CASE Seeing friends
Mr. B, age 91, presents to the emergency room (ER) for hip pain. As he is being evalu­ated, he asks a nurse to tell the “other people” around her to leave so that he can have pri­vacy. As clarification, Mr. B reports visual hal­lucinations, which prompts the ER physician to request a psychiatry consult.

Mr. B is alert and oriented to time, place, and person when he is evaluated by the on-call psychiatry resident. He reports that he has been seeing several unusual things for the last 4 to 5 months. Asked to elaborate, Mr. B admits seeing colorful and vivid images of people around him. These people come and go as they like; rarely, they talk to him. He describes the conversations as “a constant chatter” in the background and adds that it is difficult to understand what they are talking about.

Mr. B states that he has been “seeing” a cou­ple of people on a regular basis, and they are “sort of like my friends.” He endorses that these people often sing songs or dance for him. He states that, sometimes, these “friends” bring 3 or 4 friends and, although he could not make out their faces clearly, “they all are around me.” He describes the people he sees as “nice people” and does not report being scared or frightened by them.

Mr. B does not report paranoia, and denies command-type hallucinations. He and his family report no unusual changes in behavior in recent months. The medical history is remarkable for atrial fibrillation, coronary artery disease, chronic obstructive pulmonary disease, age-related macular degeneration, and glaucoma.

Mr. B denies having any ongoing mood or anxiety symptoms. He states that he knows these people are “probably not real,” and they do not bother him and just keep him company.

What could be causing Mr. B’s hallucinations?
   a) a stroke
   b) late-onset schizophrenia
   c) dementia
   d) Charles Bonnet syndrome

The authors’ observations
Visual hallucinations among geriatric pa-tients are a common and confusing pre­sentation. In addition to several medical causes for this presentation (Table 1), con­sider Charles Bonnet syndrome in patients with visual loss, presenting as visual hal­lucinations with intact insight and absence of a mental illness. Other conditions to con­sider in the differential diagnosis include Parkinson’s disease, dementia with Lewy bodies, schizophrenia, seizures, migraine, and stroke, including lesions of the thala­mus or brain stem.

Charles Bonnet syndrome was first described by Swiss philosopher Charles Bonnet in the 18th century. He reported vivid visual hallucinations in his visually impaired grandfather (bilateral cataracts).¹

It is important to recognize this syn­drome because patients can present across different specialties, including psychia­try, ophthalmology, neurology, geriat­ric medicine, and family medicine.² As life expectancy increases, this condition might be seen more often. It is prudent to identify, intervene, and refer as appropri­ate, in addition to educating patients and caregivers about the nature and course of the condition. 

EVALUATION Not psychotic
Mr. B reports good sleep and appetite. He denies using alcohol or illicit drugs. He states he slipped in the bathroom the day before coming to the ER, but denies other recent falls or injuries. Other than hip pain, he has no other physical complaints. His medication regimen includes aspirin, lisinopril, lovastatin, and metoprolol.

The ER team diagnoses a hip fracture. Mr. B is transferred to the orthopedic service; the psychiatry consult team continues to fol­low him. Mental status examination is unre­markable other than the visual hallucinations. His speech is clear, non-pressured, with goal-directed thought processing. Mini-Mental State Examination score is 23/30 with Mr. B having difficulty with object drawing and 3-object recall. Brief cognitive examination in the ER is unremarkable.

The orthopedic team decides on conserva­tive management of the hip fracture. There is no evidence of infection. Mr. B is afebrile with clear sensorium; complete blood cell count and normal liver function tests are normal; urinalysis and urine drug screen are negative; and chest radiography is unremarkable. CT and MRI of the head are unremarkable.

After 1 week in the hospital, Mr. B contin­ues to experience vivid visual imagery. No signs of active infection are found. An oph­thalmologist is consulted, who confirms Mr. B’s earlier diagnosis of glaucoma and age-related macular degeneration but does not recommend further treatment. Visual field test by confrontation is normal, with normal visual reflexes.

The authors’ observations
The reported prevalence of Charles Bonnet syndrome among visually impaired peo­ple varies from study to study—from as low as 0.4% to as high as 63%.^3-6 The rea­son for such variation can be attributed to several variables:
   • underdiagnosis
   • misdiagnosis
   • underreporting by patients because of the benign nature of the hallucinations
   • patients’ reluctance to report visual hallucinations because of fear of being labeled “mentally ill.”^7,8

Symptoms
There are no specific diagnostic criteria for Charles Bonnet syndrome (Table 2). However, the following are generally accepted for diagnosis⁹:
   • grossly intact cognition, although mild cognitive impairment may be present in some cases¹⁰
    • underlying visual disorder, usually acquired, such as glaucoma, age-related macular degeneration, diabetic retinopathy, central retinal artery occlusion, and optic neuritis^3,4,11
   • no hallucinations or perceptive difficul­ties in other sensory modalities
   • generally intact insight
   • absence of delusions
   • absence of other neurologic, psychiat­ric, toxic, or metabolic conditions; medical causes of delirium must be ruled out.

Hallucinations might not be disturb­ing to the patient. Hallucinations could be simple (light flashes, lines, or geomet­ric shapes) or complex (faces, figures, or scenes),¹² and perceived as in color or in black and white. Hallucinations mostly are pleasant and rarely have any emotional impact or meaning. Although hallucina­tions are almost exclusively visual, they can be accompanied by noise or auditory hallucinations.^13,14

Other characteristics of Charles Bonnet syndrome include:  
   • typical age of onset is approximately 72 years (range, 70 to 92 years)  
   • no sex distinction has been identified  
   • episodes can last from a few seconds to few hours; the syndrome may last a few days or a few years⁵     
   • it is not uncommon for episodes to occur in clusters, followed by symptom-free intervals and recurrences  
   • symptoms tend to fade away as patients progress to complete loss of sight.¹⁵

The course of Charles Bonnet syndrome is uncertain and unpredictable and the epi­sodic nature can be frustrating for both patient and clinician. The syndrome could be misdiagnosed as a psychiatric condition.

Pathophysiology
The precise mechanism behind simple or complex vivid hallucinations in persons with Charles Bonnet syndrome is unclear. Several theories have been proposed.

Release theory proposes a loss of input to the primary visual areas, which decreases cortical inhibition and further causes disin­hibition of visual association areas, thereby “releasing” visual hallucinations.¹⁶ Research suggests that this might be an attempt by surviving neurons to recover vision. Loss of input somehow causes surviving neurons to adapt by increased sensitivity to residual visual stimuli.

Deafferentation theory. This relatively new theory proposes deafferentation of the visual sensory pathway, which, in turn, causes disinhibition of neurons in the visual cortical regions, thereby caus­ing them to fire spontaneously. This could cause a sensation analogous to phantom limb pain, which would be called “phan­tom vision presence of brain activity in the absence of an actual visual input.” Further, biochemical and molecular changes have been proposed to explain the deafferenta­tion theory.¹⁷

Neurobiological evidence. Limited data are available for a neurobiological basis to visual hallucinations in Charles Bonnet syndrome. A few studies have used func­tional MRI and single-photon emission CT and reported possible association of visual hallucinations to specific visual areas.^18,19

Risk factors
Social or physical isolation, loneliness, low extraversion, and shyness are risk factors for Charles Bonnet syndrome in visually impaired people.²⁰ Sensory deprivation and low level of arousal favor the occur­rence of hallucinations.⁵ Rate of vision loss—not the nature of pathology or sever­ity of visual impairment—has been sug­gested to increase the risk of developing Charles Bonnet syndrome.²¹

What are the treatment options for Charles Bonnet syndrome?
   a) begin an antipsychotic
   b) do nothing; there is no cure
   c) educate the patient about the nature of the hallucinations
   d) refer the patient to an ophthalmologist for evaluation of vision loss

Treatment
There are several modalities to manage visual hallucinations in a patient with Charles Bonnet syndrome (Table 3). After ruling out medical and other psychiat­ric causes of visual hallucinations, treat­ment might not be indicated if the patient is not disturbed by the hallucinations. In most cases, reassurance and educating the patient and family about the benign nature of the visual hallucinations is all that is needed.

For patients who are disturbed by these visions or for whom there is a treatable cause, treatment could include cataract removal, medical therapy to reduce intra­ocular pressure in glaucoma, treatment of diabetic retinopathy, or laser photoco­agulation. These treatments are associ­ated with a reduction in hallucinations.²²

In some cases, hallucinations disappear as visual acuity deteriorates. Psychotropics have been used to treat Charles Bonnet syndrome, including:
   • antipsychotics, including haloperi­dol, risperidone, and olanzapine
   • anticonvulsants, including valproic acid, gabapentin, and carbamazepine
   • antidepressants, including mirtazap­ine and venlafaxine.^23-30

Some experts recommend a conserva­tive approach, which might be justified because some cases of Charles Bonnet syndrome are episodic and remit sponta­neously.³¹ Again, however, consider phar­macotherapy if a patient is disturbed by hallucinations or if hallucinations impair overall functioning.

TREATMENT Education
After discussion with Mr. B and his family, he is started on risperidone, 1 mg at bedtime, and the psychiatric team provides informa­tion about the nature of Charles Bonnet syndrome. Mr. B reportedly takes this medi­cation for a few days and then stops because he does not want the visual hallucinations to go away.

The psychiatry team sees Mr. B before dis­charge. He and his family are educated about the benign nature of the syndrome, the need for continued family support, and the fact that hallucinations will have minimal or no impli­cations for his life.

The authors’ observations
It is important to remember that a visual description of hallucinations in Charles Bonnet syndrome can be quite vivid, and that the patient might not identify his hal­lucinations as such or consider them as a problem. Be careful not to dismiss the patient’s complaints as a primary psychi­atric condition. It also is important to be mindful of the patient’s concerns with a psychiatric diagnosis; detailed discussion with the patient is helpful in most cases. A more comprehensive and empathetic approach to care could go a long way to sustain quality of life for these patients.

Bottom Line
Charles Bonnet syndrome is characterized by visual hallucinations in patients with visual impairment who have intact insight and an absence of mental illness. Taking a thorough history can help rule out medical and psychiatric causes of visual hallucinations. Educate patients and family about the nature of the hallucinations. In some cases, a psychotropic may be indicated.

Related Resources
• Nguyen ND, Osterweil D, Hoffman J. Charles Bonnet syn­drome: treating nonpsychiatric hallucinations. Consult Pharm. 2013;28(3):184-188.
• Lapid MI, Burton MC, Chang MT, et al. Clinical phenomenology and mortality in Charles Bonnet syndrome. J Geriatr Psychiatry Neurol. 2013;26(1):3-9.

Drug Brand Names
Carbamazepine • Tegretol                          Mirtazapine • Remeron
Gabapentin • Neurontin                              Olanzapine • Zyprexa
Haloperidol • Haldol                                   Risperidone • Risperdal
Lisinopril • Prinivil, Zestril                           Valproic acid • Depakene
Lovastatin • Mevacor                                  Venlafaxine • Effexor
Metoprolol • Lopressor

Acknowledgement
The authors acknowledge Barry Liskow, MD, Vice Chair of Psychiatry, Kansas University Medical Center, Kansas City, Kansas, for providing both insight into the topic and useful feedback on the manuscript.

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

CASE Seeing friends
Mr. B, age 91, presents to the emergency room (ER) for hip pain. As he is being evalu­ated, he asks a nurse to tell the “other people” around her to leave so that he can have pri­vacy. As clarification, Mr. B reports visual hal­lucinations, which prompts the ER physician to request a psychiatry consult.

Mr. B is alert and oriented to time, place, and person when he is evaluated by the on-call psychiatry resident. He reports that he has been seeing several unusual things for the last 4 to 5 months. Asked to elaborate, Mr. B admits seeing colorful and vivid images of people around him. These people come and go as they like; rarely, they talk to him. He describes the conversations as “a constant chatter” in the background and adds that it is difficult to understand what they are talking about.

Mr. B states that he has been “seeing” a cou­ple of people on a regular basis, and they are “sort of like my friends.” He endorses that these people often sing songs or dance for him. He states that, sometimes, these “friends” bring 3 or 4 friends and, although he could not make out their faces clearly, “they all are around me.” He describes the people he sees as “nice people” and does not report being scared or frightened by them.

Mr. B does not report paranoia, and denies command-type hallucinations. He and his family report no unusual changes in behavior in recent months. The medical history is remarkable for atrial fibrillation, coronary artery disease, chronic obstructive pulmonary disease, age-related macular degeneration, and glaucoma.

Mr. B denies having any ongoing mood or anxiety symptoms. He states that he knows these people are “probably not real,” and they do not bother him and just keep him company.

What could be causing Mr. B’s hallucinations?
   a) a stroke
   b) late-onset schizophrenia
   c) dementia
   d) Charles Bonnet syndrome

The authors’ observations
Visual hallucinations among geriatric pa-tients are a common and confusing pre­sentation. In addition to several medical causes for this presentation (Table 1), con­sider Charles Bonnet syndrome in patients with visual loss, presenting as visual hal­lucinations with intact insight and absence of a mental illness. Other conditions to con­sider in the differential diagnosis include Parkinson’s disease, dementia with Lewy bodies, schizophrenia, seizures, migraine, and stroke, including lesions of the thala­mus or brain stem.

Charles Bonnet syndrome was first described by Swiss philosopher Charles Bonnet in the 18th century. He reported vivid visual hallucinations in his visually impaired grandfather (bilateral cataracts).¹

It is important to recognize this syn­drome because patients can present across different specialties, including psychia­try, ophthalmology, neurology, geriat­ric medicine, and family medicine.² As life expectancy increases, this condition might be seen more often. It is prudent to identify, intervene, and refer as appropri­ate, in addition to educating patients and caregivers about the nature and course of the condition. 

EVALUATION Not psychotic
Mr. B reports good sleep and appetite. He denies using alcohol or illicit drugs. He states he slipped in the bathroom the day before coming to the ER, but denies other recent falls or injuries. Other than hip pain, he has no other physical complaints. His medication regimen includes aspirin, lisinopril, lovastatin, and metoprolol.

The ER team diagnoses a hip fracture. Mr. B is transferred to the orthopedic service; the psychiatry consult team continues to fol­low him. Mental status examination is unre­markable other than the visual hallucinations. His speech is clear, non-pressured, with goal-directed thought processing. Mini-Mental State Examination score is 23/30 with Mr. B having difficulty with object drawing and 3-object recall. Brief cognitive examination in the ER is unremarkable.

The orthopedic team decides on conserva­tive management of the hip fracture. There is no evidence of infection. Mr. B is afebrile with clear sensorium; complete blood cell count and normal liver function tests are normal; urinalysis and urine drug screen are negative; and chest radiography is unremarkable. CT and MRI of the head are unremarkable.

After 1 week in the hospital, Mr. B contin­ues to experience vivid visual imagery. No signs of active infection are found. An oph­thalmologist is consulted, who confirms Mr. B’s earlier diagnosis of glaucoma and age-related macular degeneration but does not recommend further treatment. Visual field test by confrontation is normal, with normal visual reflexes.

The authors’ observations
The reported prevalence of Charles Bonnet syndrome among visually impaired peo­ple varies from study to study—from as low as 0.4% to as high as 63%.^3-6 The rea­son for such variation can be attributed to several variables:
   • underdiagnosis
   • misdiagnosis
   • underreporting by patients because of the benign nature of the hallucinations
   • patients’ reluctance to report visual hallucinations because of fear of being labeled “mentally ill.”^7,8

Symptoms
There are no specific diagnostic criteria for Charles Bonnet syndrome (Table 2). However, the following are generally accepted for diagnosis⁹:
   • grossly intact cognition, although mild cognitive impairment may be present in some cases¹⁰
    • underlying visual disorder, usually acquired, such as glaucoma, age-related macular degeneration, diabetic retinopathy, central retinal artery occlusion, and optic neuritis^3,4,11
   • no hallucinations or perceptive difficul­ties in other sensory modalities
   • generally intact insight
   • absence of delusions
   • absence of other neurologic, psychiat­ric, toxic, or metabolic conditions; medical causes of delirium must be ruled out.

