to commit homicide. The killing might be motivated by misperceived self-defense, defense of one’s manhood, defense of one’s children, or defense of the world.

A crescendo of paranoid fear sharply increases the likelihood that a person will kill his (her) misperceived persecutor. Persecutory delusions are more likely to lead to homicide than any other psychiatric symptom.1 If people define a delusional situation as real, the situation is real in its consequences.

Based on my experience performing more than 100 insanity evaluations of paranoid persons charged with murder, I have identified 4 paranoid motives for homicide.

Self-defense. The most common paranoid motive for murder is the misperceived need to defend one’s self.

A steel worker believed that there was a conspiracy to kill him. His wife insisted that he go to a hospital emergency room for an evaluation. He then concluded that his wife was in on the conspiracy and stabbed her to death.

Defense of one’s manhood. Homosexual panic occurs in men who think of themselves as heterosexual.

A man with paranoid schizophrenia developed a delusion that his former high school football coach was having the entire team rape him at night. He shot the coach 6 times in front of 22 witnesses.

Defense of one’s children. A parent may kill to save her (his) children’s souls.

A deeply religious woman developed persecutory delusions that her 9-year-old son and 3-year-old daughter were going to be kidnapped and forced to make child pornography. To save her children’s souls, she stabbed her children more than 100 times.

Defense of the world. Homicide may be seen as a way to protect all humankind.

A woman developed a delusion that her father was Satan and would kill her. She believed that if she could kill her father (Satan) and his family she would save herself and bring about world peace. After killing her father, she thrust the sharp end of a tire iron into her grandmother’s umbilicus and vagina because those body parts were involved in “birthing Satan.”

Questioning to determine risk
I have found that, when evaluating a paranoid, delusional person for potential violence, it is better to present that person with a hypothetical question about encountering his perceived persecutor than with a generic question about homicidality.² For example, a delusional person who reports that he was afraid of being killed by the Mafia could be asked, “If you were walking down an alley and encountered a man dressed like a Mafia hit man with a bulge in his jacket, what would you do?” One interviewee might reply, “The Mafia has so much power there is nothing I could do.” Another might answer, “As soon as I got close enough I would blow his head off with my .357 Magnum.” Although both people would be reporting honestly that they have no homicidal ideas, the latter has a much lower threshold for killing in misperceived self-defense.

Summing up
Persecutory delusions are more likely than any other psychiatric symptom to lead a psychotic person to commit homicide. The killing might be motivated by misperceived self-defense, defense of one’s manhood, defense of one’s children, or defense of the world.

A crescendo of paranoid fear sharply increases the likelihood that a person will kill his (her) misperceived persecutor. Persecutory delusions are more likely to lead to homicide than any other psychiatric symptom.1 If people define a delusional situation as real, the situation is real in its consequences.

Based on my experience performing more than 100 insanity evaluations of paranoid persons charged with murder, I have identified 4 paranoid motives for homicide.

Self-defense. The most common paranoid motive for murder is the misperceived need to defend one’s self.

A steel worker believed that there was a conspiracy to kill him. His wife insisted that he go to a hospital emergency room for an evaluation. He then concluded that his wife was in on the conspiracy and stabbed her to death.

Defense of one’s manhood. Homosexual panic occurs in men who think of themselves as heterosexual.

A man with paranoid schizophrenia developed a delusion that his former high school football coach was having the entire team rape him at night. He shot the coach 6 times in front of 22 witnesses.

Defense of one’s children. A parent may kill to save her (his) children’s souls.

A deeply religious woman developed persecutory delusions that her 9-year-old son and 3-year-old daughter were going to be kidnapped and forced to make child pornography. To save her children’s souls, she stabbed her children more than 100 times.

Defense of the world. Homicide may be seen as a way to protect all humankind.

A woman developed a delusion that her father was Satan and would kill her. She believed that if she could kill her father (Satan) and his family she would save herself and bring about world peace. After killing her father, she thrust the sharp end of a tire iron into her grandmother’s umbilicus and vagina because those body parts were involved in “birthing Satan.”

Questioning to determine risk
I have found that, when evaluating a paranoid, delusional person for potential violence, it is better to present that person with a hypothetical question about encountering his perceived persecutor than with a generic question about homicidality.² For example, a delusional person who reports that he was afraid of being killed by the Mafia could be asked, “If you were walking down an alley and encountered a man dressed like a Mafia hit man with a bulge in his jacket, what would you do?” One interviewee might reply, “The Mafia has so much power there is nothing I could do.” Another might answer, “As soon as I got close enough I would blow his head off with my .357 Magnum.” Although both people would be reporting honestly that they have no homicidal ideas, the latter has a much lower threshold for killing in misperceived self-defense.

Summing up
Persecutory delusions are more likely than any other psychiatric symptom to lead a psychotic person to commit homicide. The killing might be motivated by misperceived self-defense, defense of one’s manhood, defense of one’s children, or defense of the world.

CASE Inconsistent stories
Ms. P, age 56, is an Asian American woman who was brought in by police after being found standing by her car in the middle of a busy road displaying bizarre behavior. She provides an inconsistent story about why she was brought to the hospital, saying that the police did so because she wasn’t driving fast enough and because her English is weak. At another point, she says that she had stopped her car to pick up a penny from the road and the police brought her to the hospital “to experience life, to rest, to meet people.”

Upon further questioning, Ms. P reveals that she is experiencing racing thoughts, feels full of energy, has pressured speech, and does not need much sleep. She also is sexually preoccupied, talks about having extra-marital affairs, and expresses her infatuation with TV news anchors. She says she is sexually active but is unable to offer any further details, and—while giggling—asks the treatment team not to reveal this information to her husband. Ms. P also reports hearing angels singing from the sky.

Chart review reveals that Ms. P had been admitted to same hospital 5 years earlier, at which time she was given diagnoses of late-onset schizophrenia (LOS) and mild cognitive impairment. Ms. P also had 3 psychiatric inpatient admissions in the past 2 years at a different hospital, but her records are inaccessible because she refuses to allow her chart to be released.

Ms. P has not taken the psychiatric medications prescribed for her for several months; she says, “I don’t need medication. I am self-healing.” She denies using illicit substances, including marijuana, smoking, and current alcohol use, but reports occasional social drinking in the past. Her urine drug screen is negative.

The most striking revelation in Ms. P’s social history is her high premorbid functional status. She has 2 master’s degrees and had been working as a senior accountant at a major hospital system until 7 years ago. In contrast, when interviewed at the hospital, Ms. P reports that she is working at a child care center.

On mental status exam, Ms. P is half-draped in a hospital gown, casual, overly friendly, smiling, and twirling her hair. Her mood is elevated with inappropriate affect. Her thought process is bizarre and illogical. She is alert, fully oriented, and her sensorium is clear. She has persistent ambivalence and contradictory thoughts regarding suicidal ideation. Recent and remote memory are largely intact. She does not express homicidal ideation.

What could be causing Ms. P’s psychosis and functional decline?
   a) major neurocognitive disorder
   b) schizophrenia
   c) schizoaffective disorder
   d) bipolar disorder, current manic episode

HISTORY Fired from her job
According to Ms. P’s chart from her admission 5 years earlier, police brought her to the hospital because she was causing a disturbance at a restaurant. When interviewed, Ms. P reported a false story that she fought with her husband, kicked him, and spat on his face. She said that her husband then punched her in the face, she ran out of the house, and a bystander called the police. At the time, her husband was contacted and denied the incident. He said that Ms. P had gone to the store and not returned, and he did not know what happened to her.

Her husband reported a steady and progressive decline in function and behavior dating back to 8 years ago with no known prior behavioral disturbances. In the chart from 5 years ago, her husband reported that Ms. P had been a high-functioning senior executive accountant at a major hospital system 7 years before the current admission, at which time she was fired from her job. He said that, just before being fired, Ms. P had been reading the mystery novel The Da Vinci Code and believed that events in the book specifically applied to her. Ms. P would stay up all night making clothes; when she would go to work, she was caught sleeping on the job and performing poorly, including submitting reports with incorrect information. She yelled at co-workers and was unable to take direction from her supervisors.

Ms. P’s husband also reported that she believed people were trying to “look like her,” by having plastic surgery. He reported unusual behavior at home, including eating food off the countertop that had been out for hours and was not fit for consumption.

Ms. P’s husband could not be contacted during this admission because he was out of country and they were separated. Collateral information is obtained from Ms. P’s mother, who lives apart from her but in the same city and speaks no English. She confirms Ms. P’s high premorbid functioning, and reports that her daughter’s change in behavior went back as far as 10 years. She reports that Ms. P had problems controlling anger and had frequent altercations with her husband and mother, including threatening her with a knife. Self-care and hygiene then declined strikingly. She began to have odd religious beliefs (eg, she was the daughter of Jesus Christ) and insisted on dressing in peculiar ways.

No family history of psychiatric disorders, such as schizophrenia, bipolar disorder, or dementia, was reported (Table 1).

The authors’ observations
The existence of LOS as a distinct subtype of schizophrenia has been the subject of discussion and controversy as far back as Manfred Bleuler in 1943 who coined the term “late-onset schizophrenia.”¹ In 2000, a consensus statement by the International Late-Onset Schizophrenia Group standardized the nomenclature, defining LOS as onset between age 40 and 60, and very-late-onset schizophrenia-like psychosis (VLOS) as onset after age 60.² Although there is no diagnostic subcategory for LOS in DSM, DSM-5 notes that (1) women are overrepresented in late-onset cases and (2) the course generally is characterized by a predominance of psychotic symptoms with preservation of affect and social functioning.³ DSM authors comment that it is not yet clear whether LOS is the same condition as schizophrenia diagnosed earlier in life. Approximately 23% of schizophrenia cases have onset after age 40.⁴

Cognitive symptoms in LOS
The presence of cognitive deficits in schizophrenia is common and well-recognized. The intellectual impairment is generalized and global, and there also is specific impairment in a range of cognitive functions, such as executive functions, memory, psycho­motor speed, attention, and social cognition.⁵ Typically these cognitive impairments are present before onset of psychotic symptoms. Although cognitive symptoms are not part of the formal diagnostic criteria, DSM-5 acknowledges their presence.³ In a systematic review on nature and course of cognitive function in LOS, Rajji and Mulsant⁶ report that global deficits and specific deficits in executive functions, visuospatial constructional abilities, verbal fluency, and psychomotor speech have been found consistently in studies of LOS, although the presence of deficits in memory, attention, and working memory has been less consistent.

The presence of cognitive symptoms in LOS is less well-studied and understood (Table 2). The International Consensus Statement reported that no difference in type of cognitive deficit has been found in early–onset cases (onset before age 40) compared with late-onset cases, although LOS is associated with relatively milder cognitive deficits. Additionally, premorbid educational, occupational, and psychosocial functioning are less impaired in LOS than they are in early-onset schizophrenia.²

Rajji et al⁷ performed a meta-analysis comparison of patients with youth-onset schizophrenia, adults with first-episode schizophrenia, and those with LOS on their cognitive profiles. They reported that patients with youth-onset schizophrenia have globally severe cognitive deficits, whereas those with LOS demonstrate minimal deficits on arithmetic, digit symbol coding, and vocabulary but larger deficits on attention, fluency, global cognition, IQ, and visuospatial construction.⁷

There are conflicting views in the literature with regards to the course of cognitive deficits in schizophrenia. One group of researchers believes that there is progressive deterioration in cognitive functioning over time, while another maintains that cognitive impairment in schizophrenia is largely “a static encephalopathy” with no significant progression of symptoms.⁸ A number of studies referenced by Rajji and Mulsant⁶ in their systematic review report that cognitive deficits seen in patients with LOS largely are stable on follow-up with an average duration of up to 3 years. However, 2 studies with longer follow-up report evidence of cognitive decline.^9,10

Relevant findings from the literature. Brodaty et al⁹ followed 27 patients with LOS without dementia and 34 otherwise healthy participants at baseline, 1 year, and 5 years. They reported that 9 patients with LOS and none of the control group were found to have dementia (5 Alzheimer type, 1 vascular, and 3 dementia of unknown type) at 5-year follow-up. Some patients had no clinical signs of dementia at baseline or at 1-year follow-up, but were found to have dementia at 5-year follow-up. The authors speculated that LOS might be a prodrome of Alzheimer-type dementia.

Kørner et al¹⁰ studied 12,600 patients with LOS and 7,700 with VLOS, selected from the Danish nationwide registry; follow-up was 3 to 4.58 years. They concluded that patients with LOS and VLOS were at 2 to 3 times greater risk of developing dementia than patients with osteoarthritis or the general population. The most common diagnosis among patients with schizophrenia was unspecified dementia, with Alzheimer’s dementia (AD) being the most common diagnosis in control groups. The findings suggest that dementia in LOS and VLOS has a different basis than AD.

Zakzanis et al¹¹ investigated which neuropsychological tests best differentiate patients with LOS and those with AD or frontotemporal dementia. They reported that Wechsler Adult Intelligence Scale-Revised (WAIS-R) Similarities subtest and the California Verbal Learning Test (both short- and long-delay free recall) can differentiate LOS from AD, and a test battery comprising the WAIS-R Vocabulary, Information, Digit Span, and Comprehension subtests, and the Hooper Visual Organization test can differentiate LOS and frontotemporal dementia.¹²

EVALUATION Significant impairment
CT head and MRI brain scans without contrast suggest mild generalized atrophy that is more prominent in frontal and parietal areas, but the scans are otherwise unremarkable overall. A PET scan is significant for hypoactivity in the temporal and parietal lobes but, again, the images are interpreted as unremarkable overall.

Ms. P scores 21 on the Montreal Cognitive Assessment (MoCA), indicative of significant cognitive impairment (normal score, ≥26). This is a 3-point decline on a MoCA performed during her admission 5 years earlier.

Ms. P scores 8 on the Middlesex Elderly Assessment of Mental State, the lowest score in the borderline range of cognitive function for geriatric patients. She scores 13 on the Kohlman Evaluation of Living Skills, indicating that she needs maximal supervision, structure, and support to live in the community. Particularly notable is that Ms. P failed 5 out of 6 subtests in money management—a marked decline for someone who had worked as a senior accountant.

Given Ms. P’s significant cognitive decline from premorbid functioning, verified by collateral information, and current cognitive deficits established on standardized tests, we determine that, in addition to a diagnosis of schizoaffective disorder, she might meet DSM-5 criteria for unspecified major neurocognitive disorder if her functioning does not improve with treatment.

The authors’ observations
There is scant literature on late-onset schizoaffective disorder. Webster and Grossberg¹³ conducted a retrospective chart review of 1,730 patients age >65 who were admitted to a geriatric psychiatry unit from 1988 to 1995. Of these patients, 166 (approximately 10%) were found to have late life-onset psychosis. The psychosis was attributed to various causes, such as dementia, depression, bipolar disorder, medical causes, delirium, medication toxicity. Two patients were diagnosed with schizophrenia and 2 were diagnosed with schizoaffective disorder (the authors did not provide additional information about the patients with schizoaffective disorder). Brenner et al¹⁴ reports a case of late-onset schizoaffective disorder in a 70-year-old female patient. Evans et al¹⁵ compared outpatients age 45 to 77 with a diagnosis of schizoaffective disorder (n = 29), schizophrenia (n = 154), or nonpsychotic mood disorder (n = 27) and concluded that late-onset schizoaffective disorder might represent a variant of LOS in clinical symptom profiles and cognitive impairment but with additional mood symptoms.¹⁶

How would you begin treating Ms. P?
   a) start a mood stabilizer
   b) start an atypical antipsychotic
   c) obtain more history and collateral information
   d) recommend outpatient treatment

The authors’ observations
Given Ms. P’s manic symptoms, thought disorder, and history of psychotic symptoms with diagnosis of LOS, we assigned her a presumptive diagnosis of schizoaffective disorder, bipolar type. From the patient report, collateral information from her mother, earlier documented collateral from her husband, and chart review, it was apparent to us that Ms. P’s psychiatric history went back only 10 years—therefore meeting temporal criteria for LOS.

