Schizophrenia & Other Psychotic Disorders

Don’t wait to give patients with first-episode psychosis long-acting injectable formulations of second-generation antipsychotics, according to Henry A. Nasrallah, MD.

Many clinicians wait to use long-acting injectables (LAIs) until the patient has experienced multiple relapses, but using them after the first discharge may help prevent future relapse, Dr. Nasrallah, professor of psychiatry, neurology, and neuroscience at the University of Cincinnati, said at the virtual Psychopharmacology Update presented by Current Psychiatry and Global Academy for Medical Education.

LAIs and clozapine are “vastly underutilized” after the first discharge, he noted. “I really encourage everybody to use them without hesitation as early as possible.”

In patients with first-episode psychosis, “the most important thing, in my opinion, is to start establishing a therapeutic alliance with the patient from day one,” Dr. Nasrallah said. “It’s always important in psychiatry, but it’s particularly important for first-episode psychosis.”

These patients respond to low doses of antipsychotics and should not be given first-generation antipsychotics because of a risk for acute extrapyramidal symptoms, tardive dyskinesia, and neurotoxicity.

“I usually select an antipsychotic that is extended release and also available as a long-acting injectable formulation,” Dr. Nasrallah said, noting that it helps when he gives a patient a long-acting injectable right after discharge. During hospitalization, Dr. Nasrallah said, he educates the patient and their family about psychosis, treatment, how psychosis affects the brain, and adherence to treatment.

“The primary goal, of course, is to achieve remission and very importantly, to prevent a second episode,” he said. “This is the golden opportunity for us psychiatrists to prevent the patient from relapsing again and again. That is the reason for disability and for brain damage, because every psychotic episode destroys brain tissue. That is why I am very eager to not only achieve a remission in the first episode but also to position the patient to be protected after discharge by giving them long-acting injectable.”

After a clinician performs a full workup to rule out substance use or a general medical condition inducing first-episode psychosis, Dr. Nasrallah recommends paliperidone extended-release (ER), given to patients in the morning because of its tolerability and the availability of an LAI version of the drug. “I start with 3 mg a day; that’s the lowest dose,” he said. “If the patient is very sick and agitated, I might go to 6 mg a day, which is actually a very good dose for first-episode patients, and it’s still quite well tolerated.”

Oral or injectable lorazepam taken as needed may be given to a patient with first-episode psychosis with agitation. For patients who manifest akathisia, twice or thrice daily propranolol at dose of 10-20 mg can be used off label, he said. Dr. Nasrallah also recommended twice-daily omega 3 at a dose of 1,000 mg or N-acetylcysteine at a dose of 600 mg per day as supplements.

“They’re not approved by the [Food and Drug Administration] for first-episode psychosis, but there are numerous publications in the literature by academic psychiatrists showing that they are quite beneficial, and they reduce the two destructive processes during psychosis, which are neuroinflammation and oxidative stress, or free radicals,” he said. “Those two supplements can help in the acute phase of the illness.”

Another option for clinicians is to begin a patient with first-episode psychosis on oral aripiprazole at a dose of 5 mg per day for 2 days, increasing the dose to 7.5 mg per day for 2 days, then increasing to 10 mg per day. “It is not extended-release, so you have to start with low doses to protect the patient from side effects,” Dr. Nasrallah explained. “Some patients may need 15 or 20 [mg], but most first-episode patients may do well on 10 [mg] without risking side effects.”
 

 

Planning for discharge

Patients who tolerate aripiprazole can start the long-acting aripiprazole lauroxil at discharge, and clinicians have two options to choose from. One formulation “requires 2 weeks of oral supplementation, which you can do in the hospital if you start the patient on oral aripiprazole, and then you can give that injection prior to discharge.” Another option involves giving the patient “any antipsychotic you like and then switch[ing] the patient to aripiprazole lauroxil. The full dose can be given without oral supplementation on the day of discharge.”

Dr. Nasrallah emphasized the use of LAIs in patients discharged for first-episode psychosis. In a study published in JAMA Psychiatry, researchers found use of LAI risperidone in patients with first-episode psychosis significantly reduced the risk of psychotic exacerbation and relapse compared with patients who were given oral risperidone (JAMA Psychiatry. 2015;72:822-9).

“This kind of well-done study shows you that you can do a great job protecting your patient from the very beginning by giving long-acting injectables,” Dr. Nasrallah explained. “That’s why you have to develop rapport with the patient. That’s why you have to convince the patient to take the injectable, and that’s why you have to educate the patient about the hazards of psychosis to the brain, and the fact that it’s very hard to remember to take the pills, because the illness itself can interfere with that due to cognitive impairment [and] negative symptoms.” Another reason for nonadherence is that the patients might not believe they are sick, he added.

After 2 or 3 weeks, if a patient with first-episode psychosis has a minimal response or does not response at all to an LAI, clozapine is an “aggressive” option that may help nonresponders. For patients with schizophrenia, “about 65%-70% would respond to a dopamine antagonist and the remaining 30% are going to need clozapine sooner or later,” Dr. Nasrallah said. “For clozapine after one or two failures [on LAIs] with an adequate dose and adequate duration, don’t wait. Give the patient clozapine, give them an opportunity to regain their life. I’ve seen some very gratifying results with clozapine in those who respond to it.

“The outcome of schizophrenia may be far less malignant than the perception out there if we actually ensure adherence very early and manage the first-episode aggressively, like cardiologists manage the first heart attack,” he said. “[Cardiologists] do everything in their power to protect the patient from a second heart attack, and I regard psychosis as a ‘brain attack.’ ”

Global Academy and this news organization are owned by the same parent company. Dr. Nasrallah reported that he has received research grants from Acadia; served as a consultant for Acadia, Alkermes, Allergan, Janssen, Otsuka, Indivior, Intracellular, Neurocrine, Sunovion, Teva, and Boehringer-Ingelheim; and is on the speakers bureau for Acadia, Alkermes, Allergan, Janssen, Otsuka, Indivior, Intracellular, Neurocrine, Noven, Sunovion, and Teva.

Don’t wait to give patients with first-episode psychosis long-acting injectable formulations of second-generation antipsychotics, according to Henry A. Nasrallah, MD.

Many clinicians wait to use long-acting injectables (LAIs) until the patient has experienced multiple relapses, but using them after the first discharge may help prevent future relapse, Dr. Nasrallah, professor of psychiatry, neurology, and neuroscience at the University of Cincinnati, said at the virtual Psychopharmacology Update presented by Current Psychiatry and Global Academy for Medical Education.

LAIs and clozapine are “vastly underutilized” after the first discharge, he noted. “I really encourage everybody to use them without hesitation as early as possible.”

In patients with first-episode psychosis, “the most important thing, in my opinion, is to start establishing a therapeutic alliance with the patient from day one,” Dr. Nasrallah said. “It’s always important in psychiatry, but it’s particularly important for first-episode psychosis.”

These patients respond to low doses of antipsychotics and should not be given first-generation antipsychotics because of a risk for acute extrapyramidal symptoms, tardive dyskinesia, and neurotoxicity.

“I usually select an antipsychotic that is extended release and also available as a long-acting injectable formulation,” Dr. Nasrallah said, noting that it helps when he gives a patient a long-acting injectable right after discharge. During hospitalization, Dr. Nasrallah said, he educates the patient and their family about psychosis, treatment, how psychosis affects the brain, and adherence to treatment.

“The primary goal, of course, is to achieve remission and very importantly, to prevent a second episode,” he said. “This is the golden opportunity for us psychiatrists to prevent the patient from relapsing again and again. That is the reason for disability and for brain damage, because every psychotic episode destroys brain tissue. That is why I am very eager to not only achieve a remission in the first episode but also to position the patient to be protected after discharge by giving them long-acting injectable.”

After a clinician performs a full workup to rule out substance use or a general medical condition inducing first-episode psychosis, Dr. Nasrallah recommends paliperidone extended-release (ER), given to patients in the morning because of its tolerability and the availability of an LAI version of the drug. “I start with 3 mg a day; that’s the lowest dose,” he said. “If the patient is very sick and agitated, I might go to 6 mg a day, which is actually a very good dose for first-episode patients, and it’s still quite well tolerated.”