Hallucinations might not be disturb­ing to the patient. Hallucinations could be simple (light flashes, lines, or geomet­ric shapes) or complex (faces, figures, or scenes),¹² and perceived as in color or in black and white. Hallucinations mostly are pleasant and rarely have any emotional impact or meaning. Although hallucina­tions are almost exclusively visual, they can be accompanied by noise or auditory hallucinations.^13,14

Other characteristics of Charles Bonnet syndrome include:  
   • typical age of onset is approximately 72 years (range, 70 to 92 years)  
   • no sex distinction has been identified  
   • episodes can last from a few seconds to few hours; the syndrome may last a few days or a few years⁵     
   • it is not uncommon for episodes to occur in clusters, followed by symptom-free intervals and recurrences  
   • symptoms tend to fade away as patients progress to complete loss of sight.¹⁵

The course of Charles Bonnet syndrome is uncertain and unpredictable and the epi­sodic nature can be frustrating for both patient and clinician. The syndrome could be misdiagnosed as a psychiatric condition.

Pathophysiology
The precise mechanism behind simple or complex vivid hallucinations in persons with Charles Bonnet syndrome is unclear. Several theories have been proposed.

Release theory proposes a loss of input to the primary visual areas, which decreases cortical inhibition and further causes disin­hibition of visual association areas, thereby “releasing” visual hallucinations.¹⁶ Research suggests that this might be an attempt by surviving neurons to recover vision. Loss of input somehow causes surviving neurons to adapt by increased sensitivity to residual visual stimuli.

Deafferentation theory. This relatively new theory proposes deafferentation of the visual sensory pathway, which, in turn, causes disinhibition of neurons in the visual cortical regions, thereby caus­ing them to fire spontaneously. This could cause a sensation analogous to phantom limb pain, which would be called “phan­tom vision presence of brain activity in the absence of an actual visual input.” Further, biochemical and molecular changes have been proposed to explain the deafferenta­tion theory.¹⁷

Neurobiological evidence. Limited data are available for a neurobiological basis to visual hallucinations in Charles Bonnet syndrome. A few studies have used func­tional MRI and single-photon emission CT and reported possible association of visual hallucinations to specific visual areas.^18,19

Risk factors
Social or physical isolation, loneliness, low extraversion, and shyness are risk factors for Charles Bonnet syndrome in visually impaired people.²⁰ Sensory deprivation and low level of arousal favor the occur­rence of hallucinations.⁵ Rate of vision loss—not the nature of pathology or sever­ity of visual impairment—has been sug­gested to increase the risk of developing Charles Bonnet syndrome.²¹

What are the treatment options for Charles Bonnet syndrome?
   a) begin an antipsychotic
   b) do nothing; there is no cure
   c) educate the patient about the nature of the hallucinations
   d) refer the patient to an ophthalmologist for evaluation of vision loss

Treatment
There are several modalities to manage visual hallucinations in a patient with Charles Bonnet syndrome (Table 3). After ruling out medical and other psychiat­ric causes of visual hallucinations, treat­ment might not be indicated if the patient is not disturbed by the hallucinations. In most cases, reassurance and educating the patient and family about the benign nature of the visual hallucinations is all that is needed.

For patients who are disturbed by these visions or for whom there is a treatable cause, treatment could include cataract removal, medical therapy to reduce intra­ocular pressure in glaucoma, treatment of diabetic retinopathy, or laser photoco­agulation. These treatments are associ­ated with a reduction in hallucinations.²²

In some cases, hallucinations disappear as visual acuity deteriorates. Psychotropics have been used to treat Charles Bonnet syndrome, including:
   • antipsychotics, including haloperi­dol, risperidone, and olanzapine
   • anticonvulsants, including valproic acid, gabapentin, and carbamazepine
   • antidepressants, including mirtazap­ine and venlafaxine.^23-30

Some experts recommend a conserva­tive approach, which might be justified because some cases of Charles Bonnet syndrome are episodic and remit sponta­neously.³¹ Again, however, consider phar­macotherapy if a patient is disturbed by hallucinations or if hallucinations impair overall functioning.

TREATMENT Education
After discussion with Mr. B and his family, he is started on risperidone, 1 mg at bedtime, and the psychiatric team provides informa­tion about the nature of Charles Bonnet syndrome. Mr. B reportedly takes this medi­cation for a few days and then stops because he does not want the visual hallucinations to go away.

The psychiatry team sees Mr. B before dis­charge. He and his family are educated about the benign nature of the syndrome, the need for continued family support, and the fact that hallucinations will have minimal or no impli­cations for his life.

The authors’ observations
It is important to remember that a visual description of hallucinations in Charles Bonnet syndrome can be quite vivid, and that the patient might not identify his hal­lucinations as such or consider them as a problem. Be careful not to dismiss the patient’s complaints as a primary psychi­atric condition. It also is important to be mindful of the patient’s concerns with a psychiatric diagnosis; detailed discussion with the patient is helpful in most cases. A more comprehensive and empathetic approach to care could go a long way to sustain quality of life for these patients.

Bottom Line
Charles Bonnet syndrome is characterized by visual hallucinations in patients with visual impairment who have intact insight and an absence of mental illness. Taking a thorough history can help rule out medical and psychiatric causes of visual hallucinations. Educate patients and family about the nature of the hallucinations. In some cases, a psychotropic may be indicated.

Related Resources
• Nguyen ND, Osterweil D, Hoffman J. Charles Bonnet syn­drome: treating nonpsychiatric hallucinations. Consult Pharm. 2013;28(3):184-188.
• Lapid MI, Burton MC, Chang MT, et al. Clinical phenomenology and mortality in Charles Bonnet syndrome. J Geriatr Psychiatry Neurol. 2013;26(1):3-9.

Drug Brand Names
Carbamazepine • Tegretol                          Mirtazapine • Remeron
Gabapentin • Neurontin                              Olanzapine • Zyprexa
Haloperidol • Haldol                                   Risperidone • Risperdal
Lisinopril • Prinivil, Zestril                           Valproic acid • Depakene
Lovastatin • Mevacor                                  Venlafaxine • Effexor
Metoprolol • Lopressor

Acknowledgement
The authors acknowledge Barry Liskow, MD, Vice Chair of Psychiatry, Kansas University Medical Center, Kansas City, Kansas, for providing both insight into the topic and useful feedback on the manuscript.

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

CASE Seeing friends
Mr. B, age 91, presents to the emergency room (ER) for hip pain. As he is being evalu­ated, he asks a nurse to tell the “other people” around her to leave so that he can have pri­vacy. As clarification, Mr. B reports visual hal­lucinations, which prompts the ER physician to request a psychiatry consult.

Mr. B is alert and oriented to time, place, and person when he is evaluated by the on-call psychiatry resident. He reports that he has been seeing several unusual things for the last 4 to 5 months. Asked to elaborate, Mr. B admits seeing colorful and vivid images of people around him. These people come and go as they like; rarely, they talk to him. He describes the conversations as “a constant chatter” in the background and adds that it is difficult to understand what they are talking about.

Mr. B states that he has been “seeing” a cou­ple of people on a regular basis, and they are “sort of like my friends.” He endorses that these people often sing songs or dance for him. He states that, sometimes, these “friends” bring 3 or 4 friends and, although he could not make out their faces clearly, “they all are around me.” He describes the people he sees as “nice people” and does not report being scared or frightened by them.

Mr. B does not report paranoia, and denies command-type hallucinations. He and his family report no unusual changes in behavior in recent months. The medical history is remarkable for atrial fibrillation, coronary artery disease, chronic obstructive pulmonary disease, age-related macular degeneration, and glaucoma.

Mr. B denies having any ongoing mood or anxiety symptoms. He states that he knows these people are “probably not real,” and they do not bother him and just keep him company.

What could be causing Mr. B’s hallucinations?
   a) a stroke
   b) late-onset schizophrenia
   c) dementia
   d) Charles Bonnet syndrome

The authors’ observations
Visual hallucinations among geriatric pa-tients are a common and confusing pre­sentation. In addition to several medical causes for this presentation (Table 1), con­sider Charles Bonnet syndrome in patients with visual loss, presenting as visual hal­lucinations with intact insight and absence of a mental illness. Other conditions to con­sider in the differential diagnosis include Parkinson’s disease, dementia with Lewy bodies, schizophrenia, seizures, migraine, and stroke, including lesions of the thala­mus or brain stem.

Charles Bonnet syndrome was first described by Swiss philosopher Charles Bonnet in the 18th century. He reported vivid visual hallucinations in his visually impaired grandfather (bilateral cataracts).¹

It is important to recognize this syn­drome because patients can present across different specialties, including psychia­try, ophthalmology, neurology, geriat­ric medicine, and family medicine.² As life expectancy increases, this condition might be seen more often. It is prudent to identify, intervene, and refer as appropri­ate, in addition to educating patients and caregivers about the nature and course of the condition. 

EVALUATION Not psychotic
Mr. B reports good sleep and appetite. He denies using alcohol or illicit drugs. He states he slipped in the bathroom the day before coming to the ER, but denies other recent falls or injuries. Other than hip pain, he has no other physical complaints. His medication regimen includes aspirin, lisinopril, lovastatin, and metoprolol.

The ER team diagnoses a hip fracture. Mr. B is transferred to the orthopedic service; the psychiatry consult team continues to fol­low him. Mental status examination is unre­markable other than the visual hallucinations. His speech is clear, non-pressured, with goal-directed thought processing. Mini-Mental State Examination score is 23/30 with Mr. B having difficulty with object drawing and 3-object recall. Brief cognitive examination in the ER is unremarkable.

The orthopedic team decides on conserva­tive management of the hip fracture. There is no evidence of infection. Mr. B is afebrile with clear sensorium; complete blood cell count and normal liver function tests are normal; urinalysis and urine drug screen are negative; and chest radiography is unremarkable. CT and MRI of the head are unremarkable.

After 1 week in the hospital, Mr. B contin­ues to experience vivid visual imagery. No signs of active infection are found. An oph­thalmologist is consulted, who confirms Mr. B’s earlier diagnosis of glaucoma and age-related macular degeneration but does not recommend further treatment. Visual field test by confrontation is normal, with normal visual reflexes.

The authors’ observations
The reported prevalence of Charles Bonnet syndrome among visually impaired peo­ple varies from study to study—from as low as 0.4% to as high as 63%.^3-6 The rea­son for such variation can be attributed to several variables:
   • underdiagnosis
   • misdiagnosis
   • underreporting by patients because of the benign nature of the hallucinations
   • patients’ reluctance to report visual hallucinations because of fear of being labeled “mentally ill.”^7,8

Symptoms
There are no specific diagnostic criteria for Charles Bonnet syndrome (Table 2). However, the following are generally accepted for diagnosis⁹:
   • grossly intact cognition, although mild cognitive impairment may be present in some cases¹⁰
    • underlying visual disorder, usually acquired, such as glaucoma, age-related macular degeneration, diabetic retinopathy, central retinal artery occlusion, and optic neuritis^3,4,11
   • no hallucinations or perceptive difficul­ties in other sensory modalities
   • generally intact insight
   • absence of delusions
   • absence of other neurologic, psychiat­ric, toxic, or metabolic conditions; medical causes of delirium must be ruled out.

Hallucinations might not be disturb­ing to the patient. Hallucinations could be simple (light flashes, lines, or geomet­ric shapes) or complex (faces, figures, or scenes),¹² and perceived as in color or in black and white. Hallucinations mostly are pleasant and rarely have any emotional impact or meaning. Although hallucina­tions are almost exclusively visual, they can be accompanied by noise or auditory hallucinations.^13,14

Other characteristics of Charles Bonnet syndrome include:  
   • typical age of onset is approximately 72 years (range, 70 to 92 years)  
   • no sex distinction has been identified  
   • episodes can last from a few seconds to few hours; the syndrome may last a few days or a few years⁵     
   • it is not uncommon for episodes to occur in clusters, followed by symptom-free intervals and recurrences  
   • symptoms tend to fade away as patients progress to complete loss of sight.¹⁵

The course of Charles Bonnet syndrome is uncertain and unpredictable and the epi­sodic nature can be frustrating for both patient and clinician. The syndrome could be misdiagnosed as a psychiatric condition.

Pathophysiology
The precise mechanism behind simple or complex vivid hallucinations in persons with Charles Bonnet syndrome is unclear. Several theories have been proposed.

Release theory proposes a loss of input to the primary visual areas, which decreases cortical inhibition and further causes disin­hibition of visual association areas, thereby “releasing” visual hallucinations.¹⁶ Research suggests that this might be an attempt by surviving neurons to recover vision. Loss of input somehow causes surviving neurons to adapt by increased sensitivity to residual visual stimuli.

Deafferentation theory. This relatively new theory proposes deafferentation of the visual sensory pathway, which, in turn, causes disinhibition of neurons in the visual cortical regions, thereby caus­ing them to fire spontaneously. This could cause a sensation analogous to phantom limb pain, which would be called “phan­tom vision presence of brain activity in the absence of an actual visual input.” Further, biochemical and molecular changes have been proposed to explain the deafferenta­tion theory.¹⁷

Neurobiological evidence. Limited data are available for a neurobiological basis to visual hallucinations in Charles Bonnet syndrome. A few studies have used func­tional MRI and single-photon emission CT and reported possible association of visual hallucinations to specific visual areas.^18,19

Risk factors
Social or physical isolation, loneliness, low extraversion, and shyness are risk factors for Charles Bonnet syndrome in visually impaired people.²⁰ Sensory deprivation and low level of arousal favor the occur­rence of hallucinations.⁵ Rate of vision loss—not the nature of pathology or sever­ity of visual impairment—has been sug­gested to increase the risk of developing Charles Bonnet syndrome.²¹

What are the treatment options for Charles Bonnet syndrome?
   a) begin an antipsychotic
   b) do nothing; there is no cure
   c) educate the patient about the nature of the hallucinations
   d) refer the patient to an ophthalmologist for evaluation of vision loss

Treatment
There are several modalities to manage visual hallucinations in a patient with Charles Bonnet syndrome (Table 3). After ruling out medical and other psychiat­ric causes of visual hallucinations, treat­ment might not be indicated if the patient is not disturbed by the hallucinations. In most cases, reassurance and educating the patient and family about the benign nature of the visual hallucinations is all that is needed.

For patients who are disturbed by these visions or for whom there is a treatable cause, treatment could include cataract removal, medical therapy to reduce intra­ocular pressure in glaucoma, treatment of diabetic retinopathy, or laser photoco­agulation. These treatments are associ­ated with a reduction in hallucinations.²²

In some cases, hallucinations disappear as visual acuity deteriorates. Psychotropics have been used to treat Charles Bonnet syndrome, including:
   • antipsychotics, including haloperi­dol, risperidone, and olanzapine
   • anticonvulsants, including valproic acid, gabapentin, and carbamazepine
   • antidepressants, including mirtazap­ine and venlafaxine.^23-30

Some experts recommend a conserva­tive approach, which might be justified because some cases of Charles Bonnet syndrome are episodic and remit sponta­neously.³¹ Again, however, consider phar­macotherapy if a patient is disturbed by hallucinations or if hallucinations impair overall functioning.

TREATMENT Education
After discussion with Mr. B and his family, he is started on risperidone, 1 mg at bedtime, and the psychiatric team provides informa­tion about the nature of Charles Bonnet syndrome. Mr. B reportedly takes this medi­cation for a few days and then stops because he does not want the visual hallucinations to go away.

The psychiatry team sees Mr. B before dis­charge. He and his family are educated about the benign nature of the syndrome, the need for continued family support, and the fact that hallucinations will have minimal or no impli­cations for his life.

The authors’ observations
It is important to remember that a visual description of hallucinations in Charles Bonnet syndrome can be quite vivid, and that the patient might not identify his hal­lucinations as such or consider them as a problem. Be careful not to dismiss the patient’s complaints as a primary psychi­atric condition. It also is important to be mindful of the patient’s concerns with a psychiatric diagnosis; detailed discussion with the patient is helpful in most cases. A more comprehensive and empathetic approach to care could go a long way to sustain quality of life for these patients.

Bottom Line
Charles Bonnet syndrome is characterized by visual hallucinations in patients with visual impairment who have intact insight and an absence of mental illness. Taking a thorough history can help rule out medical and psychiatric causes of visual hallucinations. Educate patients and family about the nature of the hallucinations. In some cases, a psychotropic may be indicated.