Clinical assessment (Figure) and standardized tests revealed the presence of neurocognitive deficits sufficient to meet criteria for major neurocognitive disorder (Table 3³). The pattern of neurocognitive deficits is consistent with an AD-like amnestic picture, although no clear-cut diagnosis was present, and the neurocognitive disorder was better classified as unspecified rather than of a particular type. It remains uncertain whether cognitive deficits of severity that meet criteria for major neurocognitive disorder are sufficiently accounted for by the diagnosis of LOS alone. Unless diagnostic criteria for schizophrenia are expanded to include cognitive deficits, a separate diagnosis of major neurocognitive disorder is warranted at present.

TREATMENT Pharmacotherapy
On the unit, Ms. P is observed by nursing staff wandering, with some pressured speech but no behavioral agitation. Her clothing had been bizarre, with multiple layers, and, at one point, she walks with her gown open and without undergarments. She also reports to the nurses that she has a lot of sexual thoughts. When the interview team enters her room, they find her masturbating.

Ms. P is started on aripiprazole, 10 mg/d, titrated to 20 mg/d, and divalproex sodium, 500 mg/d. The decision to initiate a cognitive enhancer, such as an acetylcholinesterase inhibitor or memantine, is deferred to outpatient care to allow for the possibility that her cognitive features will improve after the psychosis is treated.

By the end of first week, Ms. P’s manic features are no longer prominent but her thought process continues to be bizarre, with poor insight and judgment. She demonstrates severe ambivalence in all matters, consistently gives inconsistent accounts of the past, and makes dramatic false statements.

For example, when asked about her children, Ms. P tells us that she has 6 children—the youngest 3 months old, at home by himself and “probably dead by now.” In reality, she has only a 20-year-old son who is studying abroad. Talking about her marriage, Ms. P says she and her husband are not divorced on paper but that, because they haven’t had sex for 8 years, the law has provided them with an automatic divorce.

OUTCOME Significant improvement
Ms. P shows significant response to aripiprazole and divalproex, which are well tolerated without significant adverse effects. Her limitations in executive functioning and rational thought process lead the treatment team to consider nursing home placement under guardianship. Days before discharge, however, reexamination of her neuropsychiatric state suggests significant improvement in thought process, with improvement in cognitive features. Ms. P also becomes cooperative with treatment planning.

The treatment team has meetings with Ms. P’s mother to discuss monitoring and plans for discharge. Ms. P is discharged with follow-up arranged at community mental health services.

Bottom Line
Global as well as specific cognitive deficits are associated with late-onset schizophrenia. Studies have reported increased risk of dementia in these patients over the course of 3 to 5 years, usually unspecified or Alzheimer’s type. It is imperative to assess patients with schizophrenia, especially those age ≥40, for presence of neurocognitive disorder by means of neurocognitive testing.

Related Resources

• Goff DC, Hill M, Barch D. The treatment of cognitive impairment in schizophrenia. Pharmacol Biochem Behav. 2011;99(2):245-253.
• Radhakrishnan R, Butler R, Head L. Dementia in schizophrenia. Adv Psychiatr Treat. 2012;18(2):144-153.
  
  

Drug Brand Names
Aripiprazole • Abilify
Divalproex sodium • Depakote
Mematine • Namenda

Disclosures
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturer of competing products.

CASE Inconsistent stories
Ms. P, age 56, is an Asian American woman who was brought in by police after being found standing by her car in the middle of a busy road displaying bizarre behavior. She provides an inconsistent story about why she was brought to the hospital, saying that the police did so because she wasn’t driving fast enough and because her English is weak. At another point, she says that she had stopped her car to pick up a penny from the road and the police brought her to the hospital “to experience life, to rest, to meet people.”

Upon further questioning, Ms. P reveals that she is experiencing racing thoughts, feels full of energy, has pressured speech, and does not need much sleep. She also is sexually preoccupied, talks about having extra-marital affairs, and expresses her infatuation with TV news anchors. She says she is sexually active but is unable to offer any further details, and—while giggling—asks the treatment team not to reveal this information to her husband. Ms. P also reports hearing angels singing from the sky.

Chart review reveals that Ms. P had been admitted to same hospital 5 years earlier, at which time she was given diagnoses of late-onset schizophrenia (LOS) and mild cognitive impairment. Ms. P also had 3 psychiatric inpatient admissions in the past 2 years at a different hospital, but her records are inaccessible because she refuses to allow her chart to be released.

Ms. P has not taken the psychiatric medications prescribed for her for several months; she says, “I don’t need medication. I am self-healing.” She denies using illicit substances, including marijuana, smoking, and current alcohol use, but reports occasional social drinking in the past. Her urine drug screen is negative.

The most striking revelation in Ms. P’s social history is her high premorbid functional status. She has 2 master’s degrees and had been working as a senior accountant at a major hospital system until 7 years ago. In contrast, when interviewed at the hospital, Ms. P reports that she is working at a child care center.

On mental status exam, Ms. P is half-draped in a hospital gown, casual, overly friendly, smiling, and twirling her hair. Her mood is elevated with inappropriate affect. Her thought process is bizarre and illogical. She is alert, fully oriented, and her sensorium is clear. She has persistent ambivalence and contradictory thoughts regarding suicidal ideation. Recent and remote memory are largely intact. She does not express homicidal ideation.

What could be causing Ms. P’s psychosis and functional decline?
   a) major neurocognitive disorder
   b) schizophrenia
   c) schizoaffective disorder
   d) bipolar disorder, current manic episode

HISTORY Fired from her job
According to Ms. P’s chart from her admission 5 years earlier, police brought her to the hospital because she was causing a disturbance at a restaurant. When interviewed, Ms. P reported a false story that she fought with her husband, kicked him, and spat on his face. She said that her husband then punched her in the face, she ran out of the house, and a bystander called the police. At the time, her husband was contacted and denied the incident. He said that Ms. P had gone to the store and not returned, and he did not know what happened to her.

Her husband reported a steady and progressive decline in function and behavior dating back to 8 years ago with no known prior behavioral disturbances. In the chart from 5 years ago, her husband reported that Ms. P had been a high-functioning senior executive accountant at a major hospital system 7 years before the current admission, at which time she was fired from her job. He said that, just before being fired, Ms. P had been reading the mystery novel The Da Vinci Code and believed that events in the book specifically applied to her. Ms. P would stay up all night making clothes; when she would go to work, she was caught sleeping on the job and performing poorly, including submitting reports with incorrect information. She yelled at co-workers and was unable to take direction from her supervisors.

Ms. P’s husband also reported that she believed people were trying to “look like her,” by having plastic surgery. He reported unusual behavior at home, including eating food off the countertop that had been out for hours and was not fit for consumption.

Ms. P’s husband could not be contacted during this admission because he was out of country and they were separated. Collateral information is obtained from Ms. P’s mother, who lives apart from her but in the same city and speaks no English. She confirms Ms. P’s high premorbid functioning, and reports that her daughter’s change in behavior went back as far as 10 years. She reports that Ms. P had problems controlling anger and had frequent altercations with her husband and mother, including threatening her with a knife. Self-care and hygiene then declined strikingly. She began to have odd religious beliefs (eg, she was the daughter of Jesus Christ) and insisted on dressing in peculiar ways.

No family history of psychiatric disorders, such as schizophrenia, bipolar disorder, or dementia, was reported (Table 1).

The authors’ observations
The existence of LOS as a distinct subtype of schizophrenia has been the subject of discussion and controversy as far back as Manfred Bleuler in 1943 who coined the term “late-onset schizophrenia.”¹ In 2000, a consensus statement by the International Late-Onset Schizophrenia Group standardized the nomenclature, defining LOS as onset between age 40 and 60, and very-late-onset schizophrenia-like psychosis (VLOS) as onset after age 60.² Although there is no diagnostic subcategory for LOS in DSM, DSM-5 notes that (1) women are overrepresented in late-onset cases and (2) the course generally is characterized by a predominance of psychotic symptoms with preservation of affect and social functioning.³ DSM authors comment that it is not yet clear whether LOS is the same condition as schizophrenia diagnosed earlier in life. Approximately 23% of schizophrenia cases have onset after age 40.⁴

Cognitive symptoms in LOS
The presence of cognitive deficits in schizophrenia is common and well-recognized. The intellectual impairment is generalized and global, and there also is specific impairment in a range of cognitive functions, such as executive functions, memory, psycho­motor speed, attention, and social cognition.⁵ Typically these cognitive impairments are present before onset of psychotic symptoms. Although cognitive symptoms are not part of the formal diagnostic criteria, DSM-5 acknowledges their presence.³ In a systematic review on nature and course of cognitive function in LOS, Rajji and Mulsant⁶ report that global deficits and specific deficits in executive functions, visuospatial constructional abilities, verbal fluency, and psychomotor speech have been found consistently in studies of LOS, although the presence of deficits in memory, attention, and working memory has been less consistent.

The presence of cognitive symptoms in LOS is less well-studied and understood (Table 2). The International Consensus Statement reported that no difference in type of cognitive deficit has been found in early–onset cases (onset before age 40) compared with late-onset cases, although LOS is associated with relatively milder cognitive deficits. Additionally, premorbid educational, occupational, and psychosocial functioning are less impaired in LOS than they are in early-onset schizophrenia.²

Rajji et al⁷ performed a meta-analysis comparison of patients with youth-onset schizophrenia, adults with first-episode schizophrenia, and those with LOS on their cognitive profiles. They reported that patients with youth-onset schizophrenia have globally severe cognitive deficits, whereas those with LOS demonstrate minimal deficits on arithmetic, digit symbol coding, and vocabulary but larger deficits on attention, fluency, global cognition, IQ, and visuospatial construction.⁷

There are conflicting views in the literature with regards to the course of cognitive deficits in schizophrenia. One group of researchers believes that there is progressive deterioration in cognitive functioning over time, while another maintains that cognitive impairment in schizophrenia is largely “a static encephalopathy” with no significant progression of symptoms.⁸ A number of studies referenced by Rajji and Mulsant⁶ in their systematic review report that cognitive deficits seen in patients with LOS largely are stable on follow-up with an average duration of up to 3 years. However, 2 studies with longer follow-up report evidence of cognitive decline.^9,10

Relevant findings from the literature. Brodaty et al⁹ followed 27 patients with LOS without dementia and 34 otherwise healthy participants at baseline, 1 year, and 5 years. They reported that 9 patients with LOS and none of the control group were found to have dementia (5 Alzheimer type, 1 vascular, and 3 dementia of unknown type) at 5-year follow-up. Some patients had no clinical signs of dementia at baseline or at 1-year follow-up, but were found to have dementia at 5-year follow-up. The authors speculated that LOS might be a prodrome of Alzheimer-type dementia.

Kørner et al¹⁰ studied 12,600 patients with LOS and 7,700 with VLOS, selected from the Danish nationwide registry; follow-up was 3 to 4.58 years. They concluded that patients with LOS and VLOS were at 2 to 3 times greater risk of developing dementia than patients with osteoarthritis or the general population. The most common diagnosis among patients with schizophrenia was unspecified dementia, with Alzheimer’s dementia (AD) being the most common diagnosis in control groups. The findings suggest that dementia in LOS and VLOS has a different basis than AD.

Zakzanis et al¹¹ investigated which neuropsychological tests best differentiate patients with LOS and those with AD or frontotemporal dementia. They reported that Wechsler Adult Intelligence Scale-Revised (WAIS-R) Similarities subtest and the California Verbal Learning Test (both short- and long-delay free recall) can differentiate LOS from AD, and a test battery comprising the WAIS-R Vocabulary, Information, Digit Span, and Comprehension subtests, and the Hooper Visual Organization test can differentiate LOS and frontotemporal dementia.¹²

EVALUATION Significant impairment
CT head and MRI brain scans without contrast suggest mild generalized atrophy that is more prominent in frontal and parietal areas, but the scans are otherwise unremarkable overall. A PET scan is significant for hypoactivity in the temporal and parietal lobes but, again, the images are interpreted as unremarkable overall.

Ms. P scores 21 on the Montreal Cognitive Assessment (MoCA), indicative of significant cognitive impairment (normal score, ≥26). This is a 3-point decline on a MoCA performed during her admission 5 years earlier.

Ms. P scores 8 on the Middlesex Elderly Assessment of Mental State, the lowest score in the borderline range of cognitive function for geriatric patients. She scores 13 on the Kohlman Evaluation of Living Skills, indicating that she needs maximal supervision, structure, and support to live in the community. Particularly notable is that Ms. P failed 5 out of 6 subtests in money management—a marked decline for someone who had worked as a senior accountant.

Given Ms. P’s significant cognitive decline from premorbid functioning, verified by collateral information, and current cognitive deficits established on standardized tests, we determine that, in addition to a diagnosis of schizoaffective disorder, she might meet DSM-5 criteria for unspecified major neurocognitive disorder if her functioning does not improve with treatment.

The authors’ observations
There is scant literature on late-onset schizoaffective disorder. Webster and Grossberg¹³ conducted a retrospective chart review of 1,730 patients age >65 who were admitted to a geriatric psychiatry unit from 1988 to 1995. Of these patients, 166 (approximately 10%) were found to have late life-onset psychosis. The psychosis was attributed to various causes, such as dementia, depression, bipolar disorder, medical causes, delirium, medication toxicity. Two patients were diagnosed with schizophrenia and 2 were diagnosed with schizoaffective disorder (the authors did not provide additional information about the patients with schizoaffective disorder). Brenner et al¹⁴ reports a case of late-onset schizoaffective disorder in a 70-year-old female patient. Evans et al¹⁵ compared outpatients age 45 to 77 with a diagnosis of schizoaffective disorder (n = 29), schizophrenia (n = 154), or nonpsychotic mood disorder (n = 27) and concluded that late-onset schizoaffective disorder might represent a variant of LOS in clinical symptom profiles and cognitive impairment but with additional mood symptoms.¹⁶

How would you begin treating Ms. P?
   a) start a mood stabilizer
   b) start an atypical antipsychotic
   c) obtain more history and collateral information
   d) recommend outpatient treatment

The authors’ observations
Given Ms. P’s manic symptoms, thought disorder, and history of psychotic symptoms with diagnosis of LOS, we assigned her a presumptive diagnosis of schizoaffective disorder, bipolar type. From the patient report, collateral information from her mother, earlier documented collateral from her husband, and chart review, it was apparent to us that Ms. P’s psychiatric history went back only 10 years—therefore meeting temporal criteria for LOS.

Clinical assessment (Figure) and standardized tests revealed the presence of neurocognitive deficits sufficient to meet criteria for major neurocognitive disorder (Table 3³). The pattern of neurocognitive deficits is consistent with an AD-like amnestic picture, although no clear-cut diagnosis was present, and the neurocognitive disorder was better classified as unspecified rather than of a particular type. It remains uncertain whether cognitive deficits of severity that meet criteria for major neurocognitive disorder are sufficiently accounted for by the diagnosis of LOS alone. Unless diagnostic criteria for schizophrenia are expanded to include cognitive deficits, a separate diagnosis of major neurocognitive disorder is warranted at present.

TREATMENT Pharmacotherapy
On the unit, Ms. P is observed by nursing staff wandering, with some pressured speech but no behavioral agitation. Her clothing had been bizarre, with multiple layers, and, at one point, she walks with her gown open and without undergarments. She also reports to the nurses that she has a lot of sexual thoughts. When the interview team enters her room, they find her masturbating.