Oral or injectable lorazepam taken as needed may be given to a patient with first-episode psychosis with agitation. For patients who manifest akathisia, twice or thrice daily propranolol at dose of 10-20 mg can be used off label, he said. Dr. Nasrallah also recommended twice-daily omega 3 at a dose of 1,000 mg or N-acetylcysteine at a dose of 600 mg per day as supplements.

“They’re not approved by the [Food and Drug Administration] for first-episode psychosis, but there are numerous publications in the literature by academic psychiatrists showing that they are quite beneficial, and they reduce the two destructive processes during psychosis, which are neuroinflammation and oxidative stress, or free radicals,” he said. “Those two supplements can help in the acute phase of the illness.”

Another option for clinicians is to begin a patient with first-episode psychosis on oral aripiprazole at a dose of 5 mg per day for 2 days, increasing the dose to 7.5 mg per day for 2 days, then increasing to 10 mg per day. “It is not extended-release, so you have to start with low doses to protect the patient from side effects,” Dr. Nasrallah explained. “Some patients may need 15 or 20 [mg], but most first-episode patients may do well on 10 [mg] without risking side effects.”
 

 

Planning for discharge

Patients who tolerate aripiprazole can start the long-acting aripiprazole lauroxil at discharge, and clinicians have two options to choose from. One formulation “requires 2 weeks of oral supplementation, which you can do in the hospital if you start the patient on oral aripiprazole, and then you can give that injection prior to discharge.” Another option involves giving the patient “any antipsychotic you like and then switch[ing] the patient to aripiprazole lauroxil. The full dose can be given without oral supplementation on the day of discharge.”

Dr. Nasrallah emphasized the use of LAIs in patients discharged for first-episode psychosis. In a study published in JAMA Psychiatry, researchers found use of LAI risperidone in patients with first-episode psychosis significantly reduced the risk of psychotic exacerbation and relapse compared with patients who were given oral risperidone (JAMA Psychiatry. 2015;72:822-9).

“This kind of well-done study shows you that you can do a great job protecting your patient from the very beginning by giving long-acting injectables,” Dr. Nasrallah explained. “That’s why you have to develop rapport with the patient. That’s why you have to convince the patient to take the injectable, and that’s why you have to educate the patient about the hazards of psychosis to the brain, and the fact that it’s very hard to remember to take the pills, because the illness itself can interfere with that due to cognitive impairment [and] negative symptoms.” Another reason for nonadherence is that the patients might not believe they are sick, he added.

After 2 or 3 weeks, if a patient with first-episode psychosis has a minimal response or does not response at all to an LAI, clozapine is an “aggressive” option that may help nonresponders. For patients with schizophrenia, “about 65%-70% would respond to a dopamine antagonist and the remaining 30% are going to need clozapine sooner or later,” Dr. Nasrallah said. “For clozapine after one or two failures [on LAIs] with an adequate dose and adequate duration, don’t wait. Give the patient clozapine, give them an opportunity to regain their life. I’ve seen some very gratifying results with clozapine in those who respond to it.

“The outcome of schizophrenia may be far less malignant than the perception out there if we actually ensure adherence very early and manage the first-episode aggressively, like cardiologists manage the first heart attack,” he said. “[Cardiologists] do everything in their power to protect the patient from a second heart attack, and I regard psychosis as a ‘brain attack.’ ”

Global Academy and this news organization are owned by the same parent company. Dr. Nasrallah reported that he has received research grants from Acadia; served as a consultant for Acadia, Alkermes, Allergan, Janssen, Otsuka, Indivior, Intracellular, Neurocrine, Sunovion, Teva, and Boehringer-Ingelheim; and is on the speakers bureau for Acadia, Alkermes, Allergan, Janssen, Otsuka, Indivior, Intracellular, Neurocrine, Noven, Sunovion, and Teva.

Don’t wait to give patients with first-episode psychosis long-acting injectable formulations of second-generation antipsychotics, according to Henry A. Nasrallah, MD.

Many clinicians wait to use long-acting injectables (LAIs) until the patient has experienced multiple relapses, but using them after the first discharge may help prevent future relapse, Dr. Nasrallah, professor of psychiatry, neurology, and neuroscience at the University of Cincinnati, said at the virtual Psychopharmacology Update presented by Current Psychiatry and Global Academy for Medical Education.

LAIs and clozapine are “vastly underutilized” after the first discharge, he noted. “I really encourage everybody to use them without hesitation as early as possible.”

In patients with first-episode psychosis, “the most important thing, in my opinion, is to start establishing a therapeutic alliance with the patient from day one,” Dr. Nasrallah said. “It’s always important in psychiatry, but it’s particularly important for first-episode psychosis.”

These patients respond to low doses of antipsychotics and should not be given first-generation antipsychotics because of a risk for acute extrapyramidal symptoms, tardive dyskinesia, and neurotoxicity.

“I usually select an antipsychotic that is extended release and also available as a long-acting injectable formulation,” Dr. Nasrallah said, noting that it helps when he gives a patient a long-acting injectable right after discharge. During hospitalization, Dr. Nasrallah said, he educates the patient and their family about psychosis, treatment, how psychosis affects the brain, and adherence to treatment.

“The primary goal, of course, is to achieve remission and very importantly, to prevent a second episode,” he said. “This is the golden opportunity for us psychiatrists to prevent the patient from relapsing again and again. That is the reason for disability and for brain damage, because every psychotic episode destroys brain tissue. That is why I am very eager to not only achieve a remission in the first episode but also to position the patient to be protected after discharge by giving them long-acting injectable.”

After a clinician performs a full workup to rule out substance use or a general medical condition inducing first-episode psychosis, Dr. Nasrallah recommends paliperidone extended-release (ER), given to patients in the morning because of its tolerability and the availability of an LAI version of the drug. “I start with 3 mg a day; that’s the lowest dose,” he said. “If the patient is very sick and agitated, I might go to 6 mg a day, which is actually a very good dose for first-episode patients, and it’s still quite well tolerated.”

Oral or injectable lorazepam taken as needed may be given to a patient with first-episode psychosis with agitation. For patients who manifest akathisia, twice or thrice daily propranolol at dose of 10-20 mg can be used off label, he said. Dr. Nasrallah also recommended twice-daily omega 3 at a dose of 1,000 mg or N-acetylcysteine at a dose of 600 mg per day as supplements.

“They’re not approved by the [Food and Drug Administration] for first-episode psychosis, but there are numerous publications in the literature by academic psychiatrists showing that they are quite beneficial, and they reduce the two destructive processes during psychosis, which are neuroinflammation and oxidative stress, or free radicals,” he said. “Those two supplements can help in the acute phase of the illness.”

Another option for clinicians is to begin a patient with first-episode psychosis on oral aripiprazole at a dose of 5 mg per day for 2 days, increasing the dose to 7.5 mg per day for 2 days, then increasing to 10 mg per day. “It is not extended-release, so you have to start with low doses to protect the patient from side effects,” Dr. Nasrallah explained. “Some patients may need 15 or 20 [mg], but most first-episode patients may do well on 10 [mg] without risking side effects.”
 

 

Planning for discharge

Patients who tolerate aripiprazole can start the long-acting aripiprazole lauroxil at discharge, and clinicians have two options to choose from. One formulation “requires 2 weeks of oral supplementation, which you can do in the hospital if you start the patient on oral aripiprazole, and then you can give that injection prior to discharge.” Another option involves giving the patient “any antipsychotic you like and then switch[ing] the patient to aripiprazole lauroxil. The full dose can be given without oral supplementation on the day of discharge.”

Dr. Nasrallah emphasized the use of LAIs in patients discharged for first-episode psychosis. In a study published in JAMA Psychiatry, researchers found use of LAI risperidone in patients with first-episode psychosis significantly reduced the risk of psychotic exacerbation and relapse compared with patients who were given oral risperidone (JAMA Psychiatry. 2015;72:822-9).

“This kind of well-done study shows you that you can do a great job protecting your patient from the very beginning by giving long-acting injectables,” Dr. Nasrallah explained. “That’s why you have to develop rapport with the patient. That’s why you have to convince the patient to take the injectable, and that’s why you have to educate the patient about the hazards of psychosis to the brain, and the fact that it’s very hard to remember to take the pills, because the illness itself can interfere with that due to cognitive impairment [and] negative symptoms.” Another reason for nonadherence is that the patients might not believe they are sick, he added.