Related Resources
• Nguyen ND, Osterweil D, Hoffman J. Charles Bonnet syn­drome: treating nonpsychiatric hallucinations. Consult Pharm. 2013;28(3):184-188.
• Lapid MI, Burton MC, Chang MT, et al. Clinical phenomenology and mortality in Charles Bonnet syndrome. J Geriatr Psychiatry Neurol. 2013;26(1):3-9.

Drug Brand Names
Carbamazepine • Tegretol                          Mirtazapine • Remeron
Gabapentin • Neurontin                              Olanzapine • Zyprexa
Haloperidol • Haldol                                   Risperidone • Risperdal
Lisinopril • Prinivil, Zestril                           Valproic acid • Depakene
Lovastatin • Mevacor                                  Venlafaxine • Effexor
Metoprolol • Lopressor

Acknowledgement
The authors acknowledge Barry Liskow, MD, Vice Chair of Psychiatry, Kansas University Medical Center, Kansas City, Kansas, for providing both insight into the topic and useful feedback on the manuscript.

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

Police bring Ms. R, age 35, to the psychiat­ric ER after they find her asleep in a park. She is awake but drowsy, and states that she has a history of bipolar disorder. She claims that she had been stable on valproic acid (VPA), 1,500 mg/d, bupropion XL, 300 mg/d, quetiap­ine, 400 mg/d, and trazodone, 100 mg/d, until 2 weeks ago, when her best friend died and she stopped taking her medications all together. The previous evening, feeling “alone, hopeless, and sad,” she attempted suicide by ingesting a handful of VPA and clonazepam, obtained from a friend, and 2 liters of vodka. She complains of nausea, vomiting, and abdominal pain. Ele­vated laboratory chemistries included aspartate aminotransferase (AST), 220 U/L; alanine ami­notransferase (ALT), 182 U/L; alkaline phospha­tase (AP), 75 U/L; γ-glutamyltransferase (GGT), 104 U/L; total bilirubin, 1.4 mg/dL; and an ele­vated VPA serum concentration of 152 μg/mL.

Drug-induced hepatotoxicity accounts for approximately 50% of acute liver failure cases, and almost 10% of liver transplants in some facilities.¹ The incidence of drug-induced hepatotoxicity is between 0.001% and 0.1% in patients on standard medication doses.² Drug-induced hepatotoxicity is char­acterized by:
   • abnormalities in laboratory parameters (hepatocellular, cholestatic, or mixed)
   • mechanisms of toxicity (direct, immune-mediated, idiosyncratic, mito­chondrial toxicity)
   • liver biopsy histology (steatosis, sinu­soidal obstruction syndrome).3

Liver function test results of hepatocel­lular injury are characterized by ALT ele­vation and minimal AP elevation, whereas cholestatic injury manifests as high AP. Table 1³ categorizes psychotropics based on type of liver injury and how each injury manifest in liver function tests. Delayed idiosyncratic reactions occur after tak­ing the drug, whereas direct toxicities are dose-dependent and more predictable. By definition, a clinically significant hepato­toxicity is associated with an ALT >3 times the upper limit of normal.³

VPA-induced liver injury occurs in approximately 1 in 37,000 persons taking the drug.⁴ Patients at an increased risk of VPA-induced liver injury include:
   • children
   • patients with mitochondrial enzyme deficiencies
   • Reye’s syndrome
   • Friedreich’s ataxia
   • polypharmacy patients
   • patients with a sibling who has experi­enced VPA toxicity.⁴

Benign enzyme elevations occur in approximately 20% of patients taking VPA.⁵ In Ms. R’s case, concomitant VPA, clonazepam, and alcohol may have led to elevations in ALT, AST, and GGT. Her nausea, vomiting, and abdominal pain are consistent with hepatic dysfunction.

Carnitine is effective in increasing sur­vival of patients with VPA-induced hepa­totoxicity.⁴ Because Ms. R is symptomatic, discontinuing VPA and administering IV L-carnitine is warranted.⁵ L-carnitine can be initiated at 100 mg/kg as an IV bolus, followed by 50 mg/kg as an IV infusion every 8 hours, with a maximum dosage of 3,000 mg.⁶ Patients may require sev­eral days of therapy based on symptoms. L-carnitine should be continued until a patient shows clinical improvement, such as decreases in ALT and AST.

Ms. R experienced a VPA-induced hepa­totoxic reaction. However, continuous mon­itoring is appropriate for all patients who are prescribed any potentially hepatotoxic psychotropic, especially after hepatic inju­ries resolve. This includes mood stabilizers, antipsychotics, benzodiazepines, selective serotonin reuptake inhibitors (SSRIs), and serotonin-norepinephrine reuptake inhibi­tors, especially when given concomitantly with other hepatotoxic agents.

Table 2 lists dosing recommen­dations for commonly used psychotro­pics in patients with hepatic impairment. Among mood stabilizers, carbamazepine and VPA are associated with the highest incidence of hepatotoxicity.² A follow-up study of more than 1,000,000 VPA prescrip­tions found 29 cases of fatal hepatotoxicity in a 7-year period.⁷ Although there are case reports of hepatotoxicity with oxcarbaze­pine, it may have a better liver safety profile than carbamazepine.² Hepatotoxicity with lamotrigine is rare, although fatal cases have been reported.⁵

When initiating an antipsychotic, a tem­porary, benign increase in liver enzymes can be expected, but typically discontinuation is unnecessary.² Phenothiazines in particular can cause increases in liver enzymes in 20% of patients.² Hepatotoxicity with benzodi­azepines is infrequent, with a few cases of cholestatic injury reported with diazepam, chlordiazepoxide, and flurazepam.²

SSRIs are relatively safe; incidents of hepatic injury are rare. Among SSRIs, parox­etine is most frequently associated with hep­atotoxicity. Abnormal liver function tests have been observed with fluoxetine (0.5% of long-term recipients) and other SSRIs.^1,2,4

Among antidepressants with dual serotonergic action, nefazodone carries a black-box warning for hepatotoxicity and is used rarely, whereas trazodone is not regarded as hepatotoxic.² Antidepressants with dual norepinephrine and serotonin reuptake inhibitor properties carry a higher risk of liver injury, especially duloxetine. Hepatocellular, cholestatic, and mixed types of hepatotoxicity are associated with duloxetine-induced hepatotoxicity.²

Monitoring recommendations
Before prescribing potentially hepatotoxic medications, order baseline liver function tests. During therapy, periodic liver func­tion monitoring is recommended. Elevated transaminase concentrations (>3 × the upper limit of normal), bilirubin (>2 × the upper limit of normal), and prolonged pro­thrombin times are indicators of hepatic injury.² Caution should be taken to prevent polypharmacy with multiple hepatotoxic medications and over-the-counter use of hepatotoxic drugs and supplements.

When choosing a psychotropic, take into account patient-specific factors, such as underlying liver disease and alcohol con­sumption. Patients on potentially hepato­toxic medications should be counseled to recognize and report symptoms of liver dysfunction, including nausea, vomiting, jaundice, and lower-extremity edema.² If liver injury occurs, modify therapy with the potential offending agent and check liver function periodically.

Related Resourcesa
• Bleibel W, Kim S, D’Silva K, et al. Drug-induced liver injury: review article. Dig Dis Sci. 2007;52(10):2463-2471.
• U.S. National Library of Medicine. LiverTox. National Institute of Health. www.livertox.nih.gov.

Drug Brand Names
Amitriptyline • Elavil                                       Lurasidone • Latuda
Molindone • Moban                                         Molindone • Moban
Aripiprazole • Abilify                                       Nefazodone • Serzone
Asenapine • Saphris                                       Nortriptyline • Pamelor
Bupropion XL • Wellbutrin XL                          Olanzapine • Zyprexa
Citalopram • Celexa                                       Oxcarbazepine • Trileptal
Carbamazepine • Tegretol                               Paroxetine • Paxil
Chlordiazepoxide • Librium                              Perphenazine • Trilafon
Chlorpromazine • Thorazine                             Phenobarbital • Luminal
Clonazepam • Klonopin                                   Phenytoin • Dilantin
Clozapine • Clozaril                                         Quetiapine • Seroquel
Desvenlafaxine • Pristiq                                   Risperidone • Risperdal
Diazepam • Valium                                         Sertraline • Zoloft
Duloxetine • Cymbalta                                    Thiothixene • Navane
Escitalopram • Lexapro                                   Trazodone • Desyrel
Fluoxetine • Prozac                                         Trifluoperazine • Stelazine
Fluphenazine • Prolixin                                    Topiramate • Topamax
Flurazepam • Dalmane                                    Valproic acid • Depakote
Haloperidol • Haldol                                        Venlafaxine • Effexor
Iloperidone • Fanapt                                       Ziprasidone • Geodon
Lamotrigine • Lamictal
Levocarnitine • L-carnitine

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

Police bring Ms. R, age 35, to the psychiat­ric ER after they find her asleep in a park. She is awake but drowsy, and states that she has a history of bipolar disorder. She claims that she had been stable on valproic acid (VPA), 1,500 mg/d, bupropion XL, 300 mg/d, quetiap­ine, 400 mg/d, and trazodone, 100 mg/d, until 2 weeks ago, when her best friend died and she stopped taking her medications all together. The previous evening, feeling “alone, hopeless, and sad,” she attempted suicide by ingesting a handful of VPA and clonazepam, obtained from a friend, and 2 liters of vodka. She complains of nausea, vomiting, and abdominal pain. Ele­vated laboratory chemistries included aspartate aminotransferase (AST), 220 U/L; alanine ami­notransferase (ALT), 182 U/L; alkaline phospha­tase (AP), 75 U/L; γ-glutamyltransferase (GGT), 104 U/L; total bilirubin, 1.4 mg/dL; and an ele­vated VPA serum concentration of 152 μg/mL.

Drug-induced hepatotoxicity accounts for approximately 50% of acute liver failure cases, and almost 10% of liver transplants in some facilities.¹ The incidence of drug-induced hepatotoxicity is between 0.001% and 0.1% in patients on standard medication doses.² Drug-induced hepatotoxicity is char­acterized by:
   • abnormalities in laboratory parameters (hepatocellular, cholestatic, or mixed)
   • mechanisms of toxicity (direct, immune-mediated, idiosyncratic, mito­chondrial toxicity)
   • liver biopsy histology (steatosis, sinu­soidal obstruction syndrome).3

Liver function test results of hepatocel­lular injury are characterized by ALT ele­vation and minimal AP elevation, whereas cholestatic injury manifests as high AP. Table 1³ categorizes psychotropics based on type of liver injury and how each injury manifest in liver function tests. Delayed idiosyncratic reactions occur after tak­ing the drug, whereas direct toxicities are dose-dependent and more predictable. By definition, a clinically significant hepato­toxicity is associated with an ALT >3 times the upper limit of normal.³

VPA-induced liver injury occurs in approximately 1 in 37,000 persons taking the drug.⁴ Patients at an increased risk of VPA-induced liver injury include:
   • children
   • patients with mitochondrial enzyme deficiencies
   • Reye’s syndrome
   • Friedreich’s ataxia
   • polypharmacy patients
   • patients with a sibling who has experi­enced VPA toxicity.⁴

Benign enzyme elevations occur in approximately 20% of patients taking VPA.⁵ In Ms. R’s case, concomitant VPA, clonazepam, and alcohol may have led to elevations in ALT, AST, and GGT. Her nausea, vomiting, and abdominal pain are consistent with hepatic dysfunction.

Carnitine is effective in increasing sur­vival of patients with VPA-induced hepa­totoxicity.⁴ Because Ms. R is symptomatic, discontinuing VPA and administering IV L-carnitine is warranted.⁵ L-carnitine can be initiated at 100 mg/kg as an IV bolus, followed by 50 mg/kg as an IV infusion every 8 hours, with a maximum dosage of 3,000 mg.⁶ Patients may require sev­eral days of therapy based on symptoms. L-carnitine should be continued until a patient shows clinical improvement, such as decreases in ALT and AST.

Ms. R experienced a VPA-induced hepa­totoxic reaction. However, continuous mon­itoring is appropriate for all patients who are prescribed any potentially hepatotoxic psychotropic, especially after hepatic inju­ries resolve. This includes mood stabilizers, antipsychotics, benzodiazepines, selective serotonin reuptake inhibitors (SSRIs), and serotonin-norepinephrine reuptake inhibi­tors, especially when given concomitantly with other hepatotoxic agents.

Table 2 lists dosing recommen­dations for commonly used psychotro­pics in patients with hepatic impairment. Among mood stabilizers, carbamazepine and VPA are associated with the highest incidence of hepatotoxicity.² A follow-up study of more than 1,000,000 VPA prescrip­tions found 29 cases of fatal hepatotoxicity in a 7-year period.⁷ Although there are case reports of hepatotoxicity with oxcarbaze­pine, it may have a better liver safety profile than carbamazepine.² Hepatotoxicity with lamotrigine is rare, although fatal cases have been reported.⁵

When initiating an antipsychotic, a tem­porary, benign increase in liver enzymes can be expected, but typically discontinuation is unnecessary.² Phenothiazines in particular can cause increases in liver enzymes in 20% of patients.² Hepatotoxicity with benzodi­azepines is infrequent, with a few cases of cholestatic injury reported with diazepam, chlordiazepoxide, and flurazepam.²

SSRIs are relatively safe; incidents of hepatic injury are rare. Among SSRIs, parox­etine is most frequently associated with hep­atotoxicity. Abnormal liver function tests have been observed with fluoxetine (0.5% of long-term recipients) and other SSRIs.^1,2,4

Among antidepressants with dual serotonergic action, nefazodone carries a black-box warning for hepatotoxicity and is used rarely, whereas trazodone is not regarded as hepatotoxic.² Antidepressants with dual norepinephrine and serotonin reuptake inhibitor properties carry a higher risk of liver injury, especially duloxetine. Hepatocellular, cholestatic, and mixed types of hepatotoxicity are associated with duloxetine-induced hepatotoxicity.²

Monitoring recommendations
Before prescribing potentially hepatotoxic medications, order baseline liver function tests. During therapy, periodic liver func­tion monitoring is recommended. Elevated transaminase concentrations (>3 × the upper limit of normal), bilirubin (>2 × the upper limit of normal), and prolonged pro­thrombin times are indicators of hepatic injury.² Caution should be taken to prevent polypharmacy with multiple hepatotoxic medications and over-the-counter use of hepatotoxic drugs and supplements.

When choosing a psychotropic, take into account patient-specific factors, such as underlying liver disease and alcohol con­sumption. Patients on potentially hepato­toxic medications should be counseled to recognize and report symptoms of liver dysfunction, including nausea, vomiting, jaundice, and lower-extremity edema.² If liver injury occurs, modify therapy with the potential offending agent and check liver function periodically.

Related Resourcesa
• Bleibel W, Kim S, D’Silva K, et al. Drug-induced liver injury: review article. Dig Dis Sci. 2007;52(10):2463-2471.
• U.S. National Library of Medicine. LiverTox. National Institute of Health. www.livertox.nih.gov.