Ms. P is started on aripiprazole, 10 mg/d, titrated to 20 mg/d, and divalproex sodium, 500 mg/d. The decision to initiate a cognitive enhancer, such as an acetylcholinesterase inhibitor or memantine, is deferred to outpatient care to allow for the possibility that her cognitive features will improve after the psychosis is treated.

By the end of first week, Ms. P’s manic features are no longer prominent but her thought process continues to be bizarre, with poor insight and judgment. She demonstrates severe ambivalence in all matters, consistently gives inconsistent accounts of the past, and makes dramatic false statements.

For example, when asked about her children, Ms. P tells us that she has 6 children—the youngest 3 months old, at home by himself and “probably dead by now.” In reality, she has only a 20-year-old son who is studying abroad. Talking about her marriage, Ms. P says she and her husband are not divorced on paper but that, because they haven’t had sex for 8 years, the law has provided them with an automatic divorce.

OUTCOME Significant improvement
Ms. P shows significant response to aripiprazole and divalproex, which are well tolerated without significant adverse effects. Her limitations in executive functioning and rational thought process lead the treatment team to consider nursing home placement under guardianship. Days before discharge, however, reexamination of her neuropsychiatric state suggests significant improvement in thought process, with improvement in cognitive features. Ms. P also becomes cooperative with treatment planning.

The treatment team has meetings with Ms. P’s mother to discuss monitoring and plans for discharge. Ms. P is discharged with follow-up arranged at community mental health services.

Bottom Line
Global as well as specific cognitive deficits are associated with late-onset schizophrenia. Studies have reported increased risk of dementia in these patients over the course of 3 to 5 years, usually unspecified or Alzheimer’s type. It is imperative to assess patients with schizophrenia, especially those age ≥40, for presence of neurocognitive disorder by means of neurocognitive testing.

Related Resources

• Goff DC, Hill M, Barch D. The treatment of cognitive impairment in schizophrenia. Pharmacol Biochem Behav. 2011;99(2):245-253.
• Radhakrishnan R, Butler R, Head L. Dementia in schizophrenia. Adv Psychiatr Treat. 2012;18(2):144-153.
  
  

Drug Brand Names
Aripiprazole • Abilify
Divalproex sodium • Depakote
Mematine • Namenda

Disclosures
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturer of competing products.

CASE Inconsistent stories
Ms. P, age 56, is an Asian American woman who was brought in by police after being found standing by her car in the middle of a busy road displaying bizarre behavior. She provides an inconsistent story about why she was brought to the hospital, saying that the police did so because she wasn’t driving fast enough and because her English is weak. At another point, she says that she had stopped her car to pick up a penny from the road and the police brought her to the hospital “to experience life, to rest, to meet people.”

Upon further questioning, Ms. P reveals that she is experiencing racing thoughts, feels full of energy, has pressured speech, and does not need much sleep. She also is sexually preoccupied, talks about having extra-marital affairs, and expresses her infatuation with TV news anchors. She says she is sexually active but is unable to offer any further details, and—while giggling—asks the treatment team not to reveal this information to her husband. Ms. P also reports hearing angels singing from the sky.

Chart review reveals that Ms. P had been admitted to same hospital 5 years earlier, at which time she was given diagnoses of late-onset schizophrenia (LOS) and mild cognitive impairment. Ms. P also had 3 psychiatric inpatient admissions in the past 2 years at a different hospital, but her records are inaccessible because she refuses to allow her chart to be released.

Ms. P has not taken the psychiatric medications prescribed for her for several months; she says, “I don’t need medication. I am self-healing.” She denies using illicit substances, including marijuana, smoking, and current alcohol use, but reports occasional social drinking in the past. Her urine drug screen is negative.

The most striking revelation in Ms. P’s social history is her high premorbid functional status. She has 2 master’s degrees and had been working as a senior accountant at a major hospital system until 7 years ago. In contrast, when interviewed at the hospital, Ms. P reports that she is working at a child care center.

On mental status exam, Ms. P is half-draped in a hospital gown, casual, overly friendly, smiling, and twirling her hair. Her mood is elevated with inappropriate affect. Her thought process is bizarre and illogical. She is alert, fully oriented, and her sensorium is clear. She has persistent ambivalence and contradictory thoughts regarding suicidal ideation. Recent and remote memory are largely intact. She does not express homicidal ideation.

What could be causing Ms. P’s psychosis and functional decline?
   a) major neurocognitive disorder
   b) schizophrenia
   c) schizoaffective disorder
   d) bipolar disorder, current manic episode

HISTORY Fired from her job
According to Ms. P’s chart from her admission 5 years earlier, police brought her to the hospital because she was causing a disturbance at a restaurant. When interviewed, Ms. P reported a false story that she fought with her husband, kicked him, and spat on his face. She said that her husband then punched her in the face, she ran out of the house, and a bystander called the police. At the time, her husband was contacted and denied the incident. He said that Ms. P had gone to the store and not returned, and he did not know what happened to her.

Her husband reported a steady and progressive decline in function and behavior dating back to 8 years ago with no known prior behavioral disturbances. In the chart from 5 years ago, her husband reported that Ms. P had been a high-functioning senior executive accountant at a major hospital system 7 years before the current admission, at which time she was fired from her job. He said that, just before being fired, Ms. P had been reading the mystery novel The Da Vinci Code and believed that events in the book specifically applied to her. Ms. P would stay up all night making clothes; when she would go to work, she was caught sleeping on the job and performing poorly, including submitting reports with incorrect information. She yelled at co-workers and was unable to take direction from her supervisors.

Ms. P’s husband also reported that she believed people were trying to “look like her,” by having plastic surgery. He reported unusual behavior at home, including eating food off the countertop that had been out for hours and was not fit for consumption.

Ms. P’s husband could not be contacted during this admission because he was out of country and they were separated. Collateral information is obtained from Ms. P’s mother, who lives apart from her but in the same city and speaks no English. She confirms Ms. P’s high premorbid functioning, and reports that her daughter’s change in behavior went back as far as 10 years. She reports that Ms. P had problems controlling anger and had frequent altercations with her husband and mother, including threatening her with a knife. Self-care and hygiene then declined strikingly. She began to have odd religious beliefs (eg, she was the daughter of Jesus Christ) and insisted on dressing in peculiar ways.

No family history of psychiatric disorders, such as schizophrenia, bipolar disorder, or dementia, was reported (Table 1).

The authors’ observations
The existence of LOS as a distinct subtype of schizophrenia has been the subject of discussion and controversy as far back as Manfred Bleuler in 1943 who coined the term “late-onset schizophrenia.”¹ In 2000, a consensus statement by the International Late-Onset Schizophrenia Group standardized the nomenclature, defining LOS as onset between age 40 and 60, and very-late-onset schizophrenia-like psychosis (VLOS) as onset after age 60.² Although there is no diagnostic subcategory for LOS in DSM, DSM-5 notes that (1) women are overrepresented in late-onset cases and (2) the course generally is characterized by a predominance of psychotic symptoms with preservation of affect and social functioning.³ DSM authors comment that it is not yet clear whether LOS is the same condition as schizophrenia diagnosed earlier in life. Approximately 23% of schizophrenia cases have onset after age 40.⁴

Cognitive symptoms in LOS
The presence of cognitive deficits in schizophrenia is common and well-recognized. The intellectual impairment is generalized and global, and there also is specific impairment in a range of cognitive functions, such as executive functions, memory, psycho­motor speed, attention, and social cognition.⁵ Typically these cognitive impairments are present before onset of psychotic symptoms. Although cognitive symptoms are not part of the formal diagnostic criteria, DSM-5 acknowledges their presence.³ In a systematic review on nature and course of cognitive function in LOS, Rajji and Mulsant⁶ report that global deficits and specific deficits in executive functions, visuospatial constructional abilities, verbal fluency, and psychomotor speech have been found consistently in studies of LOS, although the presence of deficits in memory, attention, and working memory has been less consistent.

The presence of cognitive symptoms in LOS is less well-studied and understood (Table 2). The International Consensus Statement reported that no difference in type of cognitive deficit has been found in early–onset cases (onset before age 40) compared with late-onset cases, although LOS is associated with relatively milder cognitive deficits. Additionally, premorbid educational, occupational, and psychosocial functioning are less impaired in LOS than they are in early-onset schizophrenia.²

Rajji et al⁷ performed a meta-analysis comparison of patients with youth-onset schizophrenia, adults with first-episode schizophrenia, and those with LOS on their cognitive profiles. They reported that patients with youth-onset schizophrenia have globally severe cognitive deficits, whereas those with LOS demonstrate minimal deficits on arithmetic, digit symbol coding, and vocabulary but larger deficits on attention, fluency, global cognition, IQ, and visuospatial construction.⁷

There are conflicting views in the literature with regards to the course of cognitive deficits in schizophrenia. One group of researchers believes that there is progressive deterioration in cognitive functioning over time, while another maintains that cognitive impairment in schizophrenia is largely “a static encephalopathy” with no significant progression of symptoms.⁸ A number of studies referenced by Rajji and Mulsant⁶ in their systematic review report that cognitive deficits seen in patients with LOS largely are stable on follow-up with an average duration of up to 3 years. However, 2 studies with longer follow-up report evidence of cognitive decline.^9,10

Relevant findings from the literature. Brodaty et al⁹ followed 27 patients with LOS without dementia and 34 otherwise healthy participants at baseline, 1 year, and 5 years. They reported that 9 patients with LOS and none of the control group were found to have dementia (5 Alzheimer type, 1 vascular, and 3 dementia of unknown type) at 5-year follow-up. Some patients had no clinical signs of dementia at baseline or at 1-year follow-up, but were found to have dementia at 5-year follow-up. The authors speculated that LOS might be a prodrome of Alzheimer-type dementia.

Kørner et al¹⁰ studied 12,600 patients with LOS and 7,700 with VLOS, selected from the Danish nationwide registry; follow-up was 3 to 4.58 years. They concluded that patients with LOS and VLOS were at 2 to 3 times greater risk of developing dementia than patients with osteoarthritis or the general population. The most common diagnosis among patients with schizophrenia was unspecified dementia, with Alzheimer’s dementia (AD) being the most common diagnosis in control groups. The findings suggest that dementia in LOS and VLOS has a different basis than AD.

Zakzanis et al¹¹ investigated which neuropsychological tests best differentiate patients with LOS and those with AD or frontotemporal dementia. They reported that Wechsler Adult Intelligence Scale-Revised (WAIS-R) Similarities subtest and the California Verbal Learning Test (both short- and long-delay free recall) can differentiate LOS from AD, and a test battery comprising the WAIS-R Vocabulary, Information, Digit Span, and Comprehension subtests, and the Hooper Visual Organization test can differentiate LOS and frontotemporal dementia.¹²

EVALUATION Significant impairment
CT head and MRI brain scans without contrast suggest mild generalized atrophy that is more prominent in frontal and parietal areas, but the scans are otherwise unremarkable overall. A PET scan is significant for hypoactivity in the temporal and parietal lobes but, again, the images are interpreted as unremarkable overall.

Ms. P scores 21 on the Montreal Cognitive Assessment (MoCA), indicative of significant cognitive impairment (normal score, ≥26). This is a 3-point decline on a MoCA performed during her admission 5 years earlier.

Ms. P scores 8 on the Middlesex Elderly Assessment of Mental State, the lowest score in the borderline range of cognitive function for geriatric patients. She scores 13 on the Kohlman Evaluation of Living Skills, indicating that she needs maximal supervision, structure, and support to live in the community. Particularly notable is that Ms. P failed 5 out of 6 subtests in money management—a marked decline for someone who had worked as a senior accountant.

Given Ms. P’s significant cognitive decline from premorbid functioning, verified by collateral information, and current cognitive deficits established on standardized tests, we determine that, in addition to a diagnosis of schizoaffective disorder, she might meet DSM-5 criteria for unspecified major neurocognitive disorder if her functioning does not improve with treatment.

The authors’ observations
There is scant literature on late-onset schizoaffective disorder. Webster and Grossberg¹³ conducted a retrospective chart review of 1,730 patients age >65 who were admitted to a geriatric psychiatry unit from 1988 to 1995. Of these patients, 166 (approximately 10%) were found to have late life-onset psychosis. The psychosis was attributed to various causes, such as dementia, depression, bipolar disorder, medical causes, delirium, medication toxicity. Two patients were diagnosed with schizophrenia and 2 were diagnosed with schizoaffective disorder (the authors did not provide additional information about the patients with schizoaffective disorder). Brenner et al¹⁴ reports a case of late-onset schizoaffective disorder in a 70-year-old female patient. Evans et al¹⁵ compared outpatients age 45 to 77 with a diagnosis of schizoaffective disorder (n = 29), schizophrenia (n = 154), or nonpsychotic mood disorder (n = 27) and concluded that late-onset schizoaffective disorder might represent a variant of LOS in clinical symptom profiles and cognitive impairment but with additional mood symptoms.¹⁶

How would you begin treating Ms. P?
   a) start a mood stabilizer
   b) start an atypical antipsychotic
   c) obtain more history and collateral information
   d) recommend outpatient treatment

The authors’ observations
Given Ms. P’s manic symptoms, thought disorder, and history of psychotic symptoms with diagnosis of LOS, we assigned her a presumptive diagnosis of schizoaffective disorder, bipolar type. From the patient report, collateral information from her mother, earlier documented collateral from her husband, and chart review, it was apparent to us that Ms. P’s psychiatric history went back only 10 years—therefore meeting temporal criteria for LOS.

Clinical assessment (Figure) and standardized tests revealed the presence of neurocognitive deficits sufficient to meet criteria for major neurocognitive disorder (Table 3³). The pattern of neurocognitive deficits is consistent with an AD-like amnestic picture, although no clear-cut diagnosis was present, and the neurocognitive disorder was better classified as unspecified rather than of a particular type. It remains uncertain whether cognitive deficits of severity that meet criteria for major neurocognitive disorder are sufficiently accounted for by the diagnosis of LOS alone. Unless diagnostic criteria for schizophrenia are expanded to include cognitive deficits, a separate diagnosis of major neurocognitive disorder is warranted at present.

TREATMENT Pharmacotherapy
On the unit, Ms. P is observed by nursing staff wandering, with some pressured speech but no behavioral agitation. Her clothing had been bizarre, with multiple layers, and, at one point, she walks with her gown open and without undergarments. She also reports to the nurses that she has a lot of sexual thoughts. When the interview team enters her room, they find her masturbating.

Ms. P is started on aripiprazole, 10 mg/d, titrated to 20 mg/d, and divalproex sodium, 500 mg/d. The decision to initiate a cognitive enhancer, such as an acetylcholinesterase inhibitor or memantine, is deferred to outpatient care to allow for the possibility that her cognitive features will improve after the psychosis is treated.

By the end of first week, Ms. P’s manic features are no longer prominent but her thought process continues to be bizarre, with poor insight and judgment. She demonstrates severe ambivalence in all matters, consistently gives inconsistent accounts of the past, and makes dramatic false statements.

For example, when asked about her children, Ms. P tells us that she has 6 children—the youngest 3 months old, at home by himself and “probably dead by now.” In reality, she has only a 20-year-old son who is studying abroad. Talking about her marriage, Ms. P says she and her husband are not divorced on paper but that, because they haven’t had sex for 8 years, the law has provided them with an automatic divorce.

OUTCOME Significant improvement
Ms. P shows significant response to aripiprazole and divalproex, which are well tolerated without significant adverse effects. Her limitations in executive functioning and rational thought process lead the treatment team to consider nursing home placement under guardianship. Days before discharge, however, reexamination of her neuropsychiatric state suggests significant improvement in thought process, with improvement in cognitive features. Ms. P also becomes cooperative with treatment planning.

The treatment team has meetings with Ms. P’s mother to discuss monitoring and plans for discharge. Ms. P is discharged with follow-up arranged at community mental health services.