After 2 or 3 weeks, if a patient with first-episode psychosis has a minimal response or does not response at all to an LAI, clozapine is an “aggressive” option that may help nonresponders. For patients with schizophrenia, “about 65%-70% would respond to a dopamine antagonist and the remaining 30% are going to need clozapine sooner or later,” Dr. Nasrallah said. “For clozapine after one or two failures [on LAIs] with an adequate dose and adequate duration, don’t wait. Give the patient clozapine, give them an opportunity to regain their life. I’ve seen some very gratifying results with clozapine in those who respond to it.

“The outcome of schizophrenia may be far less malignant than the perception out there if we actually ensure adherence very early and manage the first-episode aggressively, like cardiologists manage the first heart attack,” he said. “[Cardiologists] do everything in their power to protect the patient from a second heart attack, and I regard psychosis as a ‘brain attack.’ ”

Global Academy and this news organization are owned by the same parent company. Dr. Nasrallah reported that he has received research grants from Acadia; served as a consultant for Acadia, Alkermes, Allergan, Janssen, Otsuka, Indivior, Intracellular, Neurocrine, Sunovion, Teva, and Boehringer-Ingelheim; and is on the speakers bureau for Acadia, Alkermes, Allergan, Janssen, Otsuka, Indivior, Intracellular, Neurocrine, Noven, Sunovion, and Teva.

 

Determining whether patients are fatigued or experiencing sleepiness is an important criterion when diagnosing hypersomnia, according to Ruth M. Benca, MD, PhD.

©Digitial Vision/Thinkstockphotos.com

“Patients can’t always tell the difference, and unfortunately, a lot of clinicians don’t really clarify whether a patient is truly sleepy or just fatigued,” Dr. Benca, chair of the department of psychiatry and human behavior at the University of California, Irvine, said at the virtual Psychopharmacology Update presented by Current Psychiatry and Global Academy for Medical Education.

“We want to distinguish sleepiness from fatigue or tiredness. People who are tired or fatigued may wish they could sleep or feel they need to sleep, but they are actually not falling asleep in relaxed situations.”

Fatigue, feeling tired, and lack of energy are common complaints that accompany insomnia and psychiatric disorders, but these patients do not fall asleep quickly in a restful setting and will have normal multiple sleep latency test (MSLT) in a laboratory. In contrast, excessive sleepiness, or hypersomnia, occurs when patients sleep more than 11 hours in a 24-hour period.

Patients with hypersomnia fall asleep in low stimulus situations and devote more energy to staying awake during situations. This excessive sleepiness can be dangerous in the context of activities such as driving, Dr. Benca said. These patients will also have low sleep latencies (< 8 minutes) when tested through MSLT in a laboratory, she added. Patients with hypersomnia may be irritable, have reduced attention or concentration, and have poor memory.

The primary cause of hypersomnia is sleep deprivation, but “both hypersomnia and fatigue are common complaints in psychiatric patients, including depression, bipolar disorder, seasonal affective disorder, [and] psychosis,” Dr. Benca explained. Other causes of hypersomnia include sleep disorders such as sleep apnea, circadian rhythm disorders and periodic limb movements, neurologic or degenerative disorders, mental disorders, and effects of medication. Idiopathic hypersomnia and narcolepsy are uncommon causes of hypersomnia and usually diagnosed in a sleep laboratory setting, she said.

In patients with depression, hypersomnia looks like patients having “nonimperative sleepiness,” Dr. Benca said. “They may spend a lot of time in bed; they may report long and nonrefreshing naps or long sleep time.”

There also is an issue with sleep inertia in patients with depression and hypersomnia, and with patients taking a long time to wake up and begin their day. In these patients, “when we put them in the sleep laboratory, the objective studies generally do not show that they are excessively sleepy, despite their reports of subjectively being sleepy,” she said.

There is not much objective MSLT or subjective measure data for hypersomnia in patients with schizophrenia despite these patients reporting daytime sleepiness or hypersomnolence, Dr. Benca admitted. Hypersomnia in patients with schizophrenia may be related to drug effects, poor sleep hygiene, circadian rhythm abnormalities, or comorbid sleep disorders. “Excessive sleepiness may also be related to the schizophrenia itself,” she said.
 

Treatments for hypersomnia

The first priority for patients with hypersomnia is to avoid sleep deprivation and practice good sleep hygiene – factors that are important both in insomnia and hypersomnia. “Make sure that patients are having adequate time in bed and having regular hours of sleep,” Dr. Benca said.

 

For patients with comorbid psychiatric, medical and sleep disorders, focus on getting rid of medications that may cause sleepiness, including sedating medications and antidepressants, and consider using stimulants if appropriate. While there are Food and Drug Administration–approved medications for narcolepsy and some are approved for hypersomnia in patients with obstructive sleep apnea (OSA), none are officially approved to treat hypersomnia in psychiatric patients.

“Whenever we use these drugs for those reasons, we’re using them off label,” Dr. Benca said.

Modafinil/armodafinil, approved for narcolepsy, shift-work disorder, and OSA in Ehlers-Danlos syndrome, is one off-label option for patients with hypersomnia. “They are lower potency and less addictive than the amphetamines, [with] fewer side effects,” Dr. Benca explained, but should be prescribed with caution in some women because of potential reduced efficacy of oral contraceptives. Side effects of modafinil include headache, nausea, eosinophilia, diarrhea, dry mouth, and anorexia.

Methylphenidate is another option for hypersomnia, available in racemic mixture, pure D-isomer, and time-release formulations.

Patients taking methylphenidate may experience nervousness, insomnia, anorexia, nausea, dizziness, hypertension, hypotension, hypersensitivity reactions, tachycardia, and headache as side effects.

For patients with central nervous system hypersomnias, amphetamines can be used, with methamphetamines having a “very similar profile” and similar side effects, including insomnia, restlessness, tachycardia, dizziness, diarrhea, constipation, hypertension, impotence, and rare cases of psychotic episodes.

Practice parameters released by the American Academy of Sleep Medicine in 2007 suggest that modafinil may have efficacy in idiopathic hypersomnia, Parkinson’s disease, myotonic dystrophy, and multiple sclerosis. The practice parameters also suggest hypersomnias of central origin can be treated with modafinil, amphetamine, methamphetamine, dextroamphetamine, and methylphenidate based on evidence or “long history of use” (Sleep. 2007;30:1705-11).

“Interestingly, there is no mention of psychiatric disorders in these practice parameters, and they report that there are mixed results using stimulants off label for sleepiness and fatigue in traumatic brain injury and poststroke fatigue,” Dr. Benca said.

Dr. Benca reported that she is a consultant to Eisai, Idorsia, Jazz, Merck, and Sunovion. Global Academy and this news organization are owned by the same parent company.

 

Determining whether patients are fatigued or experiencing sleepiness is an important criterion when diagnosing hypersomnia, according to Ruth M. Benca, MD, PhD.

©Digitial Vision/Thinkstockphotos.com

“Patients can’t always tell the difference, and unfortunately, a lot of clinicians don’t really clarify whether a patient is truly sleepy or just fatigued,” Dr. Benca, chair of the department of psychiatry and human behavior at the University of California, Irvine, said at the virtual Psychopharmacology Update presented by Current Psychiatry and Global Academy for Medical Education.

“We want to distinguish sleepiness from fatigue or tiredness. People who are tired or fatigued may wish they could sleep or feel they need to sleep, but they are actually not falling asleep in relaxed situations.”

Fatigue, feeling tired, and lack of energy are common complaints that accompany insomnia and psychiatric disorders, but these patients do not fall asleep quickly in a restful setting and will have normal multiple sleep latency test (MSLT) in a laboratory. In contrast, excessive sleepiness, or hypersomnia, occurs when patients sleep more than 11 hours in a 24-hour period.

Patients with hypersomnia fall asleep in low stimulus situations and devote more energy to staying awake during situations. This excessive sleepiness can be dangerous in the context of activities such as driving, Dr. Benca said. These patients will also have low sleep latencies (< 8 minutes) when tested through MSLT in a laboratory, she added. Patients with hypersomnia may be irritable, have reduced attention or concentration, and have poor memory.