Drug Brand Names
Amitriptyline • Elavil                                       Lurasidone • Latuda
Molindone • Moban                                         Molindone • Moban
Aripiprazole • Abilify                                       Nefazodone • Serzone
Asenapine • Saphris                                       Nortriptyline • Pamelor
Bupropion XL • Wellbutrin XL                          Olanzapine • Zyprexa
Citalopram • Celexa                                       Oxcarbazepine • Trileptal
Carbamazepine • Tegretol                               Paroxetine • Paxil
Chlordiazepoxide • Librium                              Perphenazine • Trilafon
Chlorpromazine • Thorazine                             Phenobarbital • Luminal
Clonazepam • Klonopin                                   Phenytoin • Dilantin
Clozapine • Clozaril                                         Quetiapine • Seroquel
Desvenlafaxine • Pristiq                                   Risperidone • Risperdal
Diazepam • Valium                                         Sertraline • Zoloft
Duloxetine • Cymbalta                                    Thiothixene • Navane
Escitalopram • Lexapro                                   Trazodone • Desyrel
Fluoxetine • Prozac                                         Trifluoperazine • Stelazine
Fluphenazine • Prolixin                                    Topiramate • Topamax
Flurazepam • Dalmane                                    Valproic acid • Depakote
Haloperidol • Haldol                                        Venlafaxine • Effexor
Iloperidone • Fanapt                                       Ziprasidone • Geodon
Lamotrigine • Lamictal
Levocarnitine • L-carnitine

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

Police bring Ms. R, age 35, to the psychiat­ric ER after they find her asleep in a park. She is awake but drowsy, and states that she has a history of bipolar disorder. She claims that she had been stable on valproic acid (VPA), 1,500 mg/d, bupropion XL, 300 mg/d, quetiap­ine, 400 mg/d, and trazodone, 100 mg/d, until 2 weeks ago, when her best friend died and she stopped taking her medications all together. The previous evening, feeling “alone, hopeless, and sad,” she attempted suicide by ingesting a handful of VPA and clonazepam, obtained from a friend, and 2 liters of vodka. She complains of nausea, vomiting, and abdominal pain. Ele­vated laboratory chemistries included aspartate aminotransferase (AST), 220 U/L; alanine ami­notransferase (ALT), 182 U/L; alkaline phospha­tase (AP), 75 U/L; γ-glutamyltransferase (GGT), 104 U/L; total bilirubin, 1.4 mg/dL; and an ele­vated VPA serum concentration of 152 μg/mL.

Drug-induced hepatotoxicity accounts for approximately 50% of acute liver failure cases, and almost 10% of liver transplants in some facilities.¹ The incidence of drug-induced hepatotoxicity is between 0.001% and 0.1% in patients on standard medication doses.² Drug-induced hepatotoxicity is char­acterized by:
   • abnormalities in laboratory parameters (hepatocellular, cholestatic, or mixed)
   • mechanisms of toxicity (direct, immune-mediated, idiosyncratic, mito­chondrial toxicity)
   • liver biopsy histology (steatosis, sinu­soidal obstruction syndrome).3

Liver function test results of hepatocel­lular injury are characterized by ALT ele­vation and minimal AP elevation, whereas cholestatic injury manifests as high AP. Table 1³ categorizes psychotropics based on type of liver injury and how each injury manifest in liver function tests. Delayed idiosyncratic reactions occur after tak­ing the drug, whereas direct toxicities are dose-dependent and more predictable. By definition, a clinically significant hepato­toxicity is associated with an ALT >3 times the upper limit of normal.³

VPA-induced liver injury occurs in approximately 1 in 37,000 persons taking the drug.⁴ Patients at an increased risk of VPA-induced liver injury include:
   • children
   • patients with mitochondrial enzyme deficiencies
   • Reye’s syndrome
   • Friedreich’s ataxia
   • polypharmacy patients
   • patients with a sibling who has experi­enced VPA toxicity.⁴

Benign enzyme elevations occur in approximately 20% of patients taking VPA.⁵ In Ms. R’s case, concomitant VPA, clonazepam, and alcohol may have led to elevations in ALT, AST, and GGT. Her nausea, vomiting, and abdominal pain are consistent with hepatic dysfunction.

Carnitine is effective in increasing sur­vival of patients with VPA-induced hepa­totoxicity.⁴ Because Ms. R is symptomatic, discontinuing VPA and administering IV L-carnitine is warranted.⁵ L-carnitine can be initiated at 100 mg/kg as an IV bolus, followed by 50 mg/kg as an IV infusion every 8 hours, with a maximum dosage of 3,000 mg.⁶ Patients may require sev­eral days of therapy based on symptoms. L-carnitine should be continued until a patient shows clinical improvement, such as decreases in ALT and AST.

Ms. R experienced a VPA-induced hepa­totoxic reaction. However, continuous mon­itoring is appropriate for all patients who are prescribed any potentially hepatotoxic psychotropic, especially after hepatic inju­ries resolve. This includes mood stabilizers, antipsychotics, benzodiazepines, selective serotonin reuptake inhibitors (SSRIs), and serotonin-norepinephrine reuptake inhibi­tors, especially when given concomitantly with other hepatotoxic agents.

Table 2 lists dosing recommen­dations for commonly used psychotro­pics in patients with hepatic impairment. Among mood stabilizers, carbamazepine and VPA are associated with the highest incidence of hepatotoxicity.² A follow-up study of more than 1,000,000 VPA prescrip­tions found 29 cases of fatal hepatotoxicity in a 7-year period.⁷ Although there are case reports of hepatotoxicity with oxcarbaze­pine, it may have a better liver safety profile than carbamazepine.² Hepatotoxicity with lamotrigine is rare, although fatal cases have been reported.⁵

When initiating an antipsychotic, a tem­porary, benign increase in liver enzymes can be expected, but typically discontinuation is unnecessary.² Phenothiazines in particular can cause increases in liver enzymes in 20% of patients.² Hepatotoxicity with benzodi­azepines is infrequent, with a few cases of cholestatic injury reported with diazepam, chlordiazepoxide, and flurazepam.²

SSRIs are relatively safe; incidents of hepatic injury are rare. Among SSRIs, parox­etine is most frequently associated with hep­atotoxicity. Abnormal liver function tests have been observed with fluoxetine (0.5% of long-term recipients) and other SSRIs.^1,2,4

Among antidepressants with dual serotonergic action, nefazodone carries a black-box warning for hepatotoxicity and is used rarely, whereas trazodone is not regarded as hepatotoxic.² Antidepressants with dual norepinephrine and serotonin reuptake inhibitor properties carry a higher risk of liver injury, especially duloxetine. Hepatocellular, cholestatic, and mixed types of hepatotoxicity are associated with duloxetine-induced hepatotoxicity.²

Monitoring recommendations
Before prescribing potentially hepatotoxic medications, order baseline liver function tests. During therapy, periodic liver func­tion monitoring is recommended. Elevated transaminase concentrations (>3 × the upper limit of normal), bilirubin (>2 × the upper limit of normal), and prolonged pro­thrombin times are indicators of hepatic injury.² Caution should be taken to prevent polypharmacy with multiple hepatotoxic medications and over-the-counter use of hepatotoxic drugs and supplements.

When choosing a psychotropic, take into account patient-specific factors, such as underlying liver disease and alcohol con­sumption. Patients on potentially hepato­toxic medications should be counseled to recognize and report symptoms of liver dysfunction, including nausea, vomiting, jaundice, and lower-extremity edema.² If liver injury occurs, modify therapy with the potential offending agent and check liver function periodically.

Related Resourcesa
• Bleibel W, Kim S, D’Silva K, et al. Drug-induced liver injury: review article. Dig Dis Sci. 2007;52(10):2463-2471.
• U.S. National Library of Medicine. LiverTox. National Institute of Health. www.livertox.nih.gov.

Drug Brand Names
Amitriptyline • Elavil                                       Lurasidone • Latuda
Molindone • Moban                                         Molindone • Moban
Aripiprazole • Abilify                                       Nefazodone • Serzone
Asenapine • Saphris                                       Nortriptyline • Pamelor
Bupropion XL • Wellbutrin XL                          Olanzapine • Zyprexa
Citalopram • Celexa                                       Oxcarbazepine • Trileptal
Carbamazepine • Tegretol                               Paroxetine • Paxil
Chlordiazepoxide • Librium                              Perphenazine • Trilafon
Chlorpromazine • Thorazine                             Phenobarbital • Luminal
Clonazepam • Klonopin                                   Phenytoin • Dilantin
Clozapine • Clozaril                                         Quetiapine • Seroquel
Desvenlafaxine • Pristiq                                   Risperidone • Risperdal
Diazepam • Valium                                         Sertraline • Zoloft
Duloxetine • Cymbalta                                    Thiothixene • Navane
Escitalopram • Lexapro                                   Trazodone • Desyrel
Fluoxetine • Prozac                                         Trifluoperazine • Stelazine
Fluphenazine • Prolixin                                    Topiramate • Topamax
Flurazepam • Dalmane                                    Valproic acid • Depakote
Haloperidol • Haldol                                        Venlafaxine • Effexor
Iloperidone • Fanapt                                       Ziprasidone • Geodon
Lamotrigine • Lamictal
Levocarnitine • L-carnitine

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

Dear Dr. Mossman,

Where I practice, most health care plans won’t pay for certain medications without giving prior authorization (PA). Completing PA forms and making telephone calls take up time that could be better spent treat­ing patients. I’m tempted to set a new policy of not doing PAs. If I do, might I face legal trouble?

Submitted by “Dr. A”

If you provide clinical care, you’ve prob­ably dealt with third-party payers who require prior authorization (PA) before they will pay for certain treatments. Dr. A is not alone in feeling exasperated about the time it takes to complete a PA.¹ After spend­ing several hours each month waiting on hold and wading through stacks of paper­work, you may feel like Dr. A and consider refusing to do any more PAs.

But is Dr. A’s proposed solution a good idea? To address this question and the frus­tration that lies behind it, we’ll take a cue from Italian film director Sergio Leone and discuss:
   • how PAs affect psychiatric care: the good, the bad, and the ugly
   • potential exposure to professional liabil­ity and ethics complaints that might result from refusing or failing to seek PA
   • strategies to reduce the burden of PAs while providing efficient, effective care.

The good
Recent decades have witnessed huge increases in spending on prescription medication. Psychotropics are no excep­tion; state Medicaid spending for anti-psychotic medication grew from <$1 bil­lion in 1995 to >$5.5 billion in 2005.²

Requiring a PA for expensive drugs is one way that third-party payers try to rein in costs and hold down insurance premi­ums. Imposing financial constraints often is just one aim of a pharmacy benefit man­agement (PBM) program. Insurers also jus­tify PBMs by pointing out that feedback to practitioners whose prescribing falls well outside the norm—in the form of mailed warnings, physician second opinions, or pharmacist consultation—can improve patient safety and encourage appropriate treatment options for enrolled patients.^3,4 Examples of such benefits include reduc­ing overuse of prescription opioids⁵ and antipsychotics among children,³ misuse of buprenorphine,⁶ and adverse effects from potentially inappropriate prescriptions.⁷

The bad
The bad news for doctors: Cost savings for payers come at the expense of pro­viders and their practices, in the form of time spent doing paperwork and talking on the phone to complete PAs or contest PA decisions.⁸ Addressing PA requests costs an estimated $83,000 per physician per year. The total administrative burden for all 835,000 physicians who practice in the United States therefore is 868,000,000 hours, or $69 billion annually.⁹

To make matters worse, PA requirements may increase the overall cost of care. After Georgia Medicaid instituted PA require­ments for second-generation antipsychotics (SGAs), average monthly per member drug costs fell $19.62, but average monthly outpa­tient treatment costs rose $31.59 per mem­ber.10 Pharmacy savings that result from requiring PAs for SGAs can be offset quickly by small increases in the hospitalization rate or emergency department visits.^9,11

The ugly
Many physicians believe that the PA pro­cess undermines patient care by decreasing time devoted to direct patient contact, incen­tivizing suboptimal treatment, and limit­ing medication access.^1,12,13 But do any data support this belief? Do PAs impede treat­ment for vulnerable persons with severe mental illnesses?

The answer, some studies suggest, is “Yes.” A Maine Medicaid PA policy slowed initiation of treatment for bipolar disor­der by reducing the rate of starting non-preferred medications, although the same policy had no impact on patients already receiving treatment.¹⁴ Another study exam­ined the effect of PA processes for inpatient psychiatry treatment and found that patients were less likely to be admitted on weekends, probably because PA review was not avail­able on those days.¹⁵ A third study showed that PA requirements and resulting impedi­ments to getting refills were correlated with medication discontinuation by patients with schizophrenia or bipolar disorder, which can increase the risk of decompensation, work-related problems, and hospitalization.¹⁶

Problems with PAs
Whether they are helpful or counterpro­ductive, PAs are a practice reality. Dr. A’s proposed solution sounds appealing, but it might create ethical and legal problems.

Among the fundamental elements of ethi­cal medical practice is physicians’ obliga­tion to give patients “guidance … as to the optimal course of action” and to “advocate for patients in dealing with third parties when appropriate.”¹⁷ It’s fine for psychia­trists to consider prescribing treatments that patients’ health care coverage favors, but we also have to help patients weigh and evaluate costs, particularly when patients’ circumstances and medical interests militate strongly for options that third-party payers balk at paying for. Patients’ interests—not what’s expedient—are always physicians’ foremost concern.¹⁸

Beyond purely ethical considerations, you might face legal consequences if you refuse or fail to seek PAs for what you think is the proper medication. As Table 1 shows, one key factor is whether you are under contract with the patient’s insurance carrier; if you are, failure to seek a PA when appropriate may constitute a breach of the contract (Donna Vanderpool, written communication, October 5, 2014).

If the prescribed medication does not meet the standard of care and your patient suffers some harm, a licensing board complaint and investigation are possible. You also face exposure to a medical malpractice action. Although we do not know of any instances in which such an action has succeeded, 2 recent court decisions suggest that harm to a patient stemmed from failing to seek PA for a medication could constitute grounds for a lawsuit.^19,20 Efforts to contain medical costs have been around for decades, and courts have held that physicians, third-party pay­ers, and utilization review intermediaries are bound by “the standard of reasonable com­munity practice”²¹ and should not let cost limitations “corrupt medical judgment.”²² Physicians who do not appeal limitations at odds with their medical judgment might bear responsibility for any injuries that occur.^18,22


Managing PA requests
Given the inevitability of encountering PA requests and your ethical and professional obligations to help patients, what can you do (Table 2^9,23,27)?

Some practitioners charge patients for time spent completing PAs.²³ Although phy­sicians should “complete without charge the appropriate ‘simplified’ insurance claim form as a part of service to the patient;” they also may consider “a charge for more complex or multiple forms … in conformity with local custom.”²⁴ Legally, physicians’ contracts with insurance panels may pre­clude charging such fees, but if a patient is being seen out of network, the physician does not have a contractual obligation and may charge.⁹ If your practice setting lets you choose which insurances you accept, the impact and burden of seeking PAs is a factor to consider when deciding whether to par­ticipate in a particular panel.²³

In an interesting twist, an Ohio physi­cian successfully sued a medical insur­ance administrator for the cost of his time responding to PA inquiries.²⁵ Reasoning that the insurance administrator “should expect to pay for the reasonable value of” the doctor’s time because the PAs “were solely intended for the benefit of the insur­ance administrator” or parties whom the administrator served, the judge awarded the doctor $187.50 plus 8% interest.

Considerations that are more practi­cal relate to how to triage and address the volume of PA requests. Some large medi­cal practices centralize PAs and try to set up pre-approved plans of care or blanket approvals for frequently encountered con­ditions. Centralization also allows one key administrative assistant to develop skills in processing PA requests and to build rela­tionships with payers.²⁶

The administrative assistant also can compile lists of preferred alternative medica­tions, PA forms, and payer Web sites. Using and submitting requests through payer Web sites can speed up PA processing, which saves time and money.²⁷ As electronic health records improve, they may incorporate patients’ formularies and provide automatic alerts for required PAs.²³

Patients should be involved, too. They can help to obtain relevant formulary infor­mation and to weigh alternative therapies. You can help them understand your role in the PA process, the reasoning behind your treatment recommendations, and the delays in picking up prescribed medications that waiting for PA approval can create.

It’s easy to get angry about PAs
Your best response, however, is to practice prudent and—within reason— cost-effective medicine. When generic or insurer-preferred medications are clini­cally appropriate and meet treatment guidelines, trying them first is sensible and defensible. If your patient fails the initial low-cost treatment, or if a low-cost choice isn’t appropriate, document this clearly and seek approval for a costlier treatment.⁹
 

BOTTOM LINE
Physicians have ethical and legal obligations to advocate for their patients’ needs and best interests. This sometimes includes completing prior authorization requests. Find strategies that minimize hassle and make sense in your practice, and seek efficient ways to document the medical necessity of requested tests, procedures, or therapies.
 

Acknowledgment
Drs. Marett and Mossman thanks Donna Vanderpool, MBA, JD, and Annette Reynolds, MD, for their helpful input in preparing this article.