Bottom Line
Global as well as specific cognitive deficits are associated with late-onset schizophrenia. Studies have reported increased risk of dementia in these patients over the course of 3 to 5 years, usually unspecified or Alzheimer’s type. It is imperative to assess patients with schizophrenia, especially those age ≥40, for presence of neurocognitive disorder by means of neurocognitive testing.

Related Resources

• Goff DC, Hill M, Barch D. The treatment of cognitive impairment in schizophrenia. Pharmacol Biochem Behav. 2011;99(2):245-253.
• Radhakrishnan R, Butler R, Head L. Dementia in schizophrenia. Adv Psychiatr Treat. 2012;18(2):144-153.
  
  

Drug Brand Names
Aripiprazole • Abilify
Divalproex sodium • Depakote
Mematine • Namenda

Disclosures
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturer of competing products.

Q2: ANSWER: D

Critique

This is a patient with severe alcoholic hepatitis complicated by sepsis with a Maddrey’s discriminant function greater than 32. Pentoxifylline 400 mg t.i.d. would be the most appropriate choice for treatment. Pentoxifylline is a nonselective phosphodiesterase inhibitor that decreases tumor necrosis factor gene transcription. In one study of severe alcoholic hepatitis, it appeared to reduce both mortality and renal failure. It may have a beneficial effect in preventing HRS. Prednisone would not be optimal in the setting of active infection and sepsis. Anti-TNF treatment has been associated with increased risk of severe infections and this and propylthiouracil have not shown benefit in the treatment of alcoholic hepatitis. For this patient with severe alcoholic hepatitis, treatment will improve survival and observation would not be adequate.

References

1. O’Shea R.S., Dasarathy S., McCullough A.J.. Alcoholic liver disease. Hepatology 2010;51:307-28.
2. Mathurin P., Mendenhall C.L., et al. Corticosteroids improve short-term survival in patients with severe alcoholic hepatitis (AH): individual data analysis of the last three randomized placebo controlled double blind trials of corticosteroids in severe AH. J Hepatol. 2002;36:480-7.

Q2: ANSWER: D

Critique

This is a patient with severe alcoholic hepatitis complicated by sepsis with a Maddrey’s discriminant function greater than 32. Pentoxifylline 400 mg t.i.d. would be the most appropriate choice for treatment. Pentoxifylline is a nonselective phosphodiesterase inhibitor that decreases tumor necrosis factor gene transcription. In one study of severe alcoholic hepatitis, it appeared to reduce both mortality and renal failure. It may have a beneficial effect in preventing HRS. Prednisone would not be optimal in the setting of active infection and sepsis. Anti-TNF treatment has been associated with increased risk of severe infections and this and propylthiouracil have not shown benefit in the treatment of alcoholic hepatitis. For this patient with severe alcoholic hepatitis, treatment will improve survival and observation would not be adequate.

References

1. O’Shea R.S., Dasarathy S., McCullough A.J.. Alcoholic liver disease. Hepatology 2010;51:307-28.
2. Mathurin P., Mendenhall C.L., et al. Corticosteroids improve short-term survival in patients with severe alcoholic hepatitis (AH): individual data analysis of the last three randomized placebo controlled double blind trials of corticosteroids in severe AH. J Hepatol. 2002;36:480-7.

Q2: ANSWER: D

Critique

This is a patient with severe alcoholic hepatitis complicated by sepsis with a Maddrey’s discriminant function greater than 32. Pentoxifylline 400 mg t.i.d. would be the most appropriate choice for treatment. Pentoxifylline is a nonselective phosphodiesterase inhibitor that decreases tumor necrosis factor gene transcription. In one study of severe alcoholic hepatitis, it appeared to reduce both mortality and renal failure. It may have a beneficial effect in preventing HRS. Prednisone would not be optimal in the setting of active infection and sepsis. Anti-TNF treatment has been associated with increased risk of severe infections and this and propylthiouracil have not shown benefit in the treatment of alcoholic hepatitis. For this patient with severe alcoholic hepatitis, treatment will improve survival and observation would not be adequate.

References

1. O’Shea R.S., Dasarathy S., McCullough A.J.. Alcoholic liver disease. Hepatology 2010;51:307-28.
2. Mathurin P., Mendenhall C.L., et al. Corticosteroids improve short-term survival in patients with severe alcoholic hepatitis (AH): individual data analysis of the last three randomized placebo controlled double blind trials of corticosteroids in severe AH. J Hepatol. 2002;36:480-7.

Pain is one of the most common symptoms for which patients seek medical care, with an associated estimated annual cost of $600 billion.¹ Using a multimodal approach to care—thorough evaluation, cognitive-behavioral and psychophysiological therapy, physical therapy, medications, and other interventions—can help patients effectively manage their condition and achieve healthier outcomes.

Evaluating a patient with pain
When developing a safe, comprehensive, and effective treatment plan for patients with chronic pain, first perform a thorough history and physical exam using the following elements:

Pain history. The PQRST mnemonic (Table 1) can help you obtain critical information and assist in determining the appropriate diagnosis and cause of the patient’s pain complaints.

Psychiatric history. Document the mental health history of the patient and first-degree relatives.

Medical history. Knowing the medical history could reveal comorbidities contributing to a patient’s pain complaint.

Treatment history. Listing past and current treatments for pain, including effectiveness, helps the clinician understand if an existing treatment plan should be modified.

Functional status. Document current level of daily activity, how life activities are affected by pain; strategies used to help cope with pain; level of physical and emotional support provided in home, work, and school environments; and active stressors (eg, financial, interpersonal).

Psychosocial history. Document historical information related to coping skills, trauma history, family of origin, abuse, interpersonal relationships, social support, and academic and vocational functioning.

Substance use or abuse. Assess for use of controlled substances (ie, early refills; lost medications; obtaining medications from multiple prescribers, friends, families, or strangers; use of prescribed and non-prescribed medications for non-medical and medical purposes), nicotine, alcohol, illicit substances, and caffeine. A thorough inventory can help to identify substances a patient is using that could affect daily functioning and pain level.

Behavioral observations. Assessing mental status (eg, insight, pain behavior, co­operation) can be useful. Paying attention to pain behaviors, such as complaints of pain, decreased activity, increased medication intake, or altered facial expressions or body posture, can help the clinician gain insight to the extent that pain affects the patient’s quality of life.

The information gathered in the patient evaluation can be used to design a multimodal treatment plan to achieve maximum effectiveness.

Assessing psychiatric illness
Current approaches to pain evaluation and treatment recommend use of a biopsychosocial orientation because psychological, behavioral, and social factors can influence the experience and impact of pain, regardless of the primary cause.² A comprehensive psychiatric evaluation, diagnosis, and treatment plan should consider the broader context in which a patient’s pain occurs.

Regarding psychiatric illness, past and current symptoms, treatment history, and risk assessment should all be included. Using the “AMPS approach” (Figure)³—assessing Anxiety, Mood (depression and mania), Psychotic symptoms (paranoid ideation and hallucinations), and Substance use—helps screen for comorbid psychiatric conditions in patients with chronic pain.

Sleep assessment
Chronic pain patients often experience significant sleep disturbance that could be caused by physiological aspects of the pain condition, environmental factors (eg, uncomfortable bedding), a comorbid sleep disorder (eg, sleep apnea), a psychiatric disorder, or a combination of the above.

Obstructive and central sleep apnea are characterized by nighttime hypoxia, which leads to frequent disruption of the sleep-wake cycle and often manifests as daytime fatigue, irritability, depression, drowsiness, headaches, and increased pain sensitivity. Changes in sleep arousal can lead to neuro­psychological changes during the day, such as decreased attention, memory problems, impaired executive functioning, and reduced impulse control.

Screen patients for central and obstructive sleep apnea before prescribing opioids or benzodiazepines for pain because these medications can cause or exacerbate underlying sleep apnea. Although many screening tools, such as the Epworth Sleepiness Scale, assess daytime somnolence,⁴ the STOP-BANG questionnaire is a quick, validated, and efficient screening tool that often is used to assess sleep apnea risk^5,6 (Table 2). The presence of ≥3 risk factors identifies patients at increased risk and warrants consideration for further workup by a sleep specialist.^7,8

Pharmacotherapy for chronic pain
Non-opioid medications. Pain can be broadly categorized as neuropathic or nociceptive. Neuropathic pain can be described by patients as numbness, burning, electric-like, and tingling, and is associated with nerve damage. Nociceptive pain commonly is described as similar to a toothache with descriptors such as stabbing, sharp, or a dull aching sensation; it is often, but not always, associated with acute injury or ongoing trauma to tissue. Drug treatment is most successful when the appropriate class of medication is matched to the specific type of pain.

Nociceptive pain often is successfully treated with non-steroidal anti-inflammatory drugs and acetaminophen. Non-selective COX inhibitors (eg, ibuprofen, indomethacin, ketorolac) and COX-2 selective inhibitors (eg, celecoxib) have been associated with cardiovascular, gastrointestinal, and renal disease; acetaminophen is associated with liver dysfunction.^9-11 However, the absolute risk for complications in healthy patients is low.¹² To minimize risk, use these agents for the shortest duration and at the lowest effective dosage possible.

Neuropathic pain can be addressed with certain antidepressants¹³—specifically, those that increase serotonin and norepinephrine (eg, tricyclic antidepressants [TCAs] and serotonin-norepinephrine reuptake inhibitors [SNRIs]), or medications that block ion channels (eg, anticonvulsants). TCAs (eg, desipramine, nortriptyline, amitriptyline) are among the best studied and most cost effective medications for treating neuropathic pain,^14,15 but they can have sedating and anticholinergic effects, as well as cardiac adverse effects (ie, prolongation of the QTc interval). SNRIs (eg, venlafaxine, desvenlafaxine, duloxetine, and milnacipran) can be effective and often are better tolerated than TCAs.¹⁴

Some newer anticonvulsants (eg, gabapentin and pregabalin) have been found to be more effective than placebo for a variety of neuropathic pain conditions.^16,17 Although they have few drug-drug interactions, anticonvulsants can cause dizziness, forgetfulness, and sedation. These adverse effects can be minimized by starting at a low dosage and titrating carefully. Because hepatic or renal impairment can affect metabolism or excretion of these drugs, review the prescribing information to determine safe dosing.

Targeted injection of medications to major pain generators (eg, an epidural steroid for radicular neck and back pain; facet injections for facet-related neck and back pain; trigger point injections for myofascial pain; occipital nerve blocks for occipital neuralgia; and botulinum toxin A injections for chronic migraine headache) can be effective in reducing discomfort and increasing function in patients with chronic pain. A detailed discussion of such therapies is beyond the scope of this article, but have been reviewed extensively elsewhere.^18,19

Opioids. Although there is little evidence of long-term efficacy with chronic opioid therapy for most patients, a trial of opioids might be warranted for select patients who do not respond to other medications. Because the risk–benefit ratio for chronic opioid therapy is high,^20-22 a decision to initiate a trial of a low-dosage opioid should be made only after careful consideration of those risks. It is generally agreed that treatment of chronic pain with low-dosage opioid therapy is more likely to be successful when it is used as an adjuvant to non-opioid modalities (eg, physical reconditioning, injection therapies, spinal cord stimulation, neurobehavioral interventions, non-opioid medications).

The Federation of State Medical Boards has stated that excessive reliance on opioid medications for treating chronic pain is a deviation from best practices.²³ To maximize benefit and minimize risk, clinicians should carefully select appropriate patients, establish functional goals, and regularly monitor for efficacy and compliance. Thoroughly document these steps in the patient’s record for later reference.²³

After establishing a clinical diagnosis for the cause of the pain, you should determine the risk of opioid abuse or misuse by using any one of the available risk assessment tools (Box). Understand, however, that no single tool has been shown to be more effective than others.

Although patients and some clinicians tend to overvalue the benefits of chronic opioid therapy, many do not fully appreciate the risks (eg, respiratory depression and death), which can be exacerbated if the patient is using other substance that suppress respiration (eg, benzodiazepines, alcohol, and illicit substances). Written informed consent and treatment agreement is highly recommended; components of such a document are listed in Table 3.²³

Develop a treatment plan that emphasizes functional goals based on the patient’s physical limitations and that incorporates some type of daily, atraumatic physical activity. This plan should be documented and reviewed regularly to help monitor treatment effectiveness.

After an initial trial of a few weeks, the patient and clinician should meet to review the 5 “A”s (Table 4)²⁴ to determine the success of the opioid regimen. Consulting your state’s prescription drug monitoring program (if one is available), obtaining a random urine drug test, and doing a pill count can provide useful, objective data. If the patient has not made progress but has experienced no adverse effects, then a small dosage increase might be warranted. If any of the 5 “A”s indicates lack of improvement or increased risk, consider stopping opioid therapy and exploring non-opioid options to manage chronic pain.

Referrals to a pain specialist or an addiction specialist, or both, might be needed, depending on the patient’s condition at any given follow-up visit. Such referral decisions, as well as all treatment plans, should be documented clearly in the medical record to prevent any misunderstanding, false accusations, or medicolegal repercussions regarding the rationale for continuing or terminating opioid-based treatment.

Non-pharmaceutical therapy for treating pain
The pain management field has successfully integrated the biopsychosocial model into regular practice. This model advocates the use of multimodal non-drug interventions in conjunction with opioid and non-opioid medications. Such interventions address behavioral, cognitive, sociocultural (psychosocial), lifestyle, and physiological dimensions of pain. A partial list of non-drug interventions is provided in Table 5.

Integration of these interventions within a biopsychosocial framework can assist you in making a comprehensive treatment plan. For example, patients with focal myofascial shoulder and back pain might derive only transient benefit from trigger point injection. However, concurrent referral to a pain psychologist and physical therapist could substantially improve functional outcomes by addressing factors that directly and indirectly influence myofascial pain. Inclusion of cognitive-behavioral therapy (addressing psychosocial and lifestyle dimensions), surface electromyography, psychophysiological interventions/biofeedback (addressing psychosocial, lifestyle, and physiological dimensions), and physical therapy (addressing lifestyle and physiological dimensions) allows the patient to learn coping skills, decrease physiological arousal that can lead to unnecessary tensing of muscles, and strengthen core muscle groups.

Pain is one of the most common symptoms for which patients seek medical care, with an associated estimated annual cost of $600 billion.¹ Using a multimodal approach to care—thorough evaluation, cognitive-behavioral and psychophysiological therapy, physical therapy, medications, and other interventions—can help patients effectively manage their condition and achieve healthier outcomes.

Evaluating a patient with pain
When developing a safe, comprehensive, and effective treatment plan for patients with chronic pain, first perform a thorough history and physical exam using the following elements:

Pain history. The PQRST mnemonic (Table 1) can help you obtain critical information and assist in determining the appropriate diagnosis and cause of the patient’s pain complaints.

Psychiatric history. Document the mental health history of the patient and first-degree relatives.

Medical history. Knowing the medical history could reveal comorbidities contributing to a patient’s pain complaint.

Treatment history. Listing past and current treatments for pain, including effectiveness, helps the clinician understand if an existing treatment plan should be modified.

Functional status. Document current level of daily activity, how life activities are affected by pain; strategies used to help cope with pain; level of physical and emotional support provided in home, work, and school environments; and active stressors (eg, financial, interpersonal).

Psychosocial history. Document historical information related to coping skills, trauma history, family of origin, abuse, interpersonal relationships, social support, and academic and vocational functioning.

Substance use or abuse. Assess for use of controlled substances (ie, early refills; lost medications; obtaining medications from multiple prescribers, friends, families, or strangers; use of prescribed and non-prescribed medications for non-medical and medical purposes), nicotine, alcohol, illicit substances, and caffeine. A thorough inventory can help to identify substances a patient is using that could affect daily functioning and pain level.