The primary cause of hypersomnia is sleep deprivation, but “both hypersomnia and fatigue are common complaints in psychiatric patients, including depression, bipolar disorder, seasonal affective disorder, [and] psychosis,” Dr. Benca explained. Other causes of hypersomnia include sleep disorders such as sleep apnea, circadian rhythm disorders and periodic limb movements, neurologic or degenerative disorders, mental disorders, and effects of medication. Idiopathic hypersomnia and narcolepsy are uncommon causes of hypersomnia and usually diagnosed in a sleep laboratory setting, she said.

In patients with depression, hypersomnia looks like patients having “nonimperative sleepiness,” Dr. Benca said. “They may spend a lot of time in bed; they may report long and nonrefreshing naps or long sleep time.”

There also is an issue with sleep inertia in patients with depression and hypersomnia, and with patients taking a long time to wake up and begin their day. In these patients, “when we put them in the sleep laboratory, the objective studies generally do not show that they are excessively sleepy, despite their reports of subjectively being sleepy,” she said.

There is not much objective MSLT or subjective measure data for hypersomnia in patients with schizophrenia despite these patients reporting daytime sleepiness or hypersomnolence, Dr. Benca admitted. Hypersomnia in patients with schizophrenia may be related to drug effects, poor sleep hygiene, circadian rhythm abnormalities, or comorbid sleep disorders. “Excessive sleepiness may also be related to the schizophrenia itself,” she said.
 

Treatments for hypersomnia

The first priority for patients with hypersomnia is to avoid sleep deprivation and practice good sleep hygiene – factors that are important both in insomnia and hypersomnia. “Make sure that patients are having adequate time in bed and having regular hours of sleep,” Dr. Benca said.

 

For patients with comorbid psychiatric, medical and sleep disorders, focus on getting rid of medications that may cause sleepiness, including sedating medications and antidepressants, and consider using stimulants if appropriate. While there are Food and Drug Administration–approved medications for narcolepsy and some are approved for hypersomnia in patients with obstructive sleep apnea (OSA), none are officially approved to treat hypersomnia in psychiatric patients.

“Whenever we use these drugs for those reasons, we’re using them off label,” Dr. Benca said.

Modafinil/armodafinil, approved for narcolepsy, shift-work disorder, and OSA in Ehlers-Danlos syndrome, is one off-label option for patients with hypersomnia. “They are lower potency and less addictive than the amphetamines, [with] fewer side effects,” Dr. Benca explained, but should be prescribed with caution in some women because of potential reduced efficacy of oral contraceptives. Side effects of modafinil include headache, nausea, eosinophilia, diarrhea, dry mouth, and anorexia.

Methylphenidate is another option for hypersomnia, available in racemic mixture, pure D-isomer, and time-release formulations.

Patients taking methylphenidate may experience nervousness, insomnia, anorexia, nausea, dizziness, hypertension, hypotension, hypersensitivity reactions, tachycardia, and headache as side effects.

For patients with central nervous system hypersomnias, amphetamines can be used, with methamphetamines having a “very similar profile” and similar side effects, including insomnia, restlessness, tachycardia, dizziness, diarrhea, constipation, hypertension, impotence, and rare cases of psychotic episodes.

Practice parameters released by the American Academy of Sleep Medicine in 2007 suggest that modafinil may have efficacy in idiopathic hypersomnia, Parkinson’s disease, myotonic dystrophy, and multiple sclerosis. The practice parameters also suggest hypersomnias of central origin can be treated with modafinil, amphetamine, methamphetamine, dextroamphetamine, and methylphenidate based on evidence or “long history of use” (Sleep. 2007;30:1705-11).

“Interestingly, there is no mention of psychiatric disorders in these practice parameters, and they report that there are mixed results using stimulants off label for sleepiness and fatigue in traumatic brain injury and poststroke fatigue,” Dr. Benca said.

Dr. Benca reported that she is a consultant to Eisai, Idorsia, Jazz, Merck, and Sunovion. Global Academy and this news organization are owned by the same parent company.

 

Determining whether patients are fatigued or experiencing sleepiness is an important criterion when diagnosing hypersomnia, according to Ruth M. Benca, MD, PhD.

©Digitial Vision/Thinkstockphotos.com

“Patients can’t always tell the difference, and unfortunately, a lot of clinicians don’t really clarify whether a patient is truly sleepy or just fatigued,” Dr. Benca, chair of the department of psychiatry and human behavior at the University of California, Irvine, said at the virtual Psychopharmacology Update presented by Current Psychiatry and Global Academy for Medical Education.

“We want to distinguish sleepiness from fatigue or tiredness. People who are tired or fatigued may wish they could sleep or feel they need to sleep, but they are actually not falling asleep in relaxed situations.”

Fatigue, feeling tired, and lack of energy are common complaints that accompany insomnia and psychiatric disorders, but these patients do not fall asleep quickly in a restful setting and will have normal multiple sleep latency test (MSLT) in a laboratory. In contrast, excessive sleepiness, or hypersomnia, occurs when patients sleep more than 11 hours in a 24-hour period.

Patients with hypersomnia fall asleep in low stimulus situations and devote more energy to staying awake during situations. This excessive sleepiness can be dangerous in the context of activities such as driving, Dr. Benca said. These patients will also have low sleep latencies (< 8 minutes) when tested through MSLT in a laboratory, she added. Patients with hypersomnia may be irritable, have reduced attention or concentration, and have poor memory.

The primary cause of hypersomnia is sleep deprivation, but “both hypersomnia and fatigue are common complaints in psychiatric patients, including depression, bipolar disorder, seasonal affective disorder, [and] psychosis,” Dr. Benca explained. Other causes of hypersomnia include sleep disorders such as sleep apnea, circadian rhythm disorders and periodic limb movements, neurologic or degenerative disorders, mental disorders, and effects of medication. Idiopathic hypersomnia and narcolepsy are uncommon causes of hypersomnia and usually diagnosed in a sleep laboratory setting, she said.

In patients with depression, hypersomnia looks like patients having “nonimperative sleepiness,” Dr. Benca said. “They may spend a lot of time in bed; they may report long and nonrefreshing naps or long sleep time.”

There also is an issue with sleep inertia in patients with depression and hypersomnia, and with patients taking a long time to wake up and begin their day. In these patients, “when we put them in the sleep laboratory, the objective studies generally do not show that they are excessively sleepy, despite their reports of subjectively being sleepy,” she said.

There is not much objective MSLT or subjective measure data for hypersomnia in patients with schizophrenia despite these patients reporting daytime sleepiness or hypersomnolence, Dr. Benca admitted. Hypersomnia in patients with schizophrenia may be related to drug effects, poor sleep hygiene, circadian rhythm abnormalities, or comorbid sleep disorders. “Excessive sleepiness may also be related to the schizophrenia itself,” she said.
 

Treatments for hypersomnia

The first priority for patients with hypersomnia is to avoid sleep deprivation and practice good sleep hygiene – factors that are important both in insomnia and hypersomnia. “Make sure that patients are having adequate time in bed and having regular hours of sleep,” Dr. Benca said.

 

For patients with comorbid psychiatric, medical and sleep disorders, focus on getting rid of medications that may cause sleepiness, including sedating medications and antidepressants, and consider using stimulants if appropriate. While there are Food and Drug Administration–approved medications for narcolepsy and some are approved for hypersomnia in patients with obstructive sleep apnea (OSA), none are officially approved to treat hypersomnia in psychiatric patients.

“Whenever we use these drugs for those reasons, we’re using them off label,” Dr. Benca said.

Modafinil/armodafinil, approved for narcolepsy, shift-work disorder, and OSA in Ehlers-Danlos syndrome, is one off-label option for patients with hypersomnia. “They are lower potency and less addictive than the amphetamines, [with] fewer side effects,” Dr. Benca explained, but should be prescribed with caution in some women because of potential reduced efficacy of oral contraceptives. Side effects of modafinil include headache, nausea, eosinophilia, diarrhea, dry mouth, and anorexia.

Methylphenidate is another option for hypersomnia, available in racemic mixture, pure D-isomer, and time-release formulations.

Patients taking methylphenidate may experience nervousness, insomnia, anorexia, nausea, dizziness, hypertension, hypotension, hypersensitivity reactions, tachycardia, and headache as side effects.

For patients with central nervous system hypersomnias, amphetamines can be used, with methamphetamines having a “very similar profile” and similar side effects, including insomnia, restlessness, tachycardia, dizziness, diarrhea, constipation, hypertension, impotence, and rare cases of psychotic episodes.