Disclosure
The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dear Dr. Mossman,

Where I practice, most health care plans won’t pay for certain medications without giving prior authorization (PA). Completing PA forms and making telephone calls take up time that could be better spent treat­ing patients. I’m tempted to set a new policy of not doing PAs. If I do, might I face legal trouble?

Submitted by “Dr. A”

If you provide clinical care, you’ve prob­ably dealt with third-party payers who require prior authorization (PA) before they will pay for certain treatments. Dr. A is not alone in feeling exasperated about the time it takes to complete a PA.¹ After spend­ing several hours each month waiting on hold and wading through stacks of paper­work, you may feel like Dr. A and consider refusing to do any more PAs.

But is Dr. A’s proposed solution a good idea? To address this question and the frus­tration that lies behind it, we’ll take a cue from Italian film director Sergio Leone and discuss:
   • how PAs affect psychiatric care: the good, the bad, and the ugly
   • potential exposure to professional liabil­ity and ethics complaints that might result from refusing or failing to seek PA
   • strategies to reduce the burden of PAs while providing efficient, effective care.

The good
Recent decades have witnessed huge increases in spending on prescription medication. Psychotropics are no excep­tion; state Medicaid spending for anti-psychotic medication grew from <$1 bil­lion in 1995 to >$5.5 billion in 2005.²

Requiring a PA for expensive drugs is one way that third-party payers try to rein in costs and hold down insurance premi­ums. Imposing financial constraints often is just one aim of a pharmacy benefit man­agement (PBM) program. Insurers also jus­tify PBMs by pointing out that feedback to practitioners whose prescribing falls well outside the norm—in the form of mailed warnings, physician second opinions, or pharmacist consultation—can improve patient safety and encourage appropriate treatment options for enrolled patients.^3,4 Examples of such benefits include reduc­ing overuse of prescription opioids⁵ and antipsychotics among children,³ misuse of buprenorphine,⁶ and adverse effects from potentially inappropriate prescriptions.⁷

The bad
The bad news for doctors: Cost savings for payers come at the expense of pro­viders and their practices, in the form of time spent doing paperwork and talking on the phone to complete PAs or contest PA decisions.⁸ Addressing PA requests costs an estimated $83,000 per physician per year. The total administrative burden for all 835,000 physicians who practice in the United States therefore is 868,000,000 hours, or $69 billion annually.⁹

To make matters worse, PA requirements may increase the overall cost of care. After Georgia Medicaid instituted PA require­ments for second-generation antipsychotics (SGAs), average monthly per member drug costs fell $19.62, but average monthly outpa­tient treatment costs rose $31.59 per mem­ber.10 Pharmacy savings that result from requiring PAs for SGAs can be offset quickly by small increases in the hospitalization rate or emergency department visits.^9,11

The ugly
Many physicians believe that the PA pro­cess undermines patient care by decreasing time devoted to direct patient contact, incen­tivizing suboptimal treatment, and limit­ing medication access.^1,12,13 But do any data support this belief? Do PAs impede treat­ment for vulnerable persons with severe mental illnesses?

The answer, some studies suggest, is “Yes.” A Maine Medicaid PA policy slowed initiation of treatment for bipolar disor­der by reducing the rate of starting non-preferred medications, although the same policy had no impact on patients already receiving treatment.¹⁴ Another study exam­ined the effect of PA processes for inpatient psychiatry treatment and found that patients were less likely to be admitted on weekends, probably because PA review was not avail­able on those days.¹⁵ A third study showed that PA requirements and resulting impedi­ments to getting refills were correlated with medication discontinuation by patients with schizophrenia or bipolar disorder, which can increase the risk of decompensation, work-related problems, and hospitalization.¹⁶

Problems with PAs
Whether they are helpful or counterpro­ductive, PAs are a practice reality. Dr. A’s proposed solution sounds appealing, but it might create ethical and legal problems.

Among the fundamental elements of ethi­cal medical practice is physicians’ obliga­tion to give patients “guidance … as to the optimal course of action” and to “advocate for patients in dealing with third parties when appropriate.”¹⁷ It’s fine for psychia­trists to consider prescribing treatments that patients’ health care coverage favors, but we also have to help patients weigh and evaluate costs, particularly when patients’ circumstances and medical interests militate strongly for options that third-party payers balk at paying for. Patients’ interests—not what’s expedient—are always physicians’ foremost concern.¹⁸

Beyond purely ethical considerations, you might face legal consequences if you refuse or fail to seek PAs for what you think is the proper medication. As Table 1 shows, one key factor is whether you are under contract with the patient’s insurance carrier; if you are, failure to seek a PA when appropriate may constitute a breach of the contract (Donna Vanderpool, written communication, October 5, 2014).

If the prescribed medication does not meet the standard of care and your patient suffers some harm, a licensing board complaint and investigation are possible. You also face exposure to a medical malpractice action. Although we do not know of any instances in which such an action has succeeded, 2 recent court decisions suggest that harm to a patient stemmed from failing to seek PA for a medication could constitute grounds for a lawsuit.^19,20 Efforts to contain medical costs have been around for decades, and courts have held that physicians, third-party pay­ers, and utilization review intermediaries are bound by “the standard of reasonable com­munity practice”²¹ and should not let cost limitations “corrupt medical judgment.”²² Physicians who do not appeal limitations at odds with their medical judgment might bear responsibility for any injuries that occur.^18,22


Managing PA requests
Given the inevitability of encountering PA requests and your ethical and professional obligations to help patients, what can you do (Table 2^9,23,27)?

Some practitioners charge patients for time spent completing PAs.²³ Although phy­sicians should “complete without charge the appropriate ‘simplified’ insurance claim form as a part of service to the patient;” they also may consider “a charge for more complex or multiple forms … in conformity with local custom.”²⁴ Legally, physicians’ contracts with insurance panels may pre­clude charging such fees, but if a patient is being seen out of network, the physician does not have a contractual obligation and may charge.⁹ If your practice setting lets you choose which insurances you accept, the impact and burden of seeking PAs is a factor to consider when deciding whether to par­ticipate in a particular panel.²³

In an interesting twist, an Ohio physi­cian successfully sued a medical insur­ance administrator for the cost of his time responding to PA inquiries.²⁵ Reasoning that the insurance administrator “should expect to pay for the reasonable value of” the doctor’s time because the PAs “were solely intended for the benefit of the insur­ance administrator” or parties whom the administrator served, the judge awarded the doctor $187.50 plus 8% interest.

Considerations that are more practi­cal relate to how to triage and address the volume of PA requests. Some large medi­cal practices centralize PAs and try to set up pre-approved plans of care or blanket approvals for frequently encountered con­ditions. Centralization also allows one key administrative assistant to develop skills in processing PA requests and to build rela­tionships with payers.²⁶

The administrative assistant also can compile lists of preferred alternative medica­tions, PA forms, and payer Web sites. Using and submitting requests through payer Web sites can speed up PA processing, which saves time and money.²⁷ As electronic health records improve, they may incorporate patients’ formularies and provide automatic alerts for required PAs.²³

Patients should be involved, too. They can help to obtain relevant formulary infor­mation and to weigh alternative therapies. You can help them understand your role in the PA process, the reasoning behind your treatment recommendations, and the delays in picking up prescribed medications that waiting for PA approval can create.

It’s easy to get angry about PAs
Your best response, however, is to practice prudent and—within reason— cost-effective medicine. When generic or insurer-preferred medications are clini­cally appropriate and meet treatment guidelines, trying them first is sensible and defensible. If your patient fails the initial low-cost treatment, or if a low-cost choice isn’t appropriate, document this clearly and seek approval for a costlier treatment.⁹
 

BOTTOM LINE
Physicians have ethical and legal obligations to advocate for their patients’ needs and best interests. This sometimes includes completing prior authorization requests. Find strategies that minimize hassle and make sense in your practice, and seek efficient ways to document the medical necessity of requested tests, procedures, or therapies.
 

Acknowledgment
Drs. Marett and Mossman thanks Donna Vanderpool, MBA, JD, and Annette Reynolds, MD, for their helpful input in preparing this article.

Disclosure
The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dear Dr. Mossman,

Where I practice, most health care plans won’t pay for certain medications without giving prior authorization (PA). Completing PA forms and making telephone calls take up time that could be better spent treat­ing patients. I’m tempted to set a new policy of not doing PAs. If I do, might I face legal trouble?

Submitted by “Dr. A”

If you provide clinical care, you’ve prob­ably dealt with third-party payers who require prior authorization (PA) before they will pay for certain treatments. Dr. A is not alone in feeling exasperated about the time it takes to complete a PA.¹ After spend­ing several hours each month waiting on hold and wading through stacks of paper­work, you may feel like Dr. A and consider refusing to do any more PAs.

But is Dr. A’s proposed solution a good idea? To address this question and the frus­tration that lies behind it, we’ll take a cue from Italian film director Sergio Leone and discuss:
   • how PAs affect psychiatric care: the good, the bad, and the ugly
   • potential exposure to professional liabil­ity and ethics complaints that might result from refusing or failing to seek PA
   • strategies to reduce the burden of PAs while providing efficient, effective care.

The good
Recent decades have witnessed huge increases in spending on prescription medication. Psychotropics are no excep­tion; state Medicaid spending for anti-psychotic medication grew from <$1 bil­lion in 1995 to >$5.5 billion in 2005.²

Requiring a PA for expensive drugs is one way that third-party payers try to rein in costs and hold down insurance premi­ums. Imposing financial constraints often is just one aim of a pharmacy benefit man­agement (PBM) program. Insurers also jus­tify PBMs by pointing out that feedback to practitioners whose prescribing falls well outside the norm—in the form of mailed warnings, physician second opinions, or pharmacist consultation—can improve patient safety and encourage appropriate treatment options for enrolled patients.^3,4 Examples of such benefits include reduc­ing overuse of prescription opioids⁵ and antipsychotics among children,³ misuse of buprenorphine,⁶ and adverse effects from potentially inappropriate prescriptions.⁷

The bad
The bad news for doctors: Cost savings for payers come at the expense of pro­viders and their practices, in the form of time spent doing paperwork and talking on the phone to complete PAs or contest PA decisions.⁸ Addressing PA requests costs an estimated $83,000 per physician per year. The total administrative burden for all 835,000 physicians who practice in the United States therefore is 868,000,000 hours, or $69 billion annually.⁹

To make matters worse, PA requirements may increase the overall cost of care. After Georgia Medicaid instituted PA require­ments for second-generation antipsychotics (SGAs), average monthly per member drug costs fell $19.62, but average monthly outpa­tient treatment costs rose $31.59 per mem­ber.10 Pharmacy savings that result from requiring PAs for SGAs can be offset quickly by small increases in the hospitalization rate or emergency department visits.^9,11

The ugly
Many physicians believe that the PA pro­cess undermines patient care by decreasing time devoted to direct patient contact, incen­tivizing suboptimal treatment, and limit­ing medication access.^1,12,13 But do any data support this belief? Do PAs impede treat­ment for vulnerable persons with severe mental illnesses?

The answer, some studies suggest, is “Yes.” A Maine Medicaid PA policy slowed initiation of treatment for bipolar disor­der by reducing the rate of starting non-preferred medications, although the same policy had no impact on patients already receiving treatment.¹⁴ Another study exam­ined the effect of PA processes for inpatient psychiatry treatment and found that patients were less likely to be admitted on weekends, probably because PA review was not avail­able on those days.¹⁵ A third study showed that PA requirements and resulting impedi­ments to getting refills were correlated with medication discontinuation by patients with schizophrenia or bipolar disorder, which can increase the risk of decompensation, work-related problems, and hospitalization.¹⁶

Problems with PAs
Whether they are helpful or counterpro­ductive, PAs are a practice reality. Dr. A’s proposed solution sounds appealing, but it might create ethical and legal problems.

Among the fundamental elements of ethi­cal medical practice is physicians’ obliga­tion to give patients “guidance … as to the optimal course of action” and to “advocate for patients in dealing with third parties when appropriate.”¹⁷ It’s fine for psychia­trists to consider prescribing treatments that patients’ health care coverage favors, but we also have to help patients weigh and evaluate costs, particularly when patients’ circumstances and medical interests militate strongly for options that third-party payers balk at paying for. Patients’ interests—not what’s expedient—are always physicians’ foremost concern.¹⁸

Beyond purely ethical considerations, you might face legal consequences if you refuse or fail to seek PAs for what you think is the proper medication. As Table 1 shows, one key factor is whether you are under contract with the patient’s insurance carrier; if you are, failure to seek a PA when appropriate may constitute a breach of the contract (Donna Vanderpool, written communication, October 5, 2014).

If the prescribed medication does not meet the standard of care and your patient suffers some harm, a licensing board complaint and investigation are possible. You also face exposure to a medical malpractice action. Although we do not know of any instances in which such an action has succeeded, 2 recent court decisions suggest that harm to a patient stemmed from failing to seek PA for a medication could constitute grounds for a lawsuit.^19,20 Efforts to contain medical costs have been around for decades, and courts have held that physicians, third-party pay­ers, and utilization review intermediaries are bound by “the standard of reasonable com­munity practice”²¹ and should not let cost limitations “corrupt medical judgment.”²² Physicians who do not appeal limitations at odds with their medical judgment might bear responsibility for any injuries that occur.^18,22


Managing PA requests
Given the inevitability of encountering PA requests and your ethical and professional obligations to help patients, what can you do (Table 2^9,23,27)?

Some practitioners charge patients for time spent completing PAs.²³ Although phy­sicians should “complete without charge the appropriate ‘simplified’ insurance claim form as a part of service to the patient;” they also may consider “a charge for more complex or multiple forms … in conformity with local custom.”²⁴ Legally, physicians’ contracts with insurance panels may pre­clude charging such fees, but if a patient is being seen out of network, the physician does not have a contractual obligation and may charge.⁹ If your practice setting lets you choose which insurances you accept, the impact and burden of seeking PAs is a factor to consider when deciding whether to par­ticipate in a particular panel.²³

In an interesting twist, an Ohio physi­cian successfully sued a medical insur­ance administrator for the cost of his time responding to PA inquiries.²⁵ Reasoning that the insurance administrator “should expect to pay for the reasonable value of” the doctor’s time because the PAs “were solely intended for the benefit of the insur­ance administrator” or parties whom the administrator served, the judge awarded the doctor $187.50 plus 8% interest.

Considerations that are more practi­cal relate to how to triage and address the volume of PA requests. Some large medi­cal practices centralize PAs and try to set up pre-approved plans of care or blanket approvals for frequently encountered con­ditions. Centralization also allows one key administrative assistant to develop skills in processing PA requests and to build rela­tionships with payers.²⁶

The administrative assistant also can compile lists of preferred alternative medica­tions, PA forms, and payer Web sites. Using and submitting requests through payer Web sites can speed up PA processing, which saves time and money.²⁷ As electronic health records improve, they may incorporate patients’ formularies and provide automatic alerts for required PAs.²³

Patients should be involved, too. They can help to obtain relevant formulary infor­mation and to weigh alternative therapies. You can help them understand your role in the PA process, the reasoning behind your treatment recommendations, and the delays in picking up prescribed medications that waiting for PA approval can create.

It’s easy to get angry about PAs
Your best response, however, is to practice prudent and—within reason— cost-effective medicine. When generic or insurer-preferred medications are clini­cally appropriate and meet treatment guidelines, trying them first is sensible and defensible. If your patient fails the initial low-cost treatment, or if a low-cost choice isn’t appropriate, document this clearly and seek approval for a costlier treatment.⁹
 

BOTTOM LINE
Physicians have ethical and legal obligations to advocate for their patients’ needs and best interests. This sometimes includes completing prior authorization requests. Find strategies that minimize hassle and make sense in your practice, and seek efficient ways to document the medical necessity of requested tests, procedures, or therapies.
 

Acknowledgment
Drs. Marett and Mossman thanks Donna Vanderpool, MBA, JD, and Annette Reynolds, MD, for their helpful input in preparing this article.

Disclosure
The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Attention-deficit/hyperactivity disorder (ADHD) often persists beyond childhood into adulthood. One of the therapeutic challenges of treat­ing ADHD is identifying comorbidities, including underlying mood and anxiety disorders, and ongoing substance abuse. Effective treatment modalities tend to pri­oritize management of substance abuse, but the patient’s age may dictate the overall assessment plan.