Behavioral observations. Assessing mental status (eg, insight, pain behavior, co­operation) can be useful. Paying attention to pain behaviors, such as complaints of pain, decreased activity, increased medication intake, or altered facial expressions or body posture, can help the clinician gain insight to the extent that pain affects the patient’s quality of life.

The information gathered in the patient evaluation can be used to design a multimodal treatment plan to achieve maximum effectiveness.

Assessing psychiatric illness
Current approaches to pain evaluation and treatment recommend use of a biopsychosocial orientation because psychological, behavioral, and social factors can influence the experience and impact of pain, regardless of the primary cause.² A comprehensive psychiatric evaluation, diagnosis, and treatment plan should consider the broader context in which a patient’s pain occurs.

Regarding psychiatric illness, past and current symptoms, treatment history, and risk assessment should all be included. Using the “AMPS approach” (Figure)³—assessing Anxiety, Mood (depression and mania), Psychotic symptoms (paranoid ideation and hallucinations), and Substance use—helps screen for comorbid psychiatric conditions in patients with chronic pain.

Sleep assessment
Chronic pain patients often experience significant sleep disturbance that could be caused by physiological aspects of the pain condition, environmental factors (eg, uncomfortable bedding), a comorbid sleep disorder (eg, sleep apnea), a psychiatric disorder, or a combination of the above.

Obstructive and central sleep apnea are characterized by nighttime hypoxia, which leads to frequent disruption of the sleep-wake cycle and often manifests as daytime fatigue, irritability, depression, drowsiness, headaches, and increased pain sensitivity. Changes in sleep arousal can lead to neuro­psychological changes during the day, such as decreased attention, memory problems, impaired executive functioning, and reduced impulse control.

Screen patients for central and obstructive sleep apnea before prescribing opioids or benzodiazepines for pain because these medications can cause or exacerbate underlying sleep apnea. Although many screening tools, such as the Epworth Sleepiness Scale, assess daytime somnolence,⁴ the STOP-BANG questionnaire is a quick, validated, and efficient screening tool that often is used to assess sleep apnea risk^5,6 (Table 2). The presence of ≥3 risk factors identifies patients at increased risk and warrants consideration for further workup by a sleep specialist.^7,8

Pharmacotherapy for chronic pain
Non-opioid medications. Pain can be broadly categorized as neuropathic or nociceptive. Neuropathic pain can be described by patients as numbness, burning, electric-like, and tingling, and is associated with nerve damage. Nociceptive pain commonly is described as similar to a toothache with descriptors such as stabbing, sharp, or a dull aching sensation; it is often, but not always, associated with acute injury or ongoing trauma to tissue. Drug treatment is most successful when the appropriate class of medication is matched to the specific type of pain.

Nociceptive pain often is successfully treated with non-steroidal anti-inflammatory drugs and acetaminophen. Non-selective COX inhibitors (eg, ibuprofen, indomethacin, ketorolac) and COX-2 selective inhibitors (eg, celecoxib) have been associated with cardiovascular, gastrointestinal, and renal disease; acetaminophen is associated with liver dysfunction.^9-11 However, the absolute risk for complications in healthy patients is low.¹² To minimize risk, use these agents for the shortest duration and at the lowest effective dosage possible.

Neuropathic pain can be addressed with certain antidepressants¹³—specifically, those that increase serotonin and norepinephrine (eg, tricyclic antidepressants [TCAs] and serotonin-norepinephrine reuptake inhibitors [SNRIs]), or medications that block ion channels (eg, anticonvulsants). TCAs (eg, desipramine, nortriptyline, amitriptyline) are among the best studied and most cost effective medications for treating neuropathic pain,^14,15 but they can have sedating and anticholinergic effects, as well as cardiac adverse effects (ie, prolongation of the QTc interval). SNRIs (eg, venlafaxine, desvenlafaxine, duloxetine, and milnacipran) can be effective and often are better tolerated than TCAs.¹⁴

Some newer anticonvulsants (eg, gabapentin and pregabalin) have been found to be more effective than placebo for a variety of neuropathic pain conditions.^16,17 Although they have few drug-drug interactions, anticonvulsants can cause dizziness, forgetfulness, and sedation. These adverse effects can be minimized by starting at a low dosage and titrating carefully. Because hepatic or renal impairment can affect metabolism or excretion of these drugs, review the prescribing information to determine safe dosing.

Targeted injection of medications to major pain generators (eg, an epidural steroid for radicular neck and back pain; facet injections for facet-related neck and back pain; trigger point injections for myofascial pain; occipital nerve blocks for occipital neuralgia; and botulinum toxin A injections for chronic migraine headache) can be effective in reducing discomfort and increasing function in patients with chronic pain. A detailed discussion of such therapies is beyond the scope of this article, but have been reviewed extensively elsewhere.^18,19

Opioids. Although there is little evidence of long-term efficacy with chronic opioid therapy for most patients, a trial of opioids might be warranted for select patients who do not respond to other medications. Because the risk–benefit ratio for chronic opioid therapy is high,^20-22 a decision to initiate a trial of a low-dosage opioid should be made only after careful consideration of those risks. It is generally agreed that treatment of chronic pain with low-dosage opioid therapy is more likely to be successful when it is used as an adjuvant to non-opioid modalities (eg, physical reconditioning, injection therapies, spinal cord stimulation, neurobehavioral interventions, non-opioid medications).

The Federation of State Medical Boards has stated that excessive reliance on opioid medications for treating chronic pain is a deviation from best practices.²³ To maximize benefit and minimize risk, clinicians should carefully select appropriate patients, establish functional goals, and regularly monitor for efficacy and compliance. Thoroughly document these steps in the patient’s record for later reference.²³

After establishing a clinical diagnosis for the cause of the pain, you should determine the risk of opioid abuse or misuse by using any one of the available risk assessment tools (Box). Understand, however, that no single tool has been shown to be more effective than others.

Although patients and some clinicians tend to overvalue the benefits of chronic opioid therapy, many do not fully appreciate the risks (eg, respiratory depression and death), which can be exacerbated if the patient is using other substance that suppress respiration (eg, benzodiazepines, alcohol, and illicit substances). Written informed consent and treatment agreement is highly recommended; components of such a document are listed in Table 3.²³

Develop a treatment plan that emphasizes functional goals based on the patient’s physical limitations and that incorporates some type of daily, atraumatic physical activity. This plan should be documented and reviewed regularly to help monitor treatment effectiveness.

After an initial trial of a few weeks, the patient and clinician should meet to review the 5 “A”s (Table 4)²⁴ to determine the success of the opioid regimen. Consulting your state’s prescription drug monitoring program (if one is available), obtaining a random urine drug test, and doing a pill count can provide useful, objective data. If the patient has not made progress but has experienced no adverse effects, then a small dosage increase might be warranted. If any of the 5 “A”s indicates lack of improvement or increased risk, consider stopping opioid therapy and exploring non-opioid options to manage chronic pain.

Referrals to a pain specialist or an addiction specialist, or both, might be needed, depending on the patient’s condition at any given follow-up visit. Such referral decisions, as well as all treatment plans, should be documented clearly in the medical record to prevent any misunderstanding, false accusations, or medicolegal repercussions regarding the rationale for continuing or terminating opioid-based treatment.

Non-pharmaceutical therapy for treating pain
The pain management field has successfully integrated the biopsychosocial model into regular practice. This model advocates the use of multimodal non-drug interventions in conjunction with opioid and non-opioid medications. Such interventions address behavioral, cognitive, sociocultural (psychosocial), lifestyle, and physiological dimensions of pain. A partial list of non-drug interventions is provided in Table 5.

Integration of these interventions within a biopsychosocial framework can assist you in making a comprehensive treatment plan. For example, patients with focal myofascial shoulder and back pain might derive only transient benefit from trigger point injection. However, concurrent referral to a pain psychologist and physical therapist could substantially improve functional outcomes by addressing factors that directly and indirectly influence myofascial pain. Inclusion of cognitive-behavioral therapy (addressing psychosocial and lifestyle dimensions), surface electromyography, psychophysiological interventions/biofeedback (addressing psychosocial, lifestyle, and physiological dimensions), and physical therapy (addressing lifestyle and physiological dimensions) allows the patient to learn coping skills, decrease physiological arousal that can lead to unnecessary tensing of muscles, and strengthen core muscle groups.

Pain is one of the most common symptoms for which patients seek medical care, with an associated estimated annual cost of $600 billion.¹ Using a multimodal approach to care—thorough evaluation, cognitive-behavioral and psychophysiological therapy, physical therapy, medications, and other interventions—can help patients effectively manage their condition and achieve healthier outcomes.

Evaluating a patient with pain
When developing a safe, comprehensive, and effective treatment plan for patients with chronic pain, first perform a thorough history and physical exam using the following elements:

Pain history. The PQRST mnemonic (Table 1) can help you obtain critical information and assist in determining the appropriate diagnosis and cause of the patient’s pain complaints.

Psychiatric history. Document the mental health history of the patient and first-degree relatives.

Medical history. Knowing the medical history could reveal comorbidities contributing to a patient’s pain complaint.

Treatment history. Listing past and current treatments for pain, including effectiveness, helps the clinician understand if an existing treatment plan should be modified.

Functional status. Document current level of daily activity, how life activities are affected by pain; strategies used to help cope with pain; level of physical and emotional support provided in home, work, and school environments; and active stressors (eg, financial, interpersonal).

Psychosocial history. Document historical information related to coping skills, trauma history, family of origin, abuse, interpersonal relationships, social support, and academic and vocational functioning.

Substance use or abuse. Assess for use of controlled substances (ie, early refills; lost medications; obtaining medications from multiple prescribers, friends, families, or strangers; use of prescribed and non-prescribed medications for non-medical and medical purposes), nicotine, alcohol, illicit substances, and caffeine. A thorough inventory can help to identify substances a patient is using that could affect daily functioning and pain level.

Behavioral observations. Assessing mental status (eg, insight, pain behavior, co­operation) can be useful. Paying attention to pain behaviors, such as complaints of pain, decreased activity, increased medication intake, or altered facial expressions or body posture, can help the clinician gain insight to the extent that pain affects the patient’s quality of life.

The information gathered in the patient evaluation can be used to design a multimodal treatment plan to achieve maximum effectiveness.

Assessing psychiatric illness
Current approaches to pain evaluation and treatment recommend use of a biopsychosocial orientation because psychological, behavioral, and social factors can influence the experience and impact of pain, regardless of the primary cause.² A comprehensive psychiatric evaluation, diagnosis, and treatment plan should consider the broader context in which a patient’s pain occurs.

Regarding psychiatric illness, past and current symptoms, treatment history, and risk assessment should all be included. Using the “AMPS approach” (Figure)³—assessing Anxiety, Mood (depression and mania), Psychotic symptoms (paranoid ideation and hallucinations), and Substance use—helps screen for comorbid psychiatric conditions in patients with chronic pain.

Sleep assessment
Chronic pain patients often experience significant sleep disturbance that could be caused by physiological aspects of the pain condition, environmental factors (eg, uncomfortable bedding), a comorbid sleep disorder (eg, sleep apnea), a psychiatric disorder, or a combination of the above.

Obstructive and central sleep apnea are characterized by nighttime hypoxia, which leads to frequent disruption of the sleep-wake cycle and often manifests as daytime fatigue, irritability, depression, drowsiness, headaches, and increased pain sensitivity. Changes in sleep arousal can lead to neuro­psychological changes during the day, such as decreased attention, memory problems, impaired executive functioning, and reduced impulse control.

Screen patients for central and obstructive sleep apnea before prescribing opioids or benzodiazepines for pain because these medications can cause or exacerbate underlying sleep apnea. Although many screening tools, such as the Epworth Sleepiness Scale, assess daytime somnolence,⁴ the STOP-BANG questionnaire is a quick, validated, and efficient screening tool that often is used to assess sleep apnea risk^5,6 (Table 2). The presence of ≥3 risk factors identifies patients at increased risk and warrants consideration for further workup by a sleep specialist.^7,8

Pharmacotherapy for chronic pain
Non-opioid medications. Pain can be broadly categorized as neuropathic or nociceptive. Neuropathic pain can be described by patients as numbness, burning, electric-like, and tingling, and is associated with nerve damage. Nociceptive pain commonly is described as similar to a toothache with descriptors such as stabbing, sharp, or a dull aching sensation; it is often, but not always, associated with acute injury or ongoing trauma to tissue. Drug treatment is most successful when the appropriate class of medication is matched to the specific type of pain.

Nociceptive pain often is successfully treated with non-steroidal anti-inflammatory drugs and acetaminophen. Non-selective COX inhibitors (eg, ibuprofen, indomethacin, ketorolac) and COX-2 selective inhibitors (eg, celecoxib) have been associated with cardiovascular, gastrointestinal, and renal disease; acetaminophen is associated with liver dysfunction.^9-11 However, the absolute risk for complications in healthy patients is low.¹² To minimize risk, use these agents for the shortest duration and at the lowest effective dosage possible.

Neuropathic pain can be addressed with certain antidepressants¹³—specifically, those that increase serotonin and norepinephrine (eg, tricyclic antidepressants [TCAs] and serotonin-norepinephrine reuptake inhibitors [SNRIs]), or medications that block ion channels (eg, anticonvulsants). TCAs (eg, desipramine, nortriptyline, amitriptyline) are among the best studied and most cost effective medications for treating neuropathic pain,^14,15 but they can have sedating and anticholinergic effects, as well as cardiac adverse effects (ie, prolongation of the QTc interval). SNRIs (eg, venlafaxine, desvenlafaxine, duloxetine, and milnacipran) can be effective and often are better tolerated than TCAs.¹⁴

Some newer anticonvulsants (eg, gabapentin and pregabalin) have been found to be more effective than placebo for a variety of neuropathic pain conditions.^16,17 Although they have few drug-drug interactions, anticonvulsants can cause dizziness, forgetfulness, and sedation. These adverse effects can be minimized by starting at a low dosage and titrating carefully. Because hepatic or renal impairment can affect metabolism or excretion of these drugs, review the prescribing information to determine safe dosing.

Targeted injection of medications to major pain generators (eg, an epidural steroid for radicular neck and back pain; facet injections for facet-related neck and back pain; trigger point injections for myofascial pain; occipital nerve blocks for occipital neuralgia; and botulinum toxin A injections for chronic migraine headache) can be effective in reducing discomfort and increasing function in patients with chronic pain. A detailed discussion of such therapies is beyond the scope of this article, but have been reviewed extensively elsewhere.^18,19

Opioids. Although there is little evidence of long-term efficacy with chronic opioid therapy for most patients, a trial of opioids might be warranted for select patients who do not respond to other medications. Because the risk–benefit ratio for chronic opioid therapy is high,^20-22 a decision to initiate a trial of a low-dosage opioid should be made only after careful consideration of those risks. It is generally agreed that treatment of chronic pain with low-dosage opioid therapy is more likely to be successful when it is used as an adjuvant to non-opioid modalities (eg, physical reconditioning, injection therapies, spinal cord stimulation, neurobehavioral interventions, non-opioid medications).

The Federation of State Medical Boards has stated that excessive reliance on opioid medications for treating chronic pain is a deviation from best practices.²³ To maximize benefit and minimize risk, clinicians should carefully select appropriate patients, establish functional goals, and regularly monitor for efficacy and compliance. Thoroughly document these steps in the patient’s record for later reference.²³

After establishing a clinical diagnosis for the cause of the pain, you should determine the risk of opioid abuse or misuse by using any one of the available risk assessment tools (Box). Understand, however, that no single tool has been shown to be more effective than others.