Practice parameters released by the American Academy of Sleep Medicine in 2007 suggest that modafinil may have efficacy in idiopathic hypersomnia, Parkinson’s disease, myotonic dystrophy, and multiple sclerosis. The practice parameters also suggest hypersomnias of central origin can be treated with modafinil, amphetamine, methamphetamine, dextroamphetamine, and methylphenidate based on evidence or “long history of use” (Sleep. 2007;30:1705-11).

“Interestingly, there is no mention of psychiatric disorders in these practice parameters, and they report that there are mixed results using stimulants off label for sleepiness and fatigue in traumatic brain injury and poststroke fatigue,” Dr. Benca said.

Dr. Benca reported that she is a consultant to Eisai, Idorsia, Jazz, Merck, and Sunovion. Global Academy and this news organization are owned by the same parent company.

 

Patients with severe melancholic or psychotic depression are more likely to respond to ECT, and preliminary evidence indicates they’re also protected against ECT-induced cognitive impairment, Linda van Diermen, MD, PhD, reported at the virtual congress of the European College of Neuropsychopharmacology.

Over the decades many small, underpowered studies have looked at possible predictors of ECT response and remission, with no consensus being reached. In an effort to bring a measure of clarity, Dr. van Diermen and her coinvestigators performed a meta-analysis of 34 published studies in accord with the PRISMA-P (Preferred Reporting Items for Systematic Review and Meta-analysis Protocols) guidelines and published their findings in the British Journal of Psychiatry. They scrutinized three potential predictors of response: the presence of psychotic features, melancholic depression with psychomotor symptoms, and older age.

Psychotic depression was associated with a 1.7-fold increased likelihood of response to ECT and a 1.5-fold increased odds of remission, compared with that of ECT-treated patients without psychotic depression. Older age was also a statistically significant predictor of response. However, the findings on melancholic depression were inconclusive, with only five studies with inconsistent results being available, said Dr. van Diermen, a psychiatrist at the University of Antwerp (Belgium).

She was quick to point out that, although psychotic depression and older age were statistically significant predictors of heightened likelihood of ECT response, they are of only limited clinical significance in treatment decision-making. The ECT response rate was 79% in patients with psychotic depression but still quite good at 71% in those without psychotic depression. Moreover, the average age of remitters was 59.7 years, compared with 55.4 years in nonresponders, a difference too small to be useful in guiding clinical treatment decisions.

“Age is not a valuable ECT predictor,” she said. “Although we did a meta-analysis in more than 3,200 patients that confirmed the superior effects of ECT in older patients and we recommended it at that time as one of the elements to guide decision-making when you consider ECT, our present, more detailed look at the interdependence of the predictors leads us to reconsider this statement. We now venture that age has been given too much weight in the past decades.”
 

A closer look at ECT response predictors

The studies included in the meta-analysis assessed psychotic depression and melancholic features as ECT response predictors in the typical binary way employed in clinical practice: yes/no, either present or absent. Dr. van Diermer hypothesized that a more in-depth assessment of the severity of those factors would boost their predictive power.

She found that this was indeed the case for melancholic depression as evaluated by three tools for measuring psychomotor symptoms, a core feature of this form of depression. She and her coinvestigators assessed psychomotor functioning in 65 adults with major depressive disorder before, during, and after ECT using the clinician-rated CORE scale, which measures psychomotor retardation, agitation, and noninteractiveness. In addition, the investigators had the subjects wear an accelerometer and complete a timed fine-motor drawing test.

The 41 patients with melancholic depression with psychomotor symptoms as defined by a CORE score of 8 or more were 4.9-fold more likely to reach an ECT response than were those with nonmelancholic depression. A lower baseline daytime activity level as assessed by accelerometer was also a significant predictor of increased likelihood of response, as were slower times on the drawing test.

In contrast, the investigators found that more detailed assessment of psychotic depression using the validated Psychotic Depression Assessment Scale (PDAS) was predictive of the likelihood of ECT response, but not any more so than the simple presence or absence of psychotic symptoms (J ECT. 2019 Dec;35[4]:238-44).

“In our sample, better measurement of psychotic symptoms did not improve prediction, but better measurement of psychomotor symptoms did seem to be valuable,” according to the psychiatrist.
 

 

Protection against ECT’s cognitive side effects?

Dr. van Diermen and colleagues assessed short- and long-term changes in global cognitive functioning in 65 consecutive patients treated with ECT for a major depressive episode by administering the Montreal Cognitive Assessment (MoCA) at baseline, before the third ECT session, and 1 week, 3 months, and 6 months after completing their treatment course.

During ECT, the investigators documented a limited decrease in cognitive functioning at the group level, which rebounded during the 6 months after ECT. But although there was no significant difference between MoCA scores at baseline and 6 months follow-up after ECT in the overall group of study participants, that doesn’t tell the full story. Six months after completing their course of ECT, 18% of patients demonstrated improved cognitive functioning, compared with baseline, but 8% had significantly worse cognitive functioning than pretreatment.

“Saying that ECT has no cognitive effects seems to be somewhat wrong to me. It has cognitive effects for certain people, and it will be interesting to know which people,” Dr. van Diermen said.

In what she termed “a very, very preliminary analysis,” she found that the patients with psychotic or melancholic depression were markedly less likely to have long-term cognitive impairment as defined by a worse MoCA score, compared with baseline, both at 6 months and one or more intermediate time points. Only 1 of 31 patients with psychotic depression fell into that poor cognitive outcome category, as did 4 patients with melancholic depression, compared with 12 patients without psychotic depression and 9 without melancholic depression. This, Dr. van Diermen believes, is the first report of an apparent protective effect of melancholic or psychotic depression against ECT-induced long-term cognitive worsening.

“Replication of our results is definitely necessary in larger patient samples,” she cautioned.

Dr. van Diermen reported having no financial conflicts regarding her presentation.

[email protected]

SOURCE: van Diermen L. ECNP 2020, Session EDU03.

 

Patients with severe melancholic or psychotic depression are more likely to respond to ECT, and preliminary evidence indicates they’re also protected against ECT-induced cognitive impairment, Linda van Diermen, MD, PhD, reported at the virtual congress of the European College of Neuropsychopharmacology.

Over the decades many small, underpowered studies have looked at possible predictors of ECT response and remission, with no consensus being reached. In an effort to bring a measure of clarity, Dr. van Diermen and her coinvestigators performed a meta-analysis of 34 published studies in accord with the PRISMA-P (Preferred Reporting Items for Systematic Review and Meta-analysis Protocols) guidelines and published their findings in the British Journal of Psychiatry. They scrutinized three potential predictors of response: the presence of psychotic features, melancholic depression with psychomotor symptoms, and older age.

Psychotic depression was associated with a 1.7-fold increased likelihood of response to ECT and a 1.5-fold increased odds of remission, compared with that of ECT-treated patients without psychotic depression. Older age was also a statistically significant predictor of response. However, the findings on melancholic depression were inconclusive, with only five studies with inconsistent results being available, said Dr. van Diermen, a psychiatrist at the University of Antwerp (Belgium).

She was quick to point out that, although psychotic depression and older age were statistically significant predictors of heightened likelihood of ECT response, they are of only limited clinical significance in treatment decision-making. The ECT response rate was 79% in patients with psychotic depression but still quite good at 71% in those without psychotic depression. Moreover, the average age of remitters was 59.7 years, compared with 55.4 years in nonresponders, a difference too small to be useful in guiding clinical treatment decisions.

“Age is not a valuable ECT predictor,” she said. “Although we did a meta-analysis in more than 3,200 patients that confirmed the superior effects of ECT in older patients and we recommended it at that time as one of the elements to guide decision-making when you consider ECT, our present, more detailed look at the interdependence of the predictors leads us to reconsider this statement. We now venture that age has been given too much weight in the past decades.”
 

A closer look at ECT response predictors

The studies included in the meta-analysis assessed psychotic depression and melancholic features as ECT response predictors in the typical binary way employed in clinical practice: yes/no, either present or absent. Dr. van Diermer hypothesized that a more in-depth assessment of the severity of those factors would boost their predictive power.