So-called 'reward' center
Treating childhood ADHD with stimu­lants might reduce the risk for future drug abuse.¹ It is estimated that approximately 10 million people with ADHD are undiag­nosed in the United States²; characteristic ADHD symptoms—inattention, hyperac­tivity, impulsivity—can persist in adult­hood, and affected persons might not meet societal expectations. Previously uniden­tified attention difficulties may emerge during early adulthood because of increas­ingly complex tasks at school and work.

Persons with undiagnosed ADHD might turn to potentially self-destructive means of placating inner tension. Cocaine has phar­macological properties in common with stimulants such as methylphenidate, which often is prescribed for ADHD. Cocaine and methylphenidate both work on altering brain chemistry with a similar mechanism of action, allowing for increased dopamine in the nucleus accumbens, also known as the “reward center” of the brain.

Adults with ADHD have a 300% higher risk of developing a substance use disorder than adults without ADHD.³ An estimated 15% to 25% of adults with substance abuse have comorbid ADHD. Although these patients abuse of a variety of substances including Cannabis and alcohol, cocaine is one of the most commonly abused substances among this population. These observations could point to a self-medication hypothesis.
 

Why self-medicate?
The self-medication hypothesis, formu­lated by Khantzian in 1985, was based on several clinical observations. Khantzian stated that an abuser’s drug of choice is not selected at random but, rather, by an inherent desire to suppress the attri­butes of the condition that seems to oth­erwise wreak havoc on his (her) life. Almost a century earlier, Freud men­tioned that cocaine is an antidepressant. Among persons with ADHD who have not been given that diagnosis, or treated for the disorder, cocaine is a popular drug. Because of the antidepressant features of cocaine and its ability to produce a rapid increase of dopamine levels that exert a pro-euphoric effect, coupled with a seem­ingly paradoxical calming influence that leads to increased productivity, it is not surprising to find that cocaine is abused. Reportedly, persons who have not been treated because their ADHD is undiag­nosed turn to cocaine because it improves attention, raises self-esteem, and allows users to harness a level of focus that they could not otherwise achieve.⁴

Mechanism of action
Methylphenidate reduces ADHD symp­toms by increasing extracellular dopamine in the brain, acting by means of a mechanism that is similar to that of cocaine.⁵ By block­ing reuptake of dopamine and allowing an extracellular surplus, users continue to experience the pleasurable effect the neuro-transmitter produces. Methylphenidate has been shown to be an even more potent inhibitor of the same autoreceptors. Injecting methylphenidate has been shown to produce a rapid release of dopamine sim­ilar to that of cocaine.⁵

However, methylphenidate causes a much slower increase in dopamine; its effect on the brain has been shown to be similar to that of cocaine without the increased abuse potential. Cocaine use remodels the brain by reconfiguring con­nections that are essential for craving and self-control.⁵ Therefore, substituting meth­ylphenidate for cocaine could help ADHD patients by:
   • improving overall executive functioning
   • decreasing feelings of low self-worth
   • increasing daily functioning
   • minimizing craving and the risk of sub­sequent cocaine abuse.
 

Treatment recommendations
Carefully consider pharmacodynamics and pharmacokinetics when prescribing ADHD medication. In general, children and adolescents with ADHD respond more favorably to stimulants than adults do. In children, the mainstay of treatment is slow-dose stimulants such as methylphenidate; second-line treatments are immediate-release stimulants and atomoxetine, a selec­tive norepinephrine reuptake inhibitor.⁶ Adults with ADHD might benefit from a nonstimulant, in part because of the pres­ence of complex comorbidities.⁶ Modafinil often is prescribed for adults with ADHD.

Atomoxetine readily increases norepi­nephrine and dopamine in the prefrontal cortex as it bypasses the nucleus accum­bens. Although atomoxetine is not a stimu­lant, the efficacy of the drug is based on its ability to increase norepinephrine through selective inhibition of the norepineph­rine transporter. Norepinephrine modu­lates higher cortical functions—attention, executive function, arousal—that lead to a reduction in hyperactivity, inattention, and impulsivity.

Because dopamine is released in the prefrontal cortex—not in the nucleus accumbens—the addiction potential of atomoxetine is low.⁷ The drug might be an effective intervention for patients who are using cocaine to self-medicate. Stimulants such as methylphenidate have proven effective in safely mimicking the mecha­nism of action of cocaine. Nonstimulants, such as atomoxetine and modafinil, lack abuse potential and are excellent options for treating adults with ADHD.

Clinicians generally are advised to treat a patient’s underlying ADHD symptoms before addressing ongoing substance abuse. If a patient abruptly discontinues cocaine use before ADHD symptoms are properly controlled, her (his) condition might deterio­rate further and the treatment plan might fail to progress. Some patients have experienced a reduction in craving for cocaine after they began stimulant therapy; these people no longer felt a need to self-medicate because their symptoms were being addressed.⁴

Attention-deficit/hyperactivity disorder (ADHD) often persists beyond childhood into adulthood. One of the therapeutic challenges of treat­ing ADHD is identifying comorbidities, including underlying mood and anxiety disorders, and ongoing substance abuse. Effective treatment modalities tend to pri­oritize management of substance abuse, but the patient’s age may dictate the overall assessment plan.

So-called 'reward' center
Treating childhood ADHD with stimu­lants might reduce the risk for future drug abuse.¹ It is estimated that approximately 10 million people with ADHD are undiag­nosed in the United States²; characteristic ADHD symptoms—inattention, hyperac­tivity, impulsivity—can persist in adult­hood, and affected persons might not meet societal expectations. Previously uniden­tified attention difficulties may emerge during early adulthood because of increas­ingly complex tasks at school and work.

Persons with undiagnosed ADHD might turn to potentially self-destructive means of placating inner tension. Cocaine has phar­macological properties in common with stimulants such as methylphenidate, which often is prescribed for ADHD. Cocaine and methylphenidate both work on altering brain chemistry with a similar mechanism of action, allowing for increased dopamine in the nucleus accumbens, also known as the “reward center” of the brain.

Adults with ADHD have a 300% higher risk of developing a substance use disorder than adults without ADHD.³ An estimated 15% to 25% of adults with substance abuse have comorbid ADHD. Although these patients abuse of a variety of substances including Cannabis and alcohol, cocaine is one of the most commonly abused substances among this population. These observations could point to a self-medication hypothesis.
 

Why self-medicate?
The self-medication hypothesis, formu­lated by Khantzian in 1985, was based on several clinical observations. Khantzian stated that an abuser’s drug of choice is not selected at random but, rather, by an inherent desire to suppress the attri­butes of the condition that seems to oth­erwise wreak havoc on his (her) life. Almost a century earlier, Freud men­tioned that cocaine is an antidepressant. Among persons with ADHD who have not been given that diagnosis, or treated for the disorder, cocaine is a popular drug. Because of the antidepressant features of cocaine and its ability to produce a rapid increase of dopamine levels that exert a pro-euphoric effect, coupled with a seem­ingly paradoxical calming influence that leads to increased productivity, it is not surprising to find that cocaine is abused. Reportedly, persons who have not been treated because their ADHD is undiag­nosed turn to cocaine because it improves attention, raises self-esteem, and allows users to harness a level of focus that they could not otherwise achieve.⁴

Mechanism of action
Methylphenidate reduces ADHD symp­toms by increasing extracellular dopamine in the brain, acting by means of a mechanism that is similar to that of cocaine.⁵ By block­ing reuptake of dopamine and allowing an extracellular surplus, users continue to experience the pleasurable effect the neuro-transmitter produces. Methylphenidate has been shown to be an even more potent inhibitor of the same autoreceptors. Injecting methylphenidate has been shown to produce a rapid release of dopamine sim­ilar to that of cocaine.⁵

However, methylphenidate causes a much slower increase in dopamine; its effect on the brain has been shown to be similar to that of cocaine without the increased abuse potential. Cocaine use remodels the brain by reconfiguring con­nections that are essential for craving and self-control.⁵ Therefore, substituting meth­ylphenidate for cocaine could help ADHD patients by:
   • improving overall executive functioning
   • decreasing feelings of low self-worth
   • increasing daily functioning
   • minimizing craving and the risk of sub­sequent cocaine abuse.
 

Treatment recommendations
Carefully consider pharmacodynamics and pharmacokinetics when prescribing ADHD medication. In general, children and adolescents with ADHD respond more favorably to stimulants than adults do. In children, the mainstay of treatment is slow-dose stimulants such as methylphenidate; second-line treatments are immediate-release stimulants and atomoxetine, a selec­tive norepinephrine reuptake inhibitor.⁶ Adults with ADHD might benefit from a nonstimulant, in part because of the pres­ence of complex comorbidities.⁶ Modafinil often is prescribed for adults with ADHD.

Atomoxetine readily increases norepi­nephrine and dopamine in the prefrontal cortex as it bypasses the nucleus accum­bens. Although atomoxetine is not a stimu­lant, the efficacy of the drug is based on its ability to increase norepinephrine through selective inhibition of the norepineph­rine transporter. Norepinephrine modu­lates higher cortical functions—attention, executive function, arousal—that lead to a reduction in hyperactivity, inattention, and impulsivity.

Because dopamine is released in the prefrontal cortex—not in the nucleus accumbens—the addiction potential of atomoxetine is low.⁷ The drug might be an effective intervention for patients who are using cocaine to self-medicate. Stimulants such as methylphenidate have proven effective in safely mimicking the mecha­nism of action of cocaine. Nonstimulants, such as atomoxetine and modafinil, lack abuse potential and are excellent options for treating adults with ADHD.

Clinicians generally are advised to treat a patient’s underlying ADHD symptoms before addressing ongoing substance abuse. If a patient abruptly discontinues cocaine use before ADHD symptoms are properly controlled, her (his) condition might deterio­rate further and the treatment plan might fail to progress. Some patients have experienced a reduction in craving for cocaine after they began stimulant therapy; these people no longer felt a need to self-medicate because their symptoms were being addressed.⁴

Attention-deficit/hyperactivity disorder (ADHD) often persists beyond childhood into adulthood. One of the therapeutic challenges of treat­ing ADHD is identifying comorbidities, including underlying mood and anxiety disorders, and ongoing substance abuse. Effective treatment modalities tend to pri­oritize management of substance abuse, but the patient’s age may dictate the overall assessment plan.

So-called 'reward' center
Treating childhood ADHD with stimu­lants might reduce the risk for future drug abuse.¹ It is estimated that approximately 10 million people with ADHD are undiag­nosed in the United States²; characteristic ADHD symptoms—inattention, hyperac­tivity, impulsivity—can persist in adult­hood, and affected persons might not meet societal expectations. Previously uniden­tified attention difficulties may emerge during early adulthood because of increas­ingly complex tasks at school and work.

Persons with undiagnosed ADHD might turn to potentially self-destructive means of placating inner tension. Cocaine has phar­macological properties in common with stimulants such as methylphenidate, which often is prescribed for ADHD. Cocaine and methylphenidate both work on altering brain chemistry with a similar mechanism of action, allowing for increased dopamine in the nucleus accumbens, also known as the “reward center” of the brain.

Adults with ADHD have a 300% higher risk of developing a substance use disorder than adults without ADHD.³ An estimated 15% to 25% of adults with substance abuse have comorbid ADHD. Although these patients abuse of a variety of substances including Cannabis and alcohol, cocaine is one of the most commonly abused substances among this population. These observations could point to a self-medication hypothesis.
 

Why self-medicate?
The self-medication hypothesis, formu­lated by Khantzian in 1985, was based on several clinical observations. Khantzian stated that an abuser’s drug of choice is not selected at random but, rather, by an inherent desire to suppress the attri­butes of the condition that seems to oth­erwise wreak havoc on his (her) life. Almost a century earlier, Freud men­tioned that cocaine is an antidepressant. Among persons with ADHD who have not been given that diagnosis, or treated for the disorder, cocaine is a popular drug. Because of the antidepressant features of cocaine and its ability to produce a rapid increase of dopamine levels that exert a pro-euphoric effect, coupled with a seem­ingly paradoxical calming influence that leads to increased productivity, it is not surprising to find that cocaine is abused. Reportedly, persons who have not been treated because their ADHD is undiag­nosed turn to cocaine because it improves attention, raises self-esteem, and allows users to harness a level of focus that they could not otherwise achieve.⁴

Mechanism of action
Methylphenidate reduces ADHD symp­toms by increasing extracellular dopamine in the brain, acting by means of a mechanism that is similar to that of cocaine.⁵ By block­ing reuptake of dopamine and allowing an extracellular surplus, users continue to experience the pleasurable effect the neuro-transmitter produces. Methylphenidate has been shown to be an even more potent inhibitor of the same autoreceptors. Injecting methylphenidate has been shown to produce a rapid release of dopamine sim­ilar to that of cocaine.⁵

However, methylphenidate causes a much slower increase in dopamine; its effect on the brain has been shown to be similar to that of cocaine without the increased abuse potential. Cocaine use remodels the brain by reconfiguring con­nections that are essential for craving and self-control.⁵ Therefore, substituting meth­ylphenidate for cocaine could help ADHD patients by:
   • improving overall executive functioning
   • decreasing feelings of low self-worth
   • increasing daily functioning
   • minimizing craving and the risk of sub­sequent cocaine abuse.
 

Treatment recommendations
Carefully consider pharmacodynamics and pharmacokinetics when prescribing ADHD medication. In general, children and adolescents with ADHD respond more favorably to stimulants than adults do. In children, the mainstay of treatment is slow-dose stimulants such as methylphenidate; second-line treatments are immediate-release stimulants and atomoxetine, a selec­tive norepinephrine reuptake inhibitor.⁶ Adults with ADHD might benefit from a nonstimulant, in part because of the pres­ence of complex comorbidities.⁶ Modafinil often is prescribed for adults with ADHD.

Atomoxetine readily increases norepi­nephrine and dopamine in the prefrontal cortex as it bypasses the nucleus accum­bens. Although atomoxetine is not a stimu­lant, the efficacy of the drug is based on its ability to increase norepinephrine through selective inhibition of the norepineph­rine transporter. Norepinephrine modu­lates higher cortical functions—attention, executive function, arousal—that lead to a reduction in hyperactivity, inattention, and impulsivity.

Because dopamine is released in the prefrontal cortex—not in the nucleus accumbens—the addiction potential of atomoxetine is low.⁷ The drug might be an effective intervention for patients who are using cocaine to self-medicate. Stimulants such as methylphenidate have proven effective in safely mimicking the mecha­nism of action of cocaine. Nonstimulants, such as atomoxetine and modafinil, lack abuse potential and are excellent options for treating adults with ADHD.

Clinicians generally are advised to treat a patient’s underlying ADHD symptoms before addressing ongoing substance abuse. If a patient abruptly discontinues cocaine use before ADHD symptoms are properly controlled, her (his) condition might deterio­rate further and the treatment plan might fail to progress. Some patients have experienced a reduction in craving for cocaine after they began stimulant therapy; these people no longer felt a need to self-medicate because their symptoms were being addressed.⁴

Hookahs in a shop

Credit: Steven Damron

A new study indicates that individuals exposed to hookah smoke have an increase in the uptake of benzene, a substance linked to the development of hematologic malignancies.

Levels of S-phenylmercapturic acid (SPMA), a metabolite of benzene, were more than 4 times higher after study subjects smoked a hookah than before they did.

And non-smoking subjects experienced a nearly 3-fold increase in SPMA levels after they visited a hookah lounge.

Nada Kassem, RN, DrPH, of San Diego State University in California, and her colleagues reported these findings in Cancer Epidemiology, Biomarkers & Prevention.

“Hookah smoking involves the use of burning charcoal that is needed to heat the hookah tobacco to generate the smoke that the smoker inhales,” Dr Kassem explained.

“In addition to inhaling toxicants and carcinogens found in the hookah tobacco smoke, hookah smokers and non-smokers who socialize with hookah smokers also inhale large quantities of charcoal combustion-generated toxic and carcinogenic emissions.”

To gain more insight into the dangers of hookah smoke, Dr Kassem and her colleagues analyzed levels of SPMA in the urine of 105 hookah smokers and 103 non-smokers.

The team obtained urine samples the morning of and the morning after participants attended a hookah-only smoking event at a hookah lounge or a private home.