Although patients and some clinicians tend to overvalue the benefits of chronic opioid therapy, many do not fully appreciate the risks (eg, respiratory depression and death), which can be exacerbated if the patient is using other substance that suppress respiration (eg, benzodiazepines, alcohol, and illicit substances). Written informed consent and treatment agreement is highly recommended; components of such a document are listed in Table 3.²³

Develop a treatment plan that emphasizes functional goals based on the patient’s physical limitations and that incorporates some type of daily, atraumatic physical activity. This plan should be documented and reviewed regularly to help monitor treatment effectiveness.

After an initial trial of a few weeks, the patient and clinician should meet to review the 5 “A”s (Table 4)²⁴ to determine the success of the opioid regimen. Consulting your state’s prescription drug monitoring program (if one is available), obtaining a random urine drug test, and doing a pill count can provide useful, objective data. If the patient has not made progress but has experienced no adverse effects, then a small dosage increase might be warranted. If any of the 5 “A”s indicates lack of improvement or increased risk, consider stopping opioid therapy and exploring non-opioid options to manage chronic pain.

Referrals to a pain specialist or an addiction specialist, or both, might be needed, depending on the patient’s condition at any given follow-up visit. Such referral decisions, as well as all treatment plans, should be documented clearly in the medical record to prevent any misunderstanding, false accusations, or medicolegal repercussions regarding the rationale for continuing or terminating opioid-based treatment.

Non-pharmaceutical therapy for treating pain
The pain management field has successfully integrated the biopsychosocial model into regular practice. This model advocates the use of multimodal non-drug interventions in conjunction with opioid and non-opioid medications. Such interventions address behavioral, cognitive, sociocultural (psychosocial), lifestyle, and physiological dimensions of pain. A partial list of non-drug interventions is provided in Table 5.

Integration of these interventions within a biopsychosocial framework can assist you in making a comprehensive treatment plan. For example, patients with focal myofascial shoulder and back pain might derive only transient benefit from trigger point injection. However, concurrent referral to a pain psychologist and physical therapist could substantially improve functional outcomes by addressing factors that directly and indirectly influence myofascial pain. Inclusion of cognitive-behavioral therapy (addressing psychosocial and lifestyle dimensions), surface electromyography, psychophysiological interventions/biofeedback (addressing psychosocial, lifestyle, and physiological dimensions), and physical therapy (addressing lifestyle and physiological dimensions) allows the patient to learn coping skills, decrease physiological arousal that can lead to unnecessary tensing of muscles, and strengthen core muscle groups.

Q1: ANSWER: C

Critique

The diagnosis of H. pylori may be made using either invasive or noninvasive methods. Invasive diagnostic methods either detect organisms directly (i.e., histological identification with appropriate stains or bacterial culture) or indirectly (i.e., rapid urease testing of biopsy specimens). Noninvasive methods include serum antibody, stool antigen, and detecting the metabolites of the bacterial enzyme urease (i.e., urea breath testing). It should be noted that serology should not be used to test for eradication as the antibodies may remain elevated for years after successful eradication therapy.

Treatment of H. pylori infection has become problematic recently primarily due to increasing antibiotic resistance. The eradication rate of standard triple therapy consisting of a proton pump inhibitor combined with clarithromycin (500 mg) and amoxicillin (1 g) (or metronidazole (500 mg), all given b.i.d. for 7-14 days has now declined to unacceptable levels, averaging 70%-80% but reported as low as 55%. It is currently recommended that a noninvasive method be used (other than serology) to confirm eradication in patients in whom eradication is deemed necessary.

References

1. Malfertheiner P., Megraud F., O’Morain C.A., et al. European Helicobacter Study Group. Management of Helicobacter pylori infection – the Maastricht IV/ Florence Consensus Report. Gut 2012;61:646-64.
2. De F., Giorgio F., Hassan C., et al. Worldwide H. pylori antibiotic resistance: a systematic review. J Gastrointestin Liver Dis. 2010;19:409-14.
3. Kearney D.J., Brousal A.. Treatment of Helicobacter pylori infection in clinical practice in the United States – Results from 224 patients. Dig Dis Sci. 2000;45:265-71.

Q1: ANSWER: C

Critique

The diagnosis of H. pylori may be made using either invasive or noninvasive methods. Invasive diagnostic methods either detect organisms directly (i.e., histological identification with appropriate stains or bacterial culture) or indirectly (i.e., rapid urease testing of biopsy specimens). Noninvasive methods include serum antibody, stool antigen, and detecting the metabolites of the bacterial enzyme urease (i.e., urea breath testing). It should be noted that serology should not be used to test for eradication as the antibodies may remain elevated for years after successful eradication therapy.

Treatment of H. pylori infection has become problematic recently primarily due to increasing antibiotic resistance. The eradication rate of standard triple therapy consisting of a proton pump inhibitor combined with clarithromycin (500 mg) and amoxicillin (1 g) (or metronidazole (500 mg), all given b.i.d. for 7-14 days has now declined to unacceptable levels, averaging 70%-80% but reported as low as 55%. It is currently recommended that a noninvasive method be used (other than serology) to confirm eradication in patients in whom eradication is deemed necessary.

References

1. Malfertheiner P., Megraud F., O’Morain C.A., et al. European Helicobacter Study Group. Management of Helicobacter pylori infection – the Maastricht IV/ Florence Consensus Report. Gut 2012;61:646-64.
2. De F., Giorgio F., Hassan C., et al. Worldwide H. pylori antibiotic resistance: a systematic review. J Gastrointestin Liver Dis. 2010;19:409-14.
3. Kearney D.J., Brousal A.. Treatment of Helicobacter pylori infection in clinical practice in the United States – Results from 224 patients. Dig Dis Sci. 2000;45:265-71.

Q1: ANSWER: C

Critique

The diagnosis of H. pylori may be made using either invasive or noninvasive methods. Invasive diagnostic methods either detect organisms directly (i.e., histological identification with appropriate stains or bacterial culture) or indirectly (i.e., rapid urease testing of biopsy specimens). Noninvasive methods include serum antibody, stool antigen, and detecting the metabolites of the bacterial enzyme urease (i.e., urea breath testing). It should be noted that serology should not be used to test for eradication as the antibodies may remain elevated for years after successful eradication therapy.

Treatment of H. pylori infection has become problematic recently primarily due to increasing antibiotic resistance. The eradication rate of standard triple therapy consisting of a proton pump inhibitor combined with clarithromycin (500 mg) and amoxicillin (1 g) (or metronidazole (500 mg), all given b.i.d. for 7-14 days has now declined to unacceptable levels, averaging 70%-80% but reported as low as 55%. It is currently recommended that a noninvasive method be used (other than serology) to confirm eradication in patients in whom eradication is deemed necessary.

References

1. Malfertheiner P., Megraud F., O’Morain C.A., et al. European Helicobacter Study Group. Management of Helicobacter pylori infection – the Maastricht IV/ Florence Consensus Report. Gut 2012;61:646-64.
2. De F., Giorgio F., Hassan C., et al. Worldwide H. pylori antibiotic resistance: a systematic review. J Gastrointestin Liver Dis. 2010;19:409-14.
3. Kearney D.J., Brousal A.. Treatment of Helicobacter pylori infection in clinical practice in the United States – Results from 224 patients. Dig Dis Sci. 2000;45:265-71.

The diversity of hospitalist practice—from the variety of settings (such as inpatient acute, observation, post-discharge clinics, and post-acute-care facilities) to the differences in relationships with their facilities—is a strength of the specialty. It reflects the ability of the specialty to adapt to the unique needs of its local patients and institutions.

At the same time, it presents some unique challenges to developing strategies for identifying and assessing hospitalists. As the Medicare physician payment system moves toward value-based payment, hospitalists must report quality measures in the Physician Quality Reporting System (PQRS) or face ever-increasing penalties.

Many hospitalists are part of multispecialty groups aligned with a range of physicians employed by the same facility, including many academic hospitalists and those in integrated healthcare systems. Frequently for hospitalists in these groups, the group reports via a group-practice reporting option that uses measures for outpatient providers, capitalizing on the performances of those outpatient primary care providers in the group and making it generally unnecessary for these hospitalists to independently worry about PQRS reporting. Due to their employment model, they might also be somewhat insulated from seeing firsthand any value-based reimbursement adjustments from Medicare.

Hospitalists commonly are employed by single-specialty groups, medium or large in number of HM-focused providers, or increasingly a mix of hospitalists, emergency physicians, and hospitalists focused on skilled nursing facility (SNF) care. Still others are in small hospitalist groups or independent practitioners of hospital medicine. For these hospitalists, successful reporting of PQRS is important; they cannot rely on broad-based primary care group reporting options, and penalties can have an immediate impact on revenue streams.

PQRS, just like its hospital counterpart, the Inpatient Quality Reporting (IQR) system, was designed for use in an isolated healthcare delivery silo: PQRS was meant for physicians; IQR, for hospitals. This explicit design makes the measuring of hospitalists difficult within the current value-based payment programs because while the patient-care goals of hospitalists and their hospitals overlap, hospitalists are forced to report on physician-level metrics. Following this silo logic, the Centers for Medicare & Medicaid Services (CMS) has been removing physician-level PQRS measures that it views as redundant with facility-level IQR metrics, which has contributed to the detrimental reduction of relevant PQRS metrics for hospitalists over the years.

However, in large part due to the significant advocacy efforts of SHM around last year’s Medicare Access and CHIP Reauthorization Act (MACRA), CMS now has the ability to reverse this trend and include metrics from other programs, such as IQR metrics, as part of the quality or cost component of physician value-based payment. This would help to eliminate the artificial misalignment of quality goals and metrics for hospitalists and their facilities. Including hospital IQR metrics in the mandatory Medicare physician reporting programs would help to ensure hospitalists receive credit for the care they are providing for hospitalized patients and for the measures they are commonly held accountable for as part of their jobs.

As SHM advocates for hospitalists as the new Merit-Based Incentive Payment System (MIPS) reporting program unrolls as part of MACRA, we will keep these principles in mind: reduce administrative and reporting burdens, make metrics and their resulting data as actionable and useful as possible, and account for the important work hospitalists are doing in their facilities. As we are looking ahead at the future, we encourage you to make sure you are reporting in PQRS for 2016.

For more information about 2016 PQRS reporting, visit www.hospitalmedicine.org/pqrs. TH

Joshua Lapps is SHM’s government relations manager.

The diversity of hospitalist practice—from the variety of settings (such as inpatient acute, observation, post-discharge clinics, and post-acute-care facilities) to the differences in relationships with their facilities—is a strength of the specialty. It reflects the ability of the specialty to adapt to the unique needs of its local patients and institutions.

At the same time, it presents some unique challenges to developing strategies for identifying and assessing hospitalists. As the Medicare physician payment system moves toward value-based payment, hospitalists must report quality measures in the Physician Quality Reporting System (PQRS) or face ever-increasing penalties.

Many hospitalists are part of multispecialty groups aligned with a range of physicians employed by the same facility, including many academic hospitalists and those in integrated healthcare systems. Frequently for hospitalists in these groups, the group reports via a group-practice reporting option that uses measures for outpatient providers, capitalizing on the performances of those outpatient primary care providers in the group and making it generally unnecessary for these hospitalists to independently worry about PQRS reporting. Due to their employment model, they might also be somewhat insulated from seeing firsthand any value-based reimbursement adjustments from Medicare.

Hospitalists commonly are employed by single-specialty groups, medium or large in number of HM-focused providers, or increasingly a mix of hospitalists, emergency physicians, and hospitalists focused on skilled nursing facility (SNF) care. Still others are in small hospitalist groups or independent practitioners of hospital medicine. For these hospitalists, successful reporting of PQRS is important; they cannot rely on broad-based primary care group reporting options, and penalties can have an immediate impact on revenue streams.

PQRS, just like its hospital counterpart, the Inpatient Quality Reporting (IQR) system, was designed for use in an isolated healthcare delivery silo: PQRS was meant for physicians; IQR, for hospitals. This explicit design makes the measuring of hospitalists difficult within the current value-based payment programs because while the patient-care goals of hospitalists and their hospitals overlap, hospitalists are forced to report on physician-level metrics. Following this silo logic, the Centers for Medicare & Medicaid Services (CMS) has been removing physician-level PQRS measures that it views as redundant with facility-level IQR metrics, which has contributed to the detrimental reduction of relevant PQRS metrics for hospitalists over the years.

However, in large part due to the significant advocacy efforts of SHM around last year’s Medicare Access and CHIP Reauthorization Act (MACRA), CMS now has the ability to reverse this trend and include metrics from other programs, such as IQR metrics, as part of the quality or cost component of physician value-based payment. This would help to eliminate the artificial misalignment of quality goals and metrics for hospitalists and their facilities. Including hospital IQR metrics in the mandatory Medicare physician reporting programs would help to ensure hospitalists receive credit for the care they are providing for hospitalized patients and for the measures they are commonly held accountable for as part of their jobs.

As SHM advocates for hospitalists as the new Merit-Based Incentive Payment System (MIPS) reporting program unrolls as part of MACRA, we will keep these principles in mind: reduce administrative and reporting burdens, make metrics and their resulting data as actionable and useful as possible, and account for the important work hospitalists are doing in their facilities. As we are looking ahead at the future, we encourage you to make sure you are reporting in PQRS for 2016.

For more information about 2016 PQRS reporting, visit www.hospitalmedicine.org/pqrs. TH

Joshua Lapps is SHM’s government relations manager.

The diversity of hospitalist practice—from the variety of settings (such as inpatient acute, observation, post-discharge clinics, and post-acute-care facilities) to the differences in relationships with their facilities—is a strength of the specialty. It reflects the ability of the specialty to adapt to the unique needs of its local patients and institutions.

At the same time, it presents some unique challenges to developing strategies for identifying and assessing hospitalists. As the Medicare physician payment system moves toward value-based payment, hospitalists must report quality measures in the Physician Quality Reporting System (PQRS) or face ever-increasing penalties.

Many hospitalists are part of multispecialty groups aligned with a range of physicians employed by the same facility, including many academic hospitalists and those in integrated healthcare systems. Frequently for hospitalists in these groups, the group reports via a group-practice reporting option that uses measures for outpatient providers, capitalizing on the performances of those outpatient primary care providers in the group and making it generally unnecessary for these hospitalists to independently worry about PQRS reporting. Due to their employment model, they might also be somewhat insulated from seeing firsthand any value-based reimbursement adjustments from Medicare.

Hospitalists commonly are employed by single-specialty groups, medium or large in number of HM-focused providers, or increasingly a mix of hospitalists, emergency physicians, and hospitalists focused on skilled nursing facility (SNF) care. Still others are in small hospitalist groups or independent practitioners of hospital medicine. For these hospitalists, successful reporting of PQRS is important; they cannot rely on broad-based primary care group reporting options, and penalties can have an immediate impact on revenue streams.

PQRS, just like its hospital counterpart, the Inpatient Quality Reporting (IQR) system, was designed for use in an isolated healthcare delivery silo: PQRS was meant for physicians; IQR, for hospitals. This explicit design makes the measuring of hospitalists difficult within the current value-based payment programs because while the patient-care goals of hospitalists and their hospitals overlap, hospitalists are forced to report on physician-level metrics. Following this silo logic, the Centers for Medicare & Medicaid Services (CMS) has been removing physician-level PQRS measures that it views as redundant with facility-level IQR metrics, which has contributed to the detrimental reduction of relevant PQRS metrics for hospitalists over the years.

However, in large part due to the significant advocacy efforts of SHM around last year’s Medicare Access and CHIP Reauthorization Act (MACRA), CMS now has the ability to reverse this trend and include metrics from other programs, such as IQR metrics, as part of the quality or cost component of physician value-based payment. This would help to eliminate the artificial misalignment of quality goals and metrics for hospitalists and their facilities. Including hospital IQR metrics in the mandatory Medicare physician reporting programs would help to ensure hospitalists receive credit for the care they are providing for hospitalized patients and for the measures they are commonly held accountable for as part of their jobs.