She found that this was indeed the case for melancholic depression as evaluated by three tools for measuring psychomotor symptoms, a core feature of this form of depression. She and her coinvestigators assessed psychomotor functioning in 65 adults with major depressive disorder before, during, and after ECT using the clinician-rated CORE scale, which measures psychomotor retardation, agitation, and noninteractiveness. In addition, the investigators had the subjects wear an accelerometer and complete a timed fine-motor drawing test.

The 41 patients with melancholic depression with psychomotor symptoms as defined by a CORE score of 8 or more were 4.9-fold more likely to reach an ECT response than were those with nonmelancholic depression. A lower baseline daytime activity level as assessed by accelerometer was also a significant predictor of increased likelihood of response, as were slower times on the drawing test.

In contrast, the investigators found that more detailed assessment of psychotic depression using the validated Psychotic Depression Assessment Scale (PDAS) was predictive of the likelihood of ECT response, but not any more so than the simple presence or absence of psychotic symptoms (J ECT. 2019 Dec;35[4]:238-44).

“In our sample, better measurement of psychotic symptoms did not improve prediction, but better measurement of psychomotor symptoms did seem to be valuable,” according to the psychiatrist.
 

 

Protection against ECT’s cognitive side effects?

Dr. van Diermen and colleagues assessed short- and long-term changes in global cognitive functioning in 65 consecutive patients treated with ECT for a major depressive episode by administering the Montreal Cognitive Assessment (MoCA) at baseline, before the third ECT session, and 1 week, 3 months, and 6 months after completing their treatment course.

During ECT, the investigators documented a limited decrease in cognitive functioning at the group level, which rebounded during the 6 months after ECT. But although there was no significant difference between MoCA scores at baseline and 6 months follow-up after ECT in the overall group of study participants, that doesn’t tell the full story. Six months after completing their course of ECT, 18% of patients demonstrated improved cognitive functioning, compared with baseline, but 8% had significantly worse cognitive functioning than pretreatment.

“Saying that ECT has no cognitive effects seems to be somewhat wrong to me. It has cognitive effects for certain people, and it will be interesting to know which people,” Dr. van Diermen said.

In what she termed “a very, very preliminary analysis,” she found that the patients with psychotic or melancholic depression were markedly less likely to have long-term cognitive impairment as defined by a worse MoCA score, compared with baseline, both at 6 months and one or more intermediate time points. Only 1 of 31 patients with psychotic depression fell into that poor cognitive outcome category, as did 4 patients with melancholic depression, compared with 12 patients without psychotic depression and 9 without melancholic depression. This, Dr. van Diermen believes, is the first report of an apparent protective effect of melancholic or psychotic depression against ECT-induced long-term cognitive worsening.

“Replication of our results is definitely necessary in larger patient samples,” she cautioned.

Dr. van Diermen reported having no financial conflicts regarding her presentation.

[email protected]

SOURCE: van Diermen L. ECNP 2020, Session EDU03.

 

Patients with severe melancholic or psychotic depression are more likely to respond to ECT, and preliminary evidence indicates they’re also protected against ECT-induced cognitive impairment, Linda van Diermen, MD, PhD, reported at the virtual congress of the European College of Neuropsychopharmacology.

Over the decades many small, underpowered studies have looked at possible predictors of ECT response and remission, with no consensus being reached. In an effort to bring a measure of clarity, Dr. van Diermen and her coinvestigators performed a meta-analysis of 34 published studies in accord with the PRISMA-P (Preferred Reporting Items for Systematic Review and Meta-analysis Protocols) guidelines and published their findings in the British Journal of Psychiatry. They scrutinized three potential predictors of response: the presence of psychotic features, melancholic depression with psychomotor symptoms, and older age.

Psychotic depression was associated with a 1.7-fold increased likelihood of response to ECT and a 1.5-fold increased odds of remission, compared with that of ECT-treated patients without psychotic depression. Older age was also a statistically significant predictor of response. However, the findings on melancholic depression were inconclusive, with only five studies with inconsistent results being available, said Dr. van Diermen, a psychiatrist at the University of Antwerp (Belgium).

She was quick to point out that, although psychotic depression and older age were statistically significant predictors of heightened likelihood of ECT response, they are of only limited clinical significance in treatment decision-making. The ECT response rate was 79% in patients with psychotic depression but still quite good at 71% in those without psychotic depression. Moreover, the average age of remitters was 59.7 years, compared with 55.4 years in nonresponders, a difference too small to be useful in guiding clinical treatment decisions.

“Age is not a valuable ECT predictor,” she said. “Although we did a meta-analysis in more than 3,200 patients that confirmed the superior effects of ECT in older patients and we recommended it at that time as one of the elements to guide decision-making when you consider ECT, our present, more detailed look at the interdependence of the predictors leads us to reconsider this statement. We now venture that age has been given too much weight in the past decades.”
 

A closer look at ECT response predictors

The studies included in the meta-analysis assessed psychotic depression and melancholic features as ECT response predictors in the typical binary way employed in clinical practice: yes/no, either present or absent. Dr. van Diermer hypothesized that a more in-depth assessment of the severity of those factors would boost their predictive power.

She found that this was indeed the case for melancholic depression as evaluated by three tools for measuring psychomotor symptoms, a core feature of this form of depression. She and her coinvestigators assessed psychomotor functioning in 65 adults with major depressive disorder before, during, and after ECT using the clinician-rated CORE scale, which measures psychomotor retardation, agitation, and noninteractiveness. In addition, the investigators had the subjects wear an accelerometer and complete a timed fine-motor drawing test.

The 41 patients with melancholic depression with psychomotor symptoms as defined by a CORE score of 8 or more were 4.9-fold more likely to reach an ECT response than were those with nonmelancholic depression. A lower baseline daytime activity level as assessed by accelerometer was also a significant predictor of increased likelihood of response, as were slower times on the drawing test.

In contrast, the investigators found that more detailed assessment of psychotic depression using the validated Psychotic Depression Assessment Scale (PDAS) was predictive of the likelihood of ECT response, but not any more so than the simple presence or absence of psychotic symptoms (J ECT. 2019 Dec;35[4]:238-44).

“In our sample, better measurement of psychotic symptoms did not improve prediction, but better measurement of psychomotor symptoms did seem to be valuable,” according to the psychiatrist.
 

 

Protection against ECT’s cognitive side effects?

Dr. van Diermen and colleagues assessed short- and long-term changes in global cognitive functioning in 65 consecutive patients treated with ECT for a major depressive episode by administering the Montreal Cognitive Assessment (MoCA) at baseline, before the third ECT session, and 1 week, 3 months, and 6 months after completing their treatment course.

During ECT, the investigators documented a limited decrease in cognitive functioning at the group level, which rebounded during the 6 months after ECT. But although there was no significant difference between MoCA scores at baseline and 6 months follow-up after ECT in the overall group of study participants, that doesn’t tell the full story. Six months after completing their course of ECT, 18% of patients demonstrated improved cognitive functioning, compared with baseline, but 8% had significantly worse cognitive functioning than pretreatment.

“Saying that ECT has no cognitive effects seems to be somewhat wrong to me. It has cognitive effects for certain people, and it will be interesting to know which people,” Dr. van Diermen said.

In what she termed “a very, very preliminary analysis,” she found that the patients with psychotic or melancholic depression were markedly less likely to have long-term cognitive impairment as defined by a worse MoCA score, compared with baseline, both at 6 months and one or more intermediate time points. Only 1 of 31 patients with psychotic depression fell into that poor cognitive outcome category, as did 4 patients with melancholic depression, compared with 12 patients without psychotic depression and 9 without melancholic depression. This, Dr. van Diermen believes, is the first report of an apparent protective effect of melancholic or psychotic depression against ECT-induced long-term cognitive worsening.

“Replication of our results is definitely necessary in larger patient samples,” she cautioned.

Dr. van Diermen reported having no financial conflicts regarding her presentation.

[email protected]

SOURCE: van Diermen L. ECNP 2020, Session EDU03.

 

Last summer, back when people traveled, I had the pleasure of being in Amsterdam for Pride Week. With a half-million tourists, it was a colorful and costumed display of LGBTQ pride, and both the streets and canals had celebrations with food, drinks, music, and displays beyond anything I could describe.