SPMA levels in hookah smokers increased 4.2-fold after smoking at a hookah lounge (P<0.001) and increased 1.9-fold after smoking in a private home (P=0.003).

Non-smokers’ SPMA levels increased 2.6-fold after attending a social event in a hookah lounge (P=0.055).

However, non-smokers had similarly high levels of SPMA before and after attending hookah events in a private home (P=0.933). This suggests these subjects had chronic exposure to benzene before the study, according to Dr Kassem.

Regardless, she and her colleagues said the study’s results suggest hookah smoke increases the uptake of benzene, which has been linked to a range of hematologic malignancies, particularly acute myeloid leukemia.

“In contrast to what is believed, hookah tobacco smoking is not a safe alternative to smoking other forms of tobacco,” Dr Kassem said.

She and her colleagues noted that there is no safe level of exposure to benzene. And this suggests a need for interventions to reduce or prevent the use of hookahs, limit hookah-related exposure to toxic substances, and include hookah smoking in clean indoor air legislation.

Hookahs in a shop

Credit: Steven Damron

A new study indicates that individuals exposed to hookah smoke have an increase in the uptake of benzene, a substance linked to the development of hematologic malignancies.

Levels of S-phenylmercapturic acid (SPMA), a metabolite of benzene, were more than 4 times higher after study subjects smoked a hookah than before they did.

And non-smoking subjects experienced a nearly 3-fold increase in SPMA levels after they visited a hookah lounge.

Nada Kassem, RN, DrPH, of San Diego State University in California, and her colleagues reported these findings in Cancer Epidemiology, Biomarkers & Prevention.

“Hookah smoking involves the use of burning charcoal that is needed to heat the hookah tobacco to generate the smoke that the smoker inhales,” Dr Kassem explained.

“In addition to inhaling toxicants and carcinogens found in the hookah tobacco smoke, hookah smokers and non-smokers who socialize with hookah smokers also inhale large quantities of charcoal combustion-generated toxic and carcinogenic emissions.”

To gain more insight into the dangers of hookah smoke, Dr Kassem and her colleagues analyzed levels of SPMA in the urine of 105 hookah smokers and 103 non-smokers.

The team obtained urine samples the morning of and the morning after participants attended a hookah-only smoking event at a hookah lounge or a private home.

SPMA levels in hookah smokers increased 4.2-fold after smoking at a hookah lounge (P<0.001) and increased 1.9-fold after smoking in a private home (P=0.003).

Non-smokers’ SPMA levels increased 2.6-fold after attending a social event in a hookah lounge (P=0.055).

However, non-smokers had similarly high levels of SPMA before and after attending hookah events in a private home (P=0.933). This suggests these subjects had chronic exposure to benzene before the study, according to Dr Kassem.

Regardless, she and her colleagues said the study’s results suggest hookah smoke increases the uptake of benzene, which has been linked to a range of hematologic malignancies, particularly acute myeloid leukemia.

“In contrast to what is believed, hookah tobacco smoking is not a safe alternative to smoking other forms of tobacco,” Dr Kassem said.

She and her colleagues noted that there is no safe level of exposure to benzene. And this suggests a need for interventions to reduce or prevent the use of hookahs, limit hookah-related exposure to toxic substances, and include hookah smoking in clean indoor air legislation.

Hookahs in a shop

Credit: Steven Damron

A new study indicates that individuals exposed to hookah smoke have an increase in the uptake of benzene, a substance linked to the development of hematologic malignancies.

Levels of S-phenylmercapturic acid (SPMA), a metabolite of benzene, were more than 4 times higher after study subjects smoked a hookah than before they did.

And non-smoking subjects experienced a nearly 3-fold increase in SPMA levels after they visited a hookah lounge.

Nada Kassem, RN, DrPH, of San Diego State University in California, and her colleagues reported these findings in Cancer Epidemiology, Biomarkers & Prevention.

“Hookah smoking involves the use of burning charcoal that is needed to heat the hookah tobacco to generate the smoke that the smoker inhales,” Dr Kassem explained.

“In addition to inhaling toxicants and carcinogens found in the hookah tobacco smoke, hookah smokers and non-smokers who socialize with hookah smokers also inhale large quantities of charcoal combustion-generated toxic and carcinogenic emissions.”

To gain more insight into the dangers of hookah smoke, Dr Kassem and her colleagues analyzed levels of SPMA in the urine of 105 hookah smokers and 103 non-smokers.

The team obtained urine samples the morning of and the morning after participants attended a hookah-only smoking event at a hookah lounge or a private home.

SPMA levels in hookah smokers increased 4.2-fold after smoking at a hookah lounge (P<0.001) and increased 1.9-fold after smoking in a private home (P=0.003).

Non-smokers’ SPMA levels increased 2.6-fold after attending a social event in a hookah lounge (P=0.055).

However, non-smokers had similarly high levels of SPMA before and after attending hookah events in a private home (P=0.933). This suggests these subjects had chronic exposure to benzene before the study, according to Dr Kassem.

Regardless, she and her colleagues said the study’s results suggest hookah smoke increases the uptake of benzene, which has been linked to a range of hematologic malignancies, particularly acute myeloid leukemia.

“In contrast to what is believed, hookah tobacco smoking is not a safe alternative to smoking other forms of tobacco,” Dr Kassem said.

She and her colleagues noted that there is no safe level of exposure to benzene. And this suggests a need for interventions to reduce or prevent the use of hookahs, limit hookah-related exposure to toxic substances, and include hookah smoking in clean indoor air legislation.

Frederick Roth, PhD

Credit: Mount Sinai Hospital

Researchers say they’ve created the largest-scale map of direct interactions between proteins encoded by the human genome, and this has revealed dozens of genes that may be involved in cancers.

This human interactome map describes about 14,000 direct interactions between proteins.

The map is about 30% larger than previous maps and contains more high-quality interactions than have come from all previous studies combined, according to the researchers.

Frederick Roth, PhD, of the University of Toronto and Mount Sinai Hospital in Ontario, Canada, and his colleagues described their map in Cell.

First, the researchers identified protein interactions via lab experiments. Then, they used computer modelling to zoom in on proteins that connect to one or more other cancer proteins.

“We show, really for the first time, that cancer proteins are more likely to interconnect with one another than they are to connect to randomly chosen non-cancer proteins,” Dr Roth said.

“Once you see that proteins associated to the same disease are more likely to connect to each other, now you can use this network of interactions as a prediction tool to find new cancer proteins and the genes they encode.”

For example, two known cancer genes encoded two proteins that interacted with CTBP2, a protein encoded at a location tied to prostate cancer, which can spread to nearby lymph nodes. These two proteins are implicated in lymphoid tumors, suggesting that CTBP2 plays a role in the development of lymphoid tumors.

Using their predictive method, the researchers found that 60 of their predicted cancer genes fit into a known cancer pathway.

The study also revealed that the network of protein interactions in humans covers a much broader range of genes than some past research has suggested.

Dr Roth said studies often focus on “popular” proteins that have already been linked to disease or are interesting for other reasons, and this has created a bias in our understanding of protein interactions.

“One major conclusion of the paper is that when you look systematically for interactions, you find them everywhere,” he said.

He and his colleagues believe that knowledge of protein interactions is likely to inform worldwide efforts to sequence and interpret cancer genomes.

Frederick Roth, PhD

Credit: Mount Sinai Hospital

Researchers say they’ve created the largest-scale map of direct interactions between proteins encoded by the human genome, and this has revealed dozens of genes that may be involved in cancers.

This human interactome map describes about 14,000 direct interactions between proteins.

The map is about 30% larger than previous maps and contains more high-quality interactions than have come from all previous studies combined, according to the researchers.

Frederick Roth, PhD, of the University of Toronto and Mount Sinai Hospital in Ontario, Canada, and his colleagues described their map in Cell.

First, the researchers identified protein interactions via lab experiments. Then, they used computer modelling to zoom in on proteins that connect to one or more other cancer proteins.

“We show, really for the first time, that cancer proteins are more likely to interconnect with one another than they are to connect to randomly chosen non-cancer proteins,” Dr Roth said.

“Once you see that proteins associated to the same disease are more likely to connect to each other, now you can use this network of interactions as a prediction tool to find new cancer proteins and the genes they encode.”

For example, two known cancer genes encoded two proteins that interacted with CTBP2, a protein encoded at a location tied to prostate cancer, which can spread to nearby lymph nodes. These two proteins are implicated in lymphoid tumors, suggesting that CTBP2 plays a role in the development of lymphoid tumors.

Using their predictive method, the researchers found that 60 of their predicted cancer genes fit into a known cancer pathway.

The study also revealed that the network of protein interactions in humans covers a much broader range of genes than some past research has suggested.

Dr Roth said studies often focus on “popular” proteins that have already been linked to disease or are interesting for other reasons, and this has created a bias in our understanding of protein interactions.

“One major conclusion of the paper is that when you look systematically for interactions, you find them everywhere,” he said.

He and his colleagues believe that knowledge of protein interactions is likely to inform worldwide efforts to sequence and interpret cancer genomes.

Frederick Roth, PhD

Credit: Mount Sinai Hospital

Researchers say they’ve created the largest-scale map of direct interactions between proteins encoded by the human genome, and this has revealed dozens of genes that may be involved in cancers.

This human interactome map describes about 14,000 direct interactions between proteins.

The map is about 30% larger than previous maps and contains more high-quality interactions than have come from all previous studies combined, according to the researchers.

Frederick Roth, PhD, of the University of Toronto and Mount Sinai Hospital in Ontario, Canada, and his colleagues described their map in Cell.

First, the researchers identified protein interactions via lab experiments. Then, they used computer modelling to zoom in on proteins that connect to one or more other cancer proteins.

“We show, really for the first time, that cancer proteins are more likely to interconnect with one another than they are to connect to randomly chosen non-cancer proteins,” Dr Roth said.

“Once you see that proteins associated to the same disease are more likely to connect to each other, now you can use this network of interactions as a prediction tool to find new cancer proteins and the genes they encode.”

For example, two known cancer genes encoded two proteins that interacted with CTBP2, a protein encoded at a location tied to prostate cancer, which can spread to nearby lymph nodes. These two proteins are implicated in lymphoid tumors, suggesting that CTBP2 plays a role in the development of lymphoid tumors.

Using their predictive method, the researchers found that 60 of their predicted cancer genes fit into a known cancer pathway.

The study also revealed that the network of protein interactions in humans covers a much broader range of genes than some past research has suggested.

Dr Roth said studies often focus on “popular” proteins that have already been linked to disease or are interesting for other reasons, and this has created a bias in our understanding of protein interactions.

“One major conclusion of the paper is that when you look systematically for interactions, you find them everywhere,” he said.

He and his colleagues believe that knowledge of protein interactions is likely to inform worldwide efforts to sequence and interpret cancer genomes.

With no consensus regarding the normal endometrial thickness in postmenopausal women without vaginal bleeding, there are no guidelines for clinicians to follow on when to biopsy, if at all, in an older patient presenting with pelvic pain but no bleeding.

To determine at what endometrial thickness biopsy would be optimal, Michelle Louie, MD, and colleagues from Magee Women’s Hospital in Pittsburgh, Pennsylvania, performed a retrospective cohort analysis of postmenopausal women aged 50 or older who underwent transvaginal ultrasound (TVUS) for indications other than vaginal bleeding. They presented their findings in an abstract at the 43rd AAGL Global Congress in Vancouver, Canada.

Details of the study

Patients were included if they had an endometrial lining of 4 mm or greater and excluded if they had a history of tamoxifen use, hormone replacement, endometrial ablation, hereditary cancer syndrome, or no available pathology results.

Of 462 biopsies, 435 (94.2%) had benign pathology, nine (2.0%) had carcinoma, and seven (1.5%) had atypical hyperplasia.

Endometrial thickness of 14 mm or greater was associated with atypical hyperplasia (odds ratio [OR], 4.29; P = .02), with a negative predictive value of 98.3%. A thickness of 15 mm or greater was associated with carcinoma (OR, 4.53; P = .03), with a negative predictive value of 98.5%.

Under 14 mm, the risk of hyperplasia was low, the authors found, at 0.08%. Below 15 mm, the risk of cancer was 0.06%.

They found no significant associations between endometrial lining TVUS appearance, age, parity, body mass index, diabetes, hypertension, hyperlipidemia, and carcinoma or atypical hyperplasia.

When biopsy might not be necessary

Therefore, regardless of conventional risk factors for endometrial cancer, if a postmenopausal woman reports pelvic pain without vaginal bleeding, and is found to have a thickened endometrial lining of less than 14 mm on TVUS, biopsy might not be warranted, conclude the study authors.  

With no consensus regarding the normal endometrial thickness in postmenopausal women without vaginal bleeding, there are no guidelines for clinicians to follow on when to biopsy, if at all, in an older patient presenting with pelvic pain but no bleeding.

To determine at what endometrial thickness biopsy would be optimal, Michelle Louie, MD, and colleagues from Magee Women’s Hospital in Pittsburgh, Pennsylvania, performed a retrospective cohort analysis of postmenopausal women aged 50 or older who underwent transvaginal ultrasound (TVUS) for indications other than vaginal bleeding. They presented their findings in an abstract at the 43rd AAGL Global Congress in Vancouver, Canada.

Details of the study

Patients were included if they had an endometrial lining of 4 mm or greater and excluded if they had a history of tamoxifen use, hormone replacement, endometrial ablation, hereditary cancer syndrome, or no available pathology results.

Of 462 biopsies, 435 (94.2%) had benign pathology, nine (2.0%) had carcinoma, and seven (1.5%) had atypical hyperplasia.

Endometrial thickness of 14 mm or greater was associated with atypical hyperplasia (odds ratio [OR], 4.29; P = .02), with a negative predictive value of 98.3%. A thickness of 15 mm or greater was associated with carcinoma (OR, 4.53; P = .03), with a negative predictive value of 98.5%.

Under 14 mm, the risk of hyperplasia was low, the authors found, at 0.08%. Below 15 mm, the risk of cancer was 0.06%.

They found no significant associations between endometrial lining TVUS appearance, age, parity, body mass index, diabetes, hypertension, hyperlipidemia, and carcinoma or atypical hyperplasia.

When biopsy might not be necessary

Therefore, regardless of conventional risk factors for endometrial cancer, if a postmenopausal woman reports pelvic pain without vaginal bleeding, and is found to have a thickened endometrial lining of less than 14 mm on TVUS, biopsy might not be warranted, conclude the study authors.  

With no consensus regarding the normal endometrial thickness in postmenopausal women without vaginal bleeding, there are no guidelines for clinicians to follow on when to biopsy, if at all, in an older patient presenting with pelvic pain but no bleeding.

To determine at what endometrial thickness biopsy would be optimal, Michelle Louie, MD, and colleagues from Magee Women’s Hospital in Pittsburgh, Pennsylvania, performed a retrospective cohort analysis of postmenopausal women aged 50 or older who underwent transvaginal ultrasound (TVUS) for indications other than vaginal bleeding. They presented their findings in an abstract at the 43rd AAGL Global Congress in Vancouver, Canada.

Details of the study

Patients were included if they had an endometrial lining of 4 mm or greater and excluded if they had a history of tamoxifen use, hormone replacement, endometrial ablation, hereditary cancer syndrome, or no available pathology results.

Of 462 biopsies, 435 (94.2%) had benign pathology, nine (2.0%) had carcinoma, and seven (1.5%) had atypical hyperplasia.

Endometrial thickness of 14 mm or greater was associated with atypical hyperplasia (odds ratio [OR], 4.29; P = .02), with a negative predictive value of 98.3%. A thickness of 15 mm or greater was associated with carcinoma (OR, 4.53; P = .03), with a negative predictive value of 98.5%.

Under 14 mm, the risk of hyperplasia was low, the authors found, at 0.08%. Below 15 mm, the risk of cancer was 0.06%.

They found no significant associations between endometrial lining TVUS appearance, age, parity, body mass index, diabetes, hypertension, hyperlipidemia, and carcinoma or atypical hyperplasia.