As SHM advocates for hospitalists as the new Merit-Based Incentive Payment System (MIPS) reporting program unrolls as part of MACRA, we will keep these principles in mind: reduce administrative and reporting burdens, make metrics and their resulting data as actionable and useful as possible, and account for the important work hospitalists are doing in their facilities. As we are looking ahead at the future, we encourage you to make sure you are reporting in PQRS for 2016.

For more information about 2016 PQRS reporting, visit www.hospitalmedicine.org/pqrs. TH

Joshua Lapps is SHM’s government relations manager.

Cancer patient

receiving chemotherapy

Photo by Rhoda Baer

New research suggests that people living in the Appalachian region of the US are more likely to develop cancer than people in the rest of the country.

The study showed that Appalachians had a significantly higher incidence of cancer overall and higher rates of many solid tumor malignancies.

However, lymphoma rates were similar between Appalachians and non-Appalachians, and Appalachians had a significantly lower rate of myeloma.

This research was published in Cancer Epidemiology, Biomarkers & Prevention.

“The Appalachian region, which extends from parts of New York to Mississippi, spans 420 counties in 13 US states, and about 25 million people reside in this area,” said study author Reda Wilson, MPH, of the Centers for Disease Control and Prevention (CDC) in Atlanta, Georgia.

“This region is primarily made up of rural areas, with persistent poverty levels that are at least 20%, which is higher than the national average.”

In 2007, the CDC’s National Program of Cancer Registries (NPCR) published a comprehensive evaluation of cancer incidence rates in Appalachia between 2001 and 2003.

The data showed higher cancer rates in Appalachia than in the rest of the US. However, this publication had some shortcomings, including data that were not available for analysis.

“The current analyses reported here were performed to update the earlier evaluation by expanding the diagnosis years from 2004 to 2011 and including data on 100% of the Appalachian and non-Appalachian populations,” Wilson said.

For this study, Wilson and her colleagues used data from the NPCR and the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) program. Together, NPCR and SEER cover 100% of the US population.

The researchers analyzed the Appalachian population by region (north, central, and south Appalachia), gender, race (black and white only), and Appalachian Regional Commission-designated economic status (distressed, at-risk, transitional, competitive, and attainment). And the team compared these data with data on the non-Appalachian population.

The results showed that cancer incidence rates (IRs) were elevated among Appalachians regardless of how they were categorized. The IRs were per 100,000 people, age-adjusted to the 2000 US standard population.

The IR for all cancers was 565.8 for males in Appalachia and 543.0 for non-Appalachian males (P<0.05). And the cancer IRs for females were 428.7 in Appalachia and 418.2 outside the region (P<0.05).

There was no significant difference between the regions in IRs for lymphomas. The Hodgkin lymphoma IRs were 3.1 in Appalachian males, 3.2 in non-Appalachian males, and 2.5 for females in both regions.

The non-Hodgkin lymphoma IRs were 23.3 in Appalachian males, 23.4 in non-Appalachian males, 16.4 in Appalachian females, and 16.3 in non-Appalachian females.

Myeloma IRs were significantly lower in Appalachia (P<0.05). The myeloma IRs were 7.3 in Appalachian males, 7.5 in non-Appalachian males, 4.7 in Appalachian females, and 4.9 in non-Appalachian females.

There was no significant difference in leukemia IRs among males, but females in Appalachia had a significantly higher leukemia IR (P<0.05). The leukemia IRs were 16.9 in Appalachian males, 16.7 in non-Appalachian males, 10.4 in Appalachian females, and 10.2 in non-Appalachian females.

“Appalachia continues to have higher cancer incidence rates than the rest of the country,” Wilson said. “But a promising finding is that we’re seeing the gap narrow in the incidence rates between Appalachia and non-Appalachia since the 2007 analysis, with the exception of cancers of the oral cavity and pharynx, larynx, lung and bronchus, and thyroid.”

“This study helps identify types of cancer in the Appalachian region that could be reduced through more evidence-based screening and detection. Our study also emphasizes the importance of lifestyle changes needed to prevent and reduce cancer burden.”

The researchers noted that this study did not differentiate urban versus rural areas within each county, and data on screening and risk factors were based on self-reported responses.

Furthermore, cancer IRs were calculated for all ages combined and were not evaluated by age groups. Future analyses will be targeted toward capturing these finer details, Wilson said.

Cancer patient

receiving chemotherapy

Photo by Rhoda Baer

New research suggests that people living in the Appalachian region of the US are more likely to develop cancer than people in the rest of the country.

The study showed that Appalachians had a significantly higher incidence of cancer overall and higher rates of many solid tumor malignancies.

However, lymphoma rates were similar between Appalachians and non-Appalachians, and Appalachians had a significantly lower rate of myeloma.

This research was published in Cancer Epidemiology, Biomarkers & Prevention.

“The Appalachian region, which extends from parts of New York to Mississippi, spans 420 counties in 13 US states, and about 25 million people reside in this area,” said study author Reda Wilson, MPH, of the Centers for Disease Control and Prevention (CDC) in Atlanta, Georgia.

“This region is primarily made up of rural areas, with persistent poverty levels that are at least 20%, which is higher than the national average.”

In 2007, the CDC’s National Program of Cancer Registries (NPCR) published a comprehensive evaluation of cancer incidence rates in Appalachia between 2001 and 2003.

The data showed higher cancer rates in Appalachia than in the rest of the US. However, this publication had some shortcomings, including data that were not available for analysis.

“The current analyses reported here were performed to update the earlier evaluation by expanding the diagnosis years from 2004 to 2011 and including data on 100% of the Appalachian and non-Appalachian populations,” Wilson said.

For this study, Wilson and her colleagues used data from the NPCR and the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) program. Together, NPCR and SEER cover 100% of the US population.

The researchers analyzed the Appalachian population by region (north, central, and south Appalachia), gender, race (black and white only), and Appalachian Regional Commission-designated economic status (distressed, at-risk, transitional, competitive, and attainment). And the team compared these data with data on the non-Appalachian population.

The results showed that cancer incidence rates (IRs) were elevated among Appalachians regardless of how they were categorized. The IRs were per 100,000 people, age-adjusted to the 2000 US standard population.

The IR for all cancers was 565.8 for males in Appalachia and 543.0 for non-Appalachian males (P<0.05). And the cancer IRs for females were 428.7 in Appalachia and 418.2 outside the region (P<0.05).

There was no significant difference between the regions in IRs for lymphomas. The Hodgkin lymphoma IRs were 3.1 in Appalachian males, 3.2 in non-Appalachian males, and 2.5 for females in both regions.

The non-Hodgkin lymphoma IRs were 23.3 in Appalachian males, 23.4 in non-Appalachian males, 16.4 in Appalachian females, and 16.3 in non-Appalachian females.

Myeloma IRs were significantly lower in Appalachia (P<0.05). The myeloma IRs were 7.3 in Appalachian males, 7.5 in non-Appalachian males, 4.7 in Appalachian females, and 4.9 in non-Appalachian females.

There was no significant difference in leukemia IRs among males, but females in Appalachia had a significantly higher leukemia IR (P<0.05). The leukemia IRs were 16.9 in Appalachian males, 16.7 in non-Appalachian males, 10.4 in Appalachian females, and 10.2 in non-Appalachian females.

“Appalachia continues to have higher cancer incidence rates than the rest of the country,” Wilson said. “But a promising finding is that we’re seeing the gap narrow in the incidence rates between Appalachia and non-Appalachia since the 2007 analysis, with the exception of cancers of the oral cavity and pharynx, larynx, lung and bronchus, and thyroid.”

“This study helps identify types of cancer in the Appalachian region that could be reduced through more evidence-based screening and detection. Our study also emphasizes the importance of lifestyle changes needed to prevent and reduce cancer burden.”

The researchers noted that this study did not differentiate urban versus rural areas within each county, and data on screening and risk factors were based on self-reported responses.

Furthermore, cancer IRs were calculated for all ages combined and were not evaluated by age groups. Future analyses will be targeted toward capturing these finer details, Wilson said.

Cancer patient

receiving chemotherapy

Photo by Rhoda Baer

New research suggests that people living in the Appalachian region of the US are more likely to develop cancer than people in the rest of the country.

The study showed that Appalachians had a significantly higher incidence of cancer overall and higher rates of many solid tumor malignancies.

However, lymphoma rates were similar between Appalachians and non-Appalachians, and Appalachians had a significantly lower rate of myeloma.

This research was published in Cancer Epidemiology, Biomarkers & Prevention.

“The Appalachian region, which extends from parts of New York to Mississippi, spans 420 counties in 13 US states, and about 25 million people reside in this area,” said study author Reda Wilson, MPH, of the Centers for Disease Control and Prevention (CDC) in Atlanta, Georgia.

“This region is primarily made up of rural areas, with persistent poverty levels that are at least 20%, which is higher than the national average.”

In 2007, the CDC’s National Program of Cancer Registries (NPCR) published a comprehensive evaluation of cancer incidence rates in Appalachia between 2001 and 2003.

The data showed higher cancer rates in Appalachia than in the rest of the US. However, this publication had some shortcomings, including data that were not available for analysis.

“The current analyses reported here were performed to update the earlier evaluation by expanding the diagnosis years from 2004 to 2011 and including data on 100% of the Appalachian and non-Appalachian populations,” Wilson said.

For this study, Wilson and her colleagues used data from the NPCR and the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) program. Together, NPCR and SEER cover 100% of the US population.

The researchers analyzed the Appalachian population by region (north, central, and south Appalachia), gender, race (black and white only), and Appalachian Regional Commission-designated economic status (distressed, at-risk, transitional, competitive, and attainment). And the team compared these data with data on the non-Appalachian population.

The results showed that cancer incidence rates (IRs) were elevated among Appalachians regardless of how they were categorized. The IRs were per 100,000 people, age-adjusted to the 2000 US standard population.

The IR for all cancers was 565.8 for males in Appalachia and 543.0 for non-Appalachian males (P<0.05). And the cancer IRs for females were 428.7 in Appalachia and 418.2 outside the region (P<0.05).

There was no significant difference between the regions in IRs for lymphomas. The Hodgkin lymphoma IRs were 3.1 in Appalachian males, 3.2 in non-Appalachian males, and 2.5 for females in both regions.

The non-Hodgkin lymphoma IRs were 23.3 in Appalachian males, 23.4 in non-Appalachian males, 16.4 in Appalachian females, and 16.3 in non-Appalachian females.

Myeloma IRs were significantly lower in Appalachia (P<0.05). The myeloma IRs were 7.3 in Appalachian males, 7.5 in non-Appalachian males, 4.7 in Appalachian females, and 4.9 in non-Appalachian females.

There was no significant difference in leukemia IRs among males, but females in Appalachia had a significantly higher leukemia IR (P<0.05). The leukemia IRs were 16.9 in Appalachian males, 16.7 in non-Appalachian males, 10.4 in Appalachian females, and 10.2 in non-Appalachian females.

“Appalachia continues to have higher cancer incidence rates than the rest of the country,” Wilson said. “But a promising finding is that we’re seeing the gap narrow in the incidence rates between Appalachia and non-Appalachia since the 2007 analysis, with the exception of cancers of the oral cavity and pharynx, larynx, lung and bronchus, and thyroid.”

“This study helps identify types of cancer in the Appalachian region that could be reduced through more evidence-based screening and detection. Our study also emphasizes the importance of lifestyle changes needed to prevent and reduce cancer burden.”

The researchers noted that this study did not differentiate urban versus rural areas within each county, and data on screening and risk factors were based on self-reported responses.

Furthermore, cancer IRs were calculated for all ages combined and were not evaluated by age groups. Future analyses will be targeted toward capturing these finer details, Wilson said.

Panobinostat (Farydak)

Photo courtesy of Novartis

The National Institute for Health and Care Excellence (NICE) has issued a final guidance recommending panobinostat (Farydak) be made available on the National Health Service.

In the European Union, panobinostat is approved for use in combination with bortezomib and dexamethasone to treat adults with relapsed and/or refractory multiple myeloma who have received at least 2 prior treatment regimens, including bortezomib and an immunomodulatory agent.

NICE’s recommendation of panobinostat is contingent upon the drug being provided with the discount agreed upon in the patient access scheme.

NICE previously issued a guidance in which it did not recommend panobinostat, but the drug’s manufacturer, Novartis, submitted a revised economic analysis that allowed NICE to recommend the drug.

Novartis has agreed to a patient access scheme with the Department of Health. This scheme provides a discount to the list price of panobinostat, with the discount applied at the point of purchase or invoice.

The level of the discount is commercial in confidence, but the Department of Health said this patient access scheme does not constitute an excessive administrative burden on the National Health Service.

Panobinostat costs £776 per 20 mg tablet. The recommended starting dose is 20 mg, taken orally once a day, on days 1, 3, 5, 8, 10, and 12 of a 21-day cycle. Patients should receive panobinostat for 8 cycles. If they show clinical benefit, they should continue the treatment for 4 additional cycles of 6 weeks each. 

Panobinostat (Farydak)

Photo courtesy of Novartis

The National Institute for Health and Care Excellence (NICE) has issued a final guidance recommending panobinostat (Farydak) be made available on the National Health Service.

In the European Union, panobinostat is approved for use in combination with bortezomib and dexamethasone to treat adults with relapsed and/or refractory multiple myeloma who have received at least 2 prior treatment regimens, including bortezomib and an immunomodulatory agent.

NICE’s recommendation of panobinostat is contingent upon the drug being provided with the discount agreed upon in the patient access scheme.

NICE previously issued a guidance in which it did not recommend panobinostat, but the drug’s manufacturer, Novartis, submitted a revised economic analysis that allowed NICE to recommend the drug.

Novartis has agreed to a patient access scheme with the Department of Health. This scheme provides a discount to the list price of panobinostat, with the discount applied at the point of purchase or invoice.

The level of the discount is commercial in confidence, but the Department of Health said this patient access scheme does not constitute an excessive administrative burden on the National Health Service.

Panobinostat costs £776 per 20 mg tablet. The recommended starting dose is 20 mg, taken orally once a day, on days 1, 3, 5, 8, 10, and 12 of a 21-day cycle. Patients should receive panobinostat for 8 cycles. If they show clinical benefit, they should continue the treatment for 4 additional cycles of 6 weeks each. 

Panobinostat (Farydak)

Photo courtesy of Novartis

The National Institute for Health and Care Excellence (NICE) has issued a final guidance recommending panobinostat (Farydak) be made available on the National Health Service.

In the European Union, panobinostat is approved for use in combination with bortezomib and dexamethasone to treat adults with relapsed and/or refractory multiple myeloma who have received at least 2 prior treatment regimens, including bortezomib and an immunomodulatory agent.

NICE’s recommendation of panobinostat is contingent upon the drug being provided with the discount agreed upon in the patient access scheme.

NICE previously issued a guidance in which it did not recommend panobinostat, but the drug’s manufacturer, Novartis, submitted a revised economic analysis that allowed NICE to recommend the drug.

Novartis has agreed to a patient access scheme with the Department of Health. This scheme provides a discount to the list price of panobinostat, with the discount applied at the point of purchase or invoice.

The level of the discount is commercial in confidence, but the Department of Health said this patient access scheme does not constitute an excessive administrative burden on the National Health Service.

Panobinostat costs £776 per 20 mg tablet. The recommended starting dose is 20 mg, taken orally once a day, on days 1, 3, 5, 8, 10, and 12 of a 21-day cycle. Patients should receive panobinostat for 8 cycles. If they show clinical benefit, they should continue the treatment for 4 additional cycles of 6 weeks each. 

DNA helix

Image by Spencer Phillips

Researchers say they have made an improvement in CRISPR-Cas9 technology that enables a success rate of 60% when replacing a short stretch of DNA

with another.