It was all not that long ago that the American Psychiatric Association classified homosexuality as a psychiatric disorder. Now we have Pride celebrations, and I don’t think twice about mentioning my brother-in-law’s husband, or a female colleague’s wife, nor am I shocked when I hear that the children of my friends are in the process of gender transition. Obviously, the idea that people express both their gender and their sexuality in diverse ways is not accepted by everyone, but we’ve come a long way toward acceptance of people who were once stigmatized and pathologized. I’ll also point out that this shift occurred despite the fact that the gay community was affected by AIDS.

There are many other differences – and illnesses – that our society has come to either accept or sympathize with more graciously over time, and yet both mental illness and substance abuse disorders remain stigmatized and punished. To put it bluntly, we have done a terrible job of making these conditions acceptable illnesses to have, even though we have done a reasonably good job of offering effective treatments. Cancer no longer carries the stigma it once did, even though cancer is a leading cause of death, and the treatments are painful, toxic, and may include the loss of body parts and hair. But if you become ill with cancer, your friends bring casseroles (or perhaps rotisserie chickens), and if you’re hospitalized with bipolar disorder or check into a drug treatment center, you’re more likely to be the recipient of judgment and even scorn.

We have to fix this. We talk about the need to destigmatize mental illness and substance use disorders, and to make these illnesses more on par with other diseases. Maybe that is the wrong call: These disorders sometimes cause people to behave in disruptive, dangerous, and illegal ways that we don’t often see with other illnesses. Frankly psychotic people may be seen as “other,” they may smell bad, they may behave in bizarre ways, and they may be frightening. Their rare acts of violence have been publicized so much that “He’s mentally ill” is accepted by the public as a full explanation for why someone would commit a mass shooting. Depression can cause people to be irritable and unpleasant, and our society equates a lack of motivation with laziness. While people may have sympathy for the suicidal thoughts and feelings of others, completed suicide leaves behind devastated survivors. People with substance use problems may become belligerent or commit crimes to support their addictions. In 2018, over 10,500 people were killed by drivers who were impaired by alcohol. I’m not sure how we destigmatize these conditions, but commercials, billboards, and educational programs aren’t doing it.
 

Fears around treatment

Perhaps our efforts need to go toward destigmatizing treatment. It is shocking to me how resistant people are to getting help, or having others know they are getting help, when treatment often renders them free from the psychological agony or misbehaviors caused by their condition.

Since I work in an outpatient setting, I see people who have made it beyond the barrier of seeking help. Almost all of my patients are willing to try medications – there is self-selection among those who chose to see a psychiatrist as opposed to another type of psychotherapist. I also believe that direct-to-consumer advertising has helped normalize the use of psychotropic medications.

When it comes to getting a higher level of care, however, the conversations are so much harder. Many of my patients insist they will never be admitted to a psychiatric unit, and when I ask depressed people if they are having suicidal thoughts, some tell me they are afraid to let me know they are for fear I might hospitalize them. This fear of hospitalization is present in people who have never been in a hospital and have only media depictions or their imaginations to go by, but I also see this with patients who have previously been hospitalized and have emerged from their inpatient stays feeling much better. While we know that any type of hospitalization involves a loss of control, unpleasant moments, and sometimes painful procedures, I have never heard anyone say that, if they were to have a second heart attack, they would refuse an admission to the cardiac care unit.

Discussions about treatment for substance use are even more difficult. People with addictions often don’t want to abstain from the substance they are using, and this is an enormous hurdle. Beyond that, they don’t like the labels that come with acknowledging a problem – words like “junkie,” “addict,” “drunk,” and “alcoholic” are hard to escape.

People fear hospitalization for many reasons: They fear losing control, they don’t recognize that they have a problem, or they rationalize their psychosis or substance use as normal. Most of all, they fear what others will think of them and what repercussions this will have for their futures. Patients would rather continue in a state of agony and dysfunction when inpatient treatment would make them better faster. This is nothing short of tragic.

What can we do? The answer is “a lot.” We need to work harder to make the hospital experience a pleasant one for patients. Inpatient units need to be clean, safe places where patients are treated with kindness, dignity, and respect and activities are appropriate, interesting, and promote healing.

Maria, a Maryland attorney, told me about her experience with inpatient treatment. “I experienced my hospitalization as jailing and acutely felt the loss of liberty, especially in the ER, where I was confined to something I recognized from my time visiting incarcerated and detained people as a holding cell, complete with a uniformed guard. I was scared to engage in any kind of meaningful self-advocacy around leaving out of fear for my license to practice law and of lengthening my time as an inpatient. As a result, I found myself concentrating on getting out, and not on getting well. With the benefit of hindsight, I can say now that my hospitalization was a lost opportunity, and the coercive elements were barriers to accessing the treatment that I needed, both at the time and in the years following the hospitalization.”

We have too many policies in place where infractions are met with force, seclusion, and sometimes restraint, and we need to be more flexible with these policies. If a psychiatric unit requires lab work prior to admission and the patient refuses, should force be used in the emergency department if there is nothing to indicate that the patient’s health is in imminent danger? And if the hospital has a policy that all psychiatric patients must disrobe to be examined for preexisting scars or contraband – this is an admission standard for some hospitals, but not others – and the patient refuses, what then? Typically, inpatients are not allowed access to their cell phones or the Internet (for many good reasons), but patients find this very upsetting; might it make sense to allow periods where they can use devices with supervision? Hospitals often forbid smoking, and people with psychiatric disorders may smoke – while it is a wonderful health ideal, is it reasonable to forbid smoking for the course of a hospitalization? Rigid adherence to policies does not always serve our patients well, and it sometimes creates dangerous situations for everyone.

We must work to get questions about psychiatric and substance use disorders removed from any job- or licensure-related forms. There is no reason to believe that people answer these forms truthfully or that including these questions protects the public in any way. What we do know is that people don’t seek help because they, like Maria, are afraid of the consequences of getting care. It doesn’t matter if a surgeon’s abilities are limited because he has episodes of hypoglycemia or past episodes of mania, and the only question on licensing forms should be about current conditions that impair the ability to work. Every district branch of the American Psychiatric Association should be actively speaking with their state professional licensing boards about the harm these questions do.

We need better treatments that have fewer side effects, and we need to acknowledge that, while getting help is the right thing to do, not everyone finds the right treatment with the first attempt and not everyone gets better. Our party line to those who feel suicidal has been “Get Help,” often with a phone number for the National Suicide Prevention Lifeline. While this is an important resource to have readily available, many of the people who die of suicide are already in active treatment. Our party line needs to change to “Get Help, and if it isn’t working, Get Different Help.” We want to be careful that our messaging does not foster a sense of hopelessness in those who have sought care and still suffer.

It’s good to talk about the potential benefits of treatment, but we don’t have enough beds and we don’t have enough mental health clinicians. There are states where psychiatric patients who have committed no crime are held in jail cells while they wait for beds to open – that we allow this is nothing short of a disgrace. The sickest patients with treatment-resistant conditions need access to the best care, and that access should not be limited by finances or networks. And while I’m here: We need our mental health professionals to spend their time working with patients, not computer screens, check boxes, and prior authorization protocols.

Finally, we need to work with the media to show positive and accurate depictions of psychiatric treatment as something that helps. We are still undoing the harm of Nurse Ratched and the depiction of electroconvulsive therapy in the 1975 film “One Flew Over the Cuckoo’s Nest,” and the current focus on mental illness and violence does nothing to help people feel comfortable seeking care.

I’ll end with one more thought from Maria: “Mental health professionals need to talk about hospitalization up front, no matter how uncomfortable, and encourage patients to think about hospitalization as a treatment option on a continuum before it is needed, so they are not approaching hospitalization as an abstract concept, often with a lot of fear and stigma attached to it, but rather as an option that they might explore in a fact-based way.”
 

Dr. Miller is coauthor with Annette Hanson, MD, of “Committed: The Battle Over Involuntary Psychiatric Care” (Baltimore: Johns Hopkins University, 2016). She has a private practice and is assistant professor of psychiatry and behavioral sciences at Johns Hopkins University, both in Baltimore. She reported having nothing to disclose.

 

Last summer, back when people traveled, I had the pleasure of being in Amsterdam for Pride Week. With a half-million tourists, it was a colorful and costumed display of LGBTQ pride, and both the streets and canals had celebrations with food, drinks, music, and displays beyond anything I could describe.