When biopsy might not be necessary

Therefore, regardless of conventional risk factors for endometrial cancer, if a postmenopausal woman reports pelvic pain without vaginal bleeding, and is found to have a thickened endometrial lining of less than 14 mm on TVUS, biopsy might not be warranted, conclude the study authors.  

Plasma for transfusion

Credit: Cristina Granados

The US Food and Drug Administration (FDA) has accepted a clinical protocol to make the INTERCEPT Blood System available to treat plasma collected from Ebola survivors.

Transfusion of blood or plasma from recovered Ebola patients can be of benefit in patients with acute Ebola infections, but recovered patients may carry undetected pathogens such as malaria, which is where the INTERCEPT Blood System for plasma comes in.

The system is used for the preparation and storage of whole blood-derived and apheresis plasma (fresh or recently thawed). It can inactivate a range of viruses, bacteria, and parasites to reduce the risk of transmission via transfusion.

“The INTERCEPT pathogen inactivation process can diminish the risk of other pathogens that may contaminate the plasma of valuable Ebola convalescent donors and will provide a new therapeutic resource for patients with Ebola,” said Laurence Corash, MD, senior vice president and chief medical officer of Cerus Corporation, the company developing the INTERCEPT system.

The INTERCEPT Blood System for plasma does not have FDA approval. The agency has approved use of the system via an investigational device exemption (IDE). This allows for early access to a device not yet approved in the US when no satisfactory alternative is available to treat patients with serious or life-threatening conditions.

Under this IDE, investigators at Emory University will collect Ebola convalescent plasma from recovered patients and use the INTERCEPT system for onsite pathogen inactivation.

Following testing for Ebola antibodies at the Centers for Disease Control and Prevention, the treated plasma will be stored at Emory for use with future patients. If needed, Emory will also supply the treated plasma for use at other Ebola treatment centers, such as the University of Nebraska Medical Center.

To further increase the availability of convalescent plasma, Cerus and the trial investigators are collaborating with the American Red Cross and America’s Blood Centers to create a national network of plasma collection sites to access recovered Ebola patients.

“Having a supply of convalescent plasma that has been through pathogen inactivation is critical to making this therapy readily available as new Ebola patients are diagnosed and urgently require treatment,” said Anne Winkler, MD, principal investigator for the study and an assistant professor at the Emory University School of Medicine in Atlanta, Georgia.

The World Health Organization recently identified convalescent plasma as a potentially promising experimental approach to treat Ebola, issuing interim guidance suggesting how the plasma should be sourced and supplied.

The Bill & Melinda Gates Foundation recently announced a $5.7 million commitment to support efforts in Guinea and other Ebola-affected countries to scale up the production and evaluation of potential therapies for people infected with the Ebola virus, including convalescent plasma treated with pathogen inactivation.

Funding is being provided to Clinical Research Management, Inc., and an array of private sector partners to study Ebola convalescent plasma that will be collected through mobile donation units fully equipped with apheresis plasma collection systems and the INTERCEPT Blood System for plasma.

The INTERCEPT platelet and plasma systems have been approved for use in Europe for 8 years and are used in 20 countries. License applications for the systems are under FDA review, with an approval decision expected in 2015.

The FDA recently accepted Cerus’s clinical protocol to make the INTERCEPT Blood System for platelets available under an IDE to regions in the US and its territories with outbreaks of Chikungunya and dengue virus.

Plasma for transfusion

Credit: Cristina Granados

The US Food and Drug Administration (FDA) has accepted a clinical protocol to make the INTERCEPT Blood System available to treat plasma collected from Ebola survivors.

Transfusion of blood or plasma from recovered Ebola patients can be of benefit in patients with acute Ebola infections, but recovered patients may carry undetected pathogens such as malaria, which is where the INTERCEPT Blood System for plasma comes in.

The system is used for the preparation and storage of whole blood-derived and apheresis plasma (fresh or recently thawed). It can inactivate a range of viruses, bacteria, and parasites to reduce the risk of transmission via transfusion.

“The INTERCEPT pathogen inactivation process can diminish the risk of other pathogens that may contaminate the plasma of valuable Ebola convalescent donors and will provide a new therapeutic resource for patients with Ebola,” said Laurence Corash, MD, senior vice president and chief medical officer of Cerus Corporation, the company developing the INTERCEPT system.

The INTERCEPT Blood System for plasma does not have FDA approval. The agency has approved use of the system via an investigational device exemption (IDE). This allows for early access to a device not yet approved in the US when no satisfactory alternative is available to treat patients with serious or life-threatening conditions.

Under this IDE, investigators at Emory University will collect Ebola convalescent plasma from recovered patients and use the INTERCEPT system for onsite pathogen inactivation.

Following testing for Ebola antibodies at the Centers for Disease Control and Prevention, the treated plasma will be stored at Emory for use with future patients. If needed, Emory will also supply the treated plasma for use at other Ebola treatment centers, such as the University of Nebraska Medical Center.

To further increase the availability of convalescent plasma, Cerus and the trial investigators are collaborating with the American Red Cross and America’s Blood Centers to create a national network of plasma collection sites to access recovered Ebola patients.

“Having a supply of convalescent plasma that has been through pathogen inactivation is critical to making this therapy readily available as new Ebola patients are diagnosed and urgently require treatment,” said Anne Winkler, MD, principal investigator for the study and an assistant professor at the Emory University School of Medicine in Atlanta, Georgia.

The World Health Organization recently identified convalescent plasma as a potentially promising experimental approach to treat Ebola, issuing interim guidance suggesting how the plasma should be sourced and supplied.

The Bill & Melinda Gates Foundation recently announced a $5.7 million commitment to support efforts in Guinea and other Ebola-affected countries to scale up the production and evaluation of potential therapies for people infected with the Ebola virus, including convalescent plasma treated with pathogen inactivation.

Funding is being provided to Clinical Research Management, Inc., and an array of private sector partners to study Ebola convalescent plasma that will be collected through mobile donation units fully equipped with apheresis plasma collection systems and the INTERCEPT Blood System for plasma.

The INTERCEPT platelet and plasma systems have been approved for use in Europe for 8 years and are used in 20 countries. License applications for the systems are under FDA review, with an approval decision expected in 2015.

The FDA recently accepted Cerus’s clinical protocol to make the INTERCEPT Blood System for platelets available under an IDE to regions in the US and its territories with outbreaks of Chikungunya and dengue virus.

Plasma for transfusion

Credit: Cristina Granados

The US Food and Drug Administration (FDA) has accepted a clinical protocol to make the INTERCEPT Blood System available to treat plasma collected from Ebola survivors.

Transfusion of blood or plasma from recovered Ebola patients can be of benefit in patients with acute Ebola infections, but recovered patients may carry undetected pathogens such as malaria, which is where the INTERCEPT Blood System for plasma comes in.

The system is used for the preparation and storage of whole blood-derived and apheresis plasma (fresh or recently thawed). It can inactivate a range of viruses, bacteria, and parasites to reduce the risk of transmission via transfusion.

“The INTERCEPT pathogen inactivation process can diminish the risk of other pathogens that may contaminate the plasma of valuable Ebola convalescent donors and will provide a new therapeutic resource for patients with Ebola,” said Laurence Corash, MD, senior vice president and chief medical officer of Cerus Corporation, the company developing the INTERCEPT system.

The INTERCEPT Blood System for plasma does not have FDA approval. The agency has approved use of the system via an investigational device exemption (IDE). This allows for early access to a device not yet approved in the US when no satisfactory alternative is available to treat patients with serious or life-threatening conditions.

Under this IDE, investigators at Emory University will collect Ebola convalescent plasma from recovered patients and use the INTERCEPT system for onsite pathogen inactivation.

Following testing for Ebola antibodies at the Centers for Disease Control and Prevention, the treated plasma will be stored at Emory for use with future patients. If needed, Emory will also supply the treated plasma for use at other Ebola treatment centers, such as the University of Nebraska Medical Center.

To further increase the availability of convalescent plasma, Cerus and the trial investigators are collaborating with the American Red Cross and America’s Blood Centers to create a national network of plasma collection sites to access recovered Ebola patients.

“Having a supply of convalescent plasma that has been through pathogen inactivation is critical to making this therapy readily available as new Ebola patients are diagnosed and urgently require treatment,” said Anne Winkler, MD, principal investigator for the study and an assistant professor at the Emory University School of Medicine in Atlanta, Georgia.

The World Health Organization recently identified convalescent plasma as a potentially promising experimental approach to treat Ebola, issuing interim guidance suggesting how the plasma should be sourced and supplied.

The Bill & Melinda Gates Foundation recently announced a $5.7 million commitment to support efforts in Guinea and other Ebola-affected countries to scale up the production and evaluation of potential therapies for people infected with the Ebola virus, including convalescent plasma treated with pathogen inactivation.

Funding is being provided to Clinical Research Management, Inc., and an array of private sector partners to study Ebola convalescent plasma that will be collected through mobile donation units fully equipped with apheresis plasma collection systems and the INTERCEPT Blood System for plasma.

The INTERCEPT platelet and plasma systems have been approved for use in Europe for 8 years and are used in 20 countries. License applications for the systems are under FDA review, with an approval decision expected in 2015.

The FDA recently accepted Cerus’s clinical protocol to make the INTERCEPT Blood System for platelets available under an IDE to regions in the US and its territories with outbreaks of Chikungunya and dengue virus.

Researcher in the lab

Credit: NIH

A newly identified class of compounds recognize a key target in the Ras signaling pathway and could therefore prove useful in treating a range of malignancies, according to research published in Chemistry & Biology.

The lead compound, NSC-658497, targeted the catalytic activation of Ras by an enzyme called SOS1.

NSC-658497 blocked SOS1-mediated molecular signaling in the Ras pathway that causes rapid cell proliferation, tumor development, and cancer.

“While Ras pathway activation is a dominant event happening in many diseases, so far, the immediate signaling module of the Ras pathway has been difficult to target,” said study author Yi Zheng, PhD, of Cincinnati Children’s Hospital in Ohio.

“Most strategies for treatment have been geared toward hitting molecular effectors that are farther downstream. In this study, we have identified synthetic compounds that specifically recognize the catalytic pocket of SOS1 and demonstrated that they are effective inhibitors of Ras signaling in cells. This establishes a novel targeting approach for cancers and Rasopathies that is useful in developing therapeutics.”

Rasopathies include a group of 9 developmental syndromes that are caused by mutations in the Ras pathway (Noonan, LEOPARD, hereditary Gingival fibromatosis type 1, Capillary malformation-AV malformation, Neurofibromatosis type 1, Legius, Costello, Cardio-facio-cutaneous, and autoimmune lymphoproliferative syndromes).

Dysregulation of the Ras pathway (including its SOS1 catalytic activator) is also linked to a number of malignancies, such as breast, pancreatic, and cervical cancers, as well as leukemia.

To find compounds that could target the Ras pathway, Dr Zheng and his colleagues tested 30,000 synthetic molecular compounds in a database maintained by the National Cancer Institute.

The researchers looked for the compounds’ ability to dock with the catalytic site of SOS1, which led them to identify NSC-658497 and derivatives as lead candidates for the development of a prospective drug.

The team then tested NSC-658497 in cell lines of mouse fibroblasts and prostate cancer. These experiments showed the compound successfully blocked SOS1-to-Ras signaling and the proliferation of cancer cells.

Dr Zheng said one of the researchers’ next steps is to transform NSC-658497 into a drug that can be administered to a living organism so the team can begin testing the inhibitor in mouse models of different Rasopathies and cancers.

One of the targeted approaches the researchers plan to explore is whether NSC-658497 might be most promising in individuals who have a subset of disease in which SOS1 is significantly overexpressed or mutated.

Researcher in the lab

Credit: NIH

A newly identified class of compounds recognize a key target in the Ras signaling pathway and could therefore prove useful in treating a range of malignancies, according to research published in Chemistry & Biology.

The lead compound, NSC-658497, targeted the catalytic activation of Ras by an enzyme called SOS1.

NSC-658497 blocked SOS1-mediated molecular signaling in the Ras pathway that causes rapid cell proliferation, tumor development, and cancer.

“While Ras pathway activation is a dominant event happening in many diseases, so far, the immediate signaling module of the Ras pathway has been difficult to target,” said study author Yi Zheng, PhD, of Cincinnati Children’s Hospital in Ohio.

“Most strategies for treatment have been geared toward hitting molecular effectors that are farther downstream. In this study, we have identified synthetic compounds that specifically recognize the catalytic pocket of SOS1 and demonstrated that they are effective inhibitors of Ras signaling in cells. This establishes a novel targeting approach for cancers and Rasopathies that is useful in developing therapeutics.”

Rasopathies include a group of 9 developmental syndromes that are caused by mutations in the Ras pathway (Noonan, LEOPARD, hereditary Gingival fibromatosis type 1, Capillary malformation-AV malformation, Neurofibromatosis type 1, Legius, Costello, Cardio-facio-cutaneous, and autoimmune lymphoproliferative syndromes).

Dysregulation of the Ras pathway (including its SOS1 catalytic activator) is also linked to a number of malignancies, such as breast, pancreatic, and cervical cancers, as well as leukemia.

To find compounds that could target the Ras pathway, Dr Zheng and his colleagues tested 30,000 synthetic molecular compounds in a database maintained by the National Cancer Institute.

The researchers looked for the compounds’ ability to dock with the catalytic site of SOS1, which led them to identify NSC-658497 and derivatives as lead candidates for the development of a prospective drug.

The team then tested NSC-658497 in cell lines of mouse fibroblasts and prostate cancer. These experiments showed the compound successfully blocked SOS1-to-Ras signaling and the proliferation of cancer cells.

Dr Zheng said one of the researchers’ next steps is to transform NSC-658497 into a drug that can be administered to a living organism so the team can begin testing the inhibitor in mouse models of different Rasopathies and cancers.

One of the targeted approaches the researchers plan to explore is whether NSC-658497 might be most promising in individuals who have a subset of disease in which SOS1 is significantly overexpressed or mutated.

Researcher in the lab

Credit: NIH

A newly identified class of compounds recognize a key target in the Ras signaling pathway and could therefore prove useful in treating a range of malignancies, according to research published in Chemistry & Biology.

The lead compound, NSC-658497, targeted the catalytic activation of Ras by an enzyme called SOS1.

NSC-658497 blocked SOS1-mediated molecular signaling in the Ras pathway that causes rapid cell proliferation, tumor development, and cancer.

“While Ras pathway activation is a dominant event happening in many diseases, so far, the immediate signaling module of the Ras pathway has been difficult to target,” said study author Yi Zheng, PhD, of Cincinnati Children’s Hospital in Ohio.

“Most strategies for treatment have been geared toward hitting molecular effectors that are farther downstream. In this study, we have identified synthetic compounds that specifically recognize the catalytic pocket of SOS1 and demonstrated that they are effective inhibitors of Ras signaling in cells. This establishes a novel targeting approach for cancers and Rasopathies that is useful in developing therapeutics.”

Rasopathies include a group of 9 developmental syndromes that are caused by mutations in the Ras pathway (Noonan, LEOPARD, hereditary Gingival fibromatosis type 1, Capillary malformation-AV malformation, Neurofibromatosis type 1, Legius, Costello, Cardio-facio-cutaneous, and autoimmune lymphoproliferative syndromes).

Dysregulation of the Ras pathway (including its SOS1 catalytic activator) is also linked to a number of malignancies, such as breast, pancreatic, and cervical cancers, as well as leukemia.

To find compounds that could target the Ras pathway, Dr Zheng and his colleagues tested 30,000 synthetic molecular compounds in a database maintained by the National Cancer Institute.

The researchers looked for the compounds’ ability to dock with the catalytic site of SOS1, which led them to identify NSC-658497 and derivatives as lead candidates for the development of a prospective drug.

The team then tested NSC-658497 in cell lines of mouse fibroblasts and prostate cancer. These experiments showed the compound successfully blocked SOS1-to-Ras signaling and the proliferation of cancer cells.

Dr Zheng said one of the researchers’ next steps is to transform NSC-658497 into a drug that can be administered to a living organism so the team can begin testing the inhibitor in mouse models of different Rasopathies and cancers.

One of the targeted approaches the researchers plan to explore is whether NSC-658497 might be most promising in individuals who have a subset of disease in which SOS1 is significantly overexpressed or mutated.