They say this technique could be especially useful when trying to repair genetic mutations that cause hereditary diseases, such as sickle cell disease.

The technique allows researchers to patch an abnormal section of DNA with the normal sequence and potentially correct the defect.

“The exciting thing about CRISPR-Cas9 is the promise of fixing genes in place in our genome, but the efficiency for that can be very low,” said Jacob Corn, PhD, of the University of California, Berkeley.

“If you think of gene editing as a word processor, we know how to cut, but we need a more efficient way to paste and glue a new piece of DNA where we make the cut.”

Dr Corn and his colleagues described their more efficient technique in Nature Biotechnology.

“In cases where you want to change very small regions of DNA, up to 30 base pairs, this technique would be extremely effective,” said study author Christopher Richardson, PhD, of the University of California, Berkeley.

Dr Richardson invented the new approach after finding that the Cas9 protein, which does the actual DNA cutting, remains attached to the chromosome for up to 6 hours, long after it has sliced through the double-stranded DNA.

Dr Richardson looked closely at the Cas9 protein bound to the 2 strands of DNA and discovered that while the protein hangs onto 3 of the cut ends, 1 of the ends remains free.

When Cas9 cuts DNA, repair systems in the cell can grab a piece of complementary DNA, called a template, to repair the cut. Researchers can add templates containing changes that alter existing sequences in the genome.

Dr Richardson reasoned that bringing the substitute template directly to the site of the cut would improve the patching efficiency. So he constructed a piece of DNA that matches the free DNA end and carries the genetic sequence to be inserted at the other end.

The technique allowed successful repair of a mutation with up to 60% efficiency.

“Our data indicate that Cas9 breaks could be different, at a molecular level, from breaks generated by other targeted nucleases, such as TALENS and zinc-finger nucleases, which suggests that strategies like the ones we are using can give you more efficient repair of Cas9 breaks,” Dr Richardson said.

The researchers also showed that variants of the Cas9 protein that bind DNA but do not cut can also paste a new DNA sequence at the binding site, possibly by forming a “bubble” structure on the target DNA that also acts to attract the repair template.

Gene editing using Cas9 without genome cutting could be safer than typical gene editing by removing the danger of off-target cutting in the genome, Dr Corn said.

DNA helix

Image by Spencer Phillips

Researchers say they have made an improvement in CRISPR-Cas9 technology that enables a success rate of 60% when replacing a short stretch of DNA

with another.

They say this technique could be especially useful when trying to repair genetic mutations that cause hereditary diseases, such as sickle cell disease.

The technique allows researchers to patch an abnormal section of DNA with the normal sequence and potentially correct the defect.

“The exciting thing about CRISPR-Cas9 is the promise of fixing genes in place in our genome, but the efficiency for that can be very low,” said Jacob Corn, PhD, of the University of California, Berkeley.

“If you think of gene editing as a word processor, we know how to cut, but we need a more efficient way to paste and glue a new piece of DNA where we make the cut.”

Dr Corn and his colleagues described their more efficient technique in Nature Biotechnology.

“In cases where you want to change very small regions of DNA, up to 30 base pairs, this technique would be extremely effective,” said study author Christopher Richardson, PhD, of the University of California, Berkeley.

Dr Richardson invented the new approach after finding that the Cas9 protein, which does the actual DNA cutting, remains attached to the chromosome for up to 6 hours, long after it has sliced through the double-stranded DNA.

Dr Richardson looked closely at the Cas9 protein bound to the 2 strands of DNA and discovered that while the protein hangs onto 3 of the cut ends, 1 of the ends remains free.

When Cas9 cuts DNA, repair systems in the cell can grab a piece of complementary DNA, called a template, to repair the cut. Researchers can add templates containing changes that alter existing sequences in the genome.

Dr Richardson reasoned that bringing the substitute template directly to the site of the cut would improve the patching efficiency. So he constructed a piece of DNA that matches the free DNA end and carries the genetic sequence to be inserted at the other end.

The technique allowed successful repair of a mutation with up to 60% efficiency.

“Our data indicate that Cas9 breaks could be different, at a molecular level, from breaks generated by other targeted nucleases, such as TALENS and zinc-finger nucleases, which suggests that strategies like the ones we are using can give you more efficient repair of Cas9 breaks,” Dr Richardson said.

The researchers also showed that variants of the Cas9 protein that bind DNA but do not cut can also paste a new DNA sequence at the binding site, possibly by forming a “bubble” structure on the target DNA that also acts to attract the repair template.

Gene editing using Cas9 without genome cutting could be safer than typical gene editing by removing the danger of off-target cutting in the genome, Dr Corn said.

DNA helix

Image by Spencer Phillips

Researchers say they have made an improvement in CRISPR-Cas9 technology that enables a success rate of 60% when replacing a short stretch of DNA

with another.

They say this technique could be especially useful when trying to repair genetic mutations that cause hereditary diseases, such as sickle cell disease.

The technique allows researchers to patch an abnormal section of DNA with the normal sequence and potentially correct the defect.

“The exciting thing about CRISPR-Cas9 is the promise of fixing genes in place in our genome, but the efficiency for that can be very low,” said Jacob Corn, PhD, of the University of California, Berkeley.

“If you think of gene editing as a word processor, we know how to cut, but we need a more efficient way to paste and glue a new piece of DNA where we make the cut.”

Dr Corn and his colleagues described their more efficient technique in Nature Biotechnology.

“In cases where you want to change very small regions of DNA, up to 30 base pairs, this technique would be extremely effective,” said study author Christopher Richardson, PhD, of the University of California, Berkeley.

Dr Richardson invented the new approach after finding that the Cas9 protein, which does the actual DNA cutting, remains attached to the chromosome for up to 6 hours, long after it has sliced through the double-stranded DNA.

Dr Richardson looked closely at the Cas9 protein bound to the 2 strands of DNA and discovered that while the protein hangs onto 3 of the cut ends, 1 of the ends remains free.

When Cas9 cuts DNA, repair systems in the cell can grab a piece of complementary DNA, called a template, to repair the cut. Researchers can add templates containing changes that alter existing sequences in the genome.

Dr Richardson reasoned that bringing the substitute template directly to the site of the cut would improve the patching efficiency. So he constructed a piece of DNA that matches the free DNA end and carries the genetic sequence to be inserted at the other end.

The technique allowed successful repair of a mutation with up to 60% efficiency.

“Our data indicate that Cas9 breaks could be different, at a molecular level, from breaks generated by other targeted nucleases, such as TALENS and zinc-finger nucleases, which suggests that strategies like the ones we are using can give you more efficient repair of Cas9 breaks,” Dr Richardson said.

The researchers also showed that variants of the Cas9 protein that bind DNA but do not cut can also paste a new DNA sequence at the binding site, possibly by forming a “bubble” structure on the target DNA that also acts to attract the repair template.

Gene editing using Cas9 without genome cutting could be safer than typical gene editing by removing the danger of off-target cutting in the genome, Dr Corn said.

Prescription medications

Photo courtesy of the CDC

An article published in Blood suggests pharmaceutical companies use several strategies to keep affordable generic drugs from the US market.

“The timely availability of affordable generic drugs is the difference between life or death for patients with cancer and other diseases who cannot afford brand-name pharmaceuticals, the majority of which are priced at monopoly levels and protected by 20-year patents,” said lead author Hagop Kantarjian, MD, of The University of Texas MD Anderson Cancer Center in Houston.

“Unfortunately, these sorely needed generics are increasingly out of reach. As we sought to understand what keeps these affordable drugs from the market, we identified several specific strategies that pharmaceutical companies use to extend their patents and eliminate competition.”

Dr Kantarjian and his colleagues assert that pharmaceutical companies use a variety of strategies to delay, prevent, and suppress the timely availability of affordable generic drugs.

Among them, the authors detail “pay-for-delay,” in which the company that owns the patent pays a generic company to delay entry into the market. The Federal Trade Commission estimates that the pay-for-delay settlements cost taxpayers, insurance companies, and consumers approximately $3.5 billion per year.

In other cases detailed in the article, the patent-holder deters competition by creating its own version of drugs at generic prices.

While this practice may reduce costs for consumers by 4% to 8% in the short-term, the authors suggest that companies often use the authorized generics as a bargaining chip in “pay-for-delay” deals, pledging not to release their own drugs in return for the true generic company promising to delay market entry.

Other strategies the authors discuss include investing heavily in advertising the brand-name drug (often spending more on marketing than on research and development) and lobbying for laws that prevent patients from importing cheaper generics from other countries, which the authors write can cost as little as 20% to 50% of US prices.

The authors also say some drug companies buy out competitors and then increase the price of a newly acquired generic drug by several fold overnight.

In addition, the authors describe a strategy they call “product hopping,” which involves switching the market for a drug to a reformulated “new and improved” version with a slightly different tablet or capsule dose that offers no therapeutic advantage over the original but has a later-expiring patent.

The company then heavily advertises the new brand-name drug in an effort to convince patients and physicians to switch.

As a result, when the generic version of the original becomes available, pharmacists cannot substitute it for the new branded version because state laws allow substitution only if certain characteristics, such as dosing, remain the same.

In recognition of the harm and expense the authors suggest these strategies impart on both patients and the economy, they propose several solutions that would support timely access to affordable generic drugs.

These include allowing Medicare to negotiate drug prices, monitoring and penalizing pay-for-delay deals, allowing transportation of pharmaceuticals across borders for individual use, and challenging weak patents.

“Each day, in my clinic, I see leukemia patients who are harmed because they cannot afford their treatment, some risking death because they cannot pay for the medicine keeping them alive,” Dr Kantarjian said.

“Overall, these strategies demonstrate that the trend of high brand-name drug prices has recently infected generic drugs, as companies value profit at the expense of long-term utility to society. We must be vigilant in recognizing these strategies and advocating for solutions that will allow companies to accomplish their dual mission: make reasonable profits and help save and/or improve patients’ lives.”

Prescription medications

Photo courtesy of the CDC

An article published in Blood suggests pharmaceutical companies use several strategies to keep affordable generic drugs from the US market.

“The timely availability of affordable generic drugs is the difference between life or death for patients with cancer and other diseases who cannot afford brand-name pharmaceuticals, the majority of which are priced at monopoly levels and protected by 20-year patents,” said lead author Hagop Kantarjian, MD, of The University of Texas MD Anderson Cancer Center in Houston.

“Unfortunately, these sorely needed generics are increasingly out of reach. As we sought to understand what keeps these affordable drugs from the market, we identified several specific strategies that pharmaceutical companies use to extend their patents and eliminate competition.”

Dr Kantarjian and his colleagues assert that pharmaceutical companies use a variety of strategies to delay, prevent, and suppress the timely availability of affordable generic drugs.

Among them, the authors detail “pay-for-delay,” in which the company that owns the patent pays a generic company to delay entry into the market. The Federal Trade Commission estimates that the pay-for-delay settlements cost taxpayers, insurance companies, and consumers approximately $3.5 billion per year.

In other cases detailed in the article, the patent-holder deters competition by creating its own version of drugs at generic prices.

While this practice may reduce costs for consumers by 4% to 8% in the short-term, the authors suggest that companies often use the authorized generics as a bargaining chip in “pay-for-delay” deals, pledging not to release their own drugs in return for the true generic company promising to delay market entry.

Other strategies the authors discuss include investing heavily in advertising the brand-name drug (often spending more on marketing than on research and development) and lobbying for laws that prevent patients from importing cheaper generics from other countries, which the authors write can cost as little as 20% to 50% of US prices.

The authors also say some drug companies buy out competitors and then increase the price of a newly acquired generic drug by several fold overnight.

In addition, the authors describe a strategy they call “product hopping,” which involves switching the market for a drug to a reformulated “new and improved” version with a slightly different tablet or capsule dose that offers no therapeutic advantage over the original but has a later-expiring patent.

The company then heavily advertises the new brand-name drug in an effort to convince patients and physicians to switch.

As a result, when the generic version of the original becomes available, pharmacists cannot substitute it for the new branded version because state laws allow substitution only if certain characteristics, such as dosing, remain the same.

In recognition of the harm and expense the authors suggest these strategies impart on both patients and the economy, they propose several solutions that would support timely access to affordable generic drugs.

These include allowing Medicare to negotiate drug prices, monitoring and penalizing pay-for-delay deals, allowing transportation of pharmaceuticals across borders for individual use, and challenging weak patents.

“Each day, in my clinic, I see leukemia patients who are harmed because they cannot afford their treatment, some risking death because they cannot pay for the medicine keeping them alive,” Dr Kantarjian said.

“Overall, these strategies demonstrate that the trend of high brand-name drug prices has recently infected generic drugs, as companies value profit at the expense of long-term utility to society. We must be vigilant in recognizing these strategies and advocating for solutions that will allow companies to accomplish their dual mission: make reasonable profits and help save and/or improve patients’ lives.”

Prescription medications

Photo courtesy of the CDC

An article published in Blood suggests pharmaceutical companies use several strategies to keep affordable generic drugs from the US market.

“The timely availability of affordable generic drugs is the difference between life or death for patients with cancer and other diseases who cannot afford brand-name pharmaceuticals, the majority of which are priced at monopoly levels and protected by 20-year patents,” said lead author Hagop Kantarjian, MD, of The University of Texas MD Anderson Cancer Center in Houston.

“Unfortunately, these sorely needed generics are increasingly out of reach. As we sought to understand what keeps these affordable drugs from the market, we identified several specific strategies that pharmaceutical companies use to extend their patents and eliminate competition.”

Dr Kantarjian and his colleagues assert that pharmaceutical companies use a variety of strategies to delay, prevent, and suppress the timely availability of affordable generic drugs.

Among them, the authors detail “pay-for-delay,” in which the company that owns the patent pays a generic company to delay entry into the market. The Federal Trade Commission estimates that the pay-for-delay settlements cost taxpayers, insurance companies, and consumers approximately $3.5 billion per year.

In other cases detailed in the article, the patent-holder deters competition by creating its own version of drugs at generic prices.

While this practice may reduce costs for consumers by 4% to 8% in the short-term, the authors suggest that companies often use the authorized generics as a bargaining chip in “pay-for-delay” deals, pledging not to release their own drugs in return for the true generic company promising to delay market entry.

Other strategies the authors discuss include investing heavily in advertising the brand-name drug (often spending more on marketing than on research and development) and lobbying for laws that prevent patients from importing cheaper generics from other countries, which the authors write can cost as little as 20% to 50% of US prices.

The authors also say some drug companies buy out competitors and then increase the price of a newly acquired generic drug by several fold overnight.

In addition, the authors describe a strategy they call “product hopping,” which involves switching the market for a drug to a reformulated “new and improved” version with a slightly different tablet or capsule dose that offers no therapeutic advantage over the original but has a later-expiring patent.

The company then heavily advertises the new brand-name drug in an effort to convince patients and physicians to switch.

As a result, when the generic version of the original becomes available, pharmacists cannot substitute it for the new branded version because state laws allow substitution only if certain characteristics, such as dosing, remain the same.

In recognition of the harm and expense the authors suggest these strategies impart on both patients and the economy, they propose several solutions that would support timely access to affordable generic drugs.

These include allowing Medicare to negotiate drug prices, monitoring and penalizing pay-for-delay deals, allowing transportation of pharmaceuticals across borders for individual use, and challenging weak patents.

“Each day, in my clinic, I see leukemia patients who are harmed because they cannot afford their treatment, some risking death because they cannot pay for the medicine keeping them alive,” Dr Kantarjian said.

“Overall, these strategies demonstrate that the trend of high brand-name drug prices has recently infected generic drugs, as companies value profit at the expense of long-term utility to society. We must be vigilant in recognizing these strategies and advocating for solutions that will allow companies to accomplish their dual mission: make reasonable profits and help save and/or improve patients’ lives.”