It was all not that long ago that the American Psychiatric Association classified homosexuality as a psychiatric disorder. Now we have Pride celebrations, and I don’t think twice about mentioning my brother-in-law’s husband, or a female colleague’s wife, nor am I shocked when I hear that the children of my friends are in the process of gender transition. Obviously, the idea that people express both their gender and their sexuality in diverse ways is not accepted by everyone, but we’ve come a long way toward acceptance of people who were once stigmatized and pathologized. I’ll also point out that this shift occurred despite the fact that the gay community was affected by AIDS.

There are many other differences – and illnesses – that our society has come to either accept or sympathize with more graciously over time, and yet both mental illness and substance abuse disorders remain stigmatized and punished. To put it bluntly, we have done a terrible job of making these conditions acceptable illnesses to have, even though we have done a reasonably good job of offering effective treatments. Cancer no longer carries the stigma it once did, even though cancer is a leading cause of death, and the treatments are painful, toxic, and may include the loss of body parts and hair. But if you become ill with cancer, your friends bring casseroles (or perhaps rotisserie chickens), and if you’re hospitalized with bipolar disorder or check into a drug treatment center, you’re more likely to be the recipient of judgment and even scorn.

We have to fix this. We talk about the need to destigmatize mental illness and substance use disorders, and to make these illnesses more on par with other diseases. Maybe that is the wrong call: These disorders sometimes cause people to behave in disruptive, dangerous, and illegal ways that we don’t often see with other illnesses. Frankly psychotic people may be seen as “other,” they may smell bad, they may behave in bizarre ways, and they may be frightening. Their rare acts of violence have been publicized so much that “He’s mentally ill” is accepted by the public as a full explanation for why someone would commit a mass shooting. Depression can cause people to be irritable and unpleasant, and our society equates a lack of motivation with laziness. While people may have sympathy for the suicidal thoughts and feelings of others, completed suicide leaves behind devastated survivors. People with substance use problems may become belligerent or commit crimes to support their addictions. In 2018, over 10,500 people were killed by drivers who were impaired by alcohol. I’m not sure how we destigmatize these conditions, but commercials, billboards, and educational programs aren’t doing it.
 

Fears around treatment

Perhaps our efforts need to go toward destigmatizing treatment. It is shocking to me how resistant people are to getting help, or having others know they are getting help, when treatment often renders them free from the psychological agony or misbehaviors caused by their condition.

Since I work in an outpatient setting, I see people who have made it beyond the barrier of seeking help. Almost all of my patients are willing to try medications – there is self-selection among those who chose to see a psychiatrist as opposed to another type of psychotherapist. I also believe that direct-to-consumer advertising has helped normalize the use of psychotropic medications.

When it comes to getting a higher level of care, however, the conversations are so much harder. Many of my patients insist they will never be admitted to a psychiatric unit, and when I ask depressed people if they are having suicidal thoughts, some tell me they are afraid to let me know they are for fear I might hospitalize them. This fear of hospitalization is present in people who have never been in a hospital and have only media depictions or their imaginations to go by, but I also see this with patients who have previously been hospitalized and have emerged from their inpatient stays feeling much better. While we know that any type of hospitalization involves a loss of control, unpleasant moments, and sometimes painful procedures, I have never heard anyone say that, if they were to have a second heart attack, they would refuse an admission to the cardiac care unit.

Discussions about treatment for substance use are even more difficult. People with addictions often don’t want to abstain from the substance they are using, and this is an enormous hurdle. Beyond that, they don’t like the labels that come with acknowledging a problem – words like “junkie,” “addict,” “drunk,” and “alcoholic” are hard to escape.

People fear hospitalization for many reasons: They fear losing control, they don’t recognize that they have a problem, or they rationalize their psychosis or substance use as normal. Most of all, they fear what others will think of them and what repercussions this will have for their futures. Patients would rather continue in a state of agony and dysfunction when inpatient treatment would make them better faster. This is nothing short of tragic.

What can we do? The answer is “a lot.” We need to work harder to make the hospital experience a pleasant one for patients. Inpatient units need to be clean, safe places where patients are treated with kindness, dignity, and respect and activities are appropriate, interesting, and promote healing.

Maria, a Maryland attorney, told me about her experience with inpatient treatment. “I experienced my hospitalization as jailing and acutely felt the loss of liberty, especially in the ER, where I was confined to something I recognized from my time visiting incarcerated and detained people as a holding cell, complete with a uniformed guard. I was scared to engage in any kind of meaningful self-advocacy around leaving out of fear for my license to practice law and of lengthening my time as an inpatient. As a result, I found myself concentrating on getting out, and not on getting well. With the benefit of hindsight, I can say now that my hospitalization was a lost opportunity, and the coercive elements were barriers to accessing the treatment that I needed, both at the time and in the years following the hospitalization.”

We have too many policies in place where infractions are met with force, seclusion, and sometimes restraint, and we need to be more flexible with these policies. If a psychiatric unit requires lab work prior to admission and the patient refuses, should force be used in the emergency department if there is nothing to indicate that the patient’s health is in imminent danger? And if the hospital has a policy that all psychiatric patients must disrobe to be examined for preexisting scars or contraband – this is an admission standard for some hospitals, but not others – and the patient refuses, what then? Typically, inpatients are not allowed access to their cell phones or the Internet (for many good reasons), but patients find this very upsetting; might it make sense to allow periods where they can use devices with supervision? Hospitals often forbid smoking, and people with psychiatric disorders may smoke – while it is a wonderful health ideal, is it reasonable to forbid smoking for the course of a hospitalization? Rigid adherence to policies does not always serve our patients well, and it sometimes creates dangerous situations for everyone.

We must work to get questions about psychiatric and substance use disorders removed from any job- or licensure-related forms. There is no reason to believe that people answer these forms truthfully or that including these questions protects the public in any way. What we do know is that people don’t seek help because they, like Maria, are afraid of the consequences of getting care. It doesn’t matter if a surgeon’s abilities are limited because he has episodes of hypoglycemia or past episodes of mania, and the only question on licensing forms should be about current conditions that impair the ability to work. Every district branch of the American Psychiatric Association should be actively speaking with their state professional licensing boards about the harm these questions do.

We need better treatments that have fewer side effects, and we need to acknowledge that, while getting help is the right thing to do, not everyone finds the right treatment with the first attempt and not everyone gets better. Our party line to those who feel suicidal has been “Get Help,” often with a phone number for the National Suicide Prevention Lifeline. While this is an important resource to have readily available, many of the people who die of suicide are already in active treatment. Our party line needs to change to “Get Help, and if it isn’t working, Get Different Help.” We want to be careful that our messaging does not foster a sense of hopelessness in those who have sought care and still suffer.

It’s good to talk about the potential benefits of treatment, but we don’t have enough beds and we don’t have enough mental health clinicians. There are states where psychiatric patients who have committed no crime are held in jail cells while they wait for beds to open – that we allow this is nothing short of a disgrace. The sickest patients with treatment-resistant conditions need access to the best care, and that access should not be limited by finances or networks. And while I’m here: We need our mental health professionals to spend their time working with patients, not computer screens, check boxes, and prior authorization protocols.

Finally, we need to work with the media to show positive and accurate depictions of psychiatric treatment as something that helps. We are still undoing the harm of Nurse Ratched and the depiction of electroconvulsive therapy in the 1975 film “One Flew Over the Cuckoo’s Nest,” and the current focus on mental illness and violence does nothing to help people feel comfortable seeking care.

I’ll end with one more thought from Maria: “Mental health professionals need to talk about hospitalization up front, no matter how uncomfortable, and encourage patients to think about hospitalization as a treatment option on a continuum before it is needed, so they are not approaching hospitalization as an abstract concept, often with a lot of fear and stigma attached to it, but rather as an option that they might explore in a fact-based way.”
 

Dr. Miller is coauthor with Annette Hanson, MD, of “Committed: The Battle Over Involuntary Psychiatric Care” (Baltimore: Johns Hopkins University, 2016). She has a private practice and is assistant professor of psychiatry and behavioral sciences at Johns Hopkins University, both in Baltimore. She reported having nothing to disclose.

 

Last summer, back when people traveled, I had the pleasure of being in Amsterdam for Pride Week. With a half-million tourists, it was a colorful and costumed display of LGBTQ pride, and both the streets and canals had celebrations with food, drinks, music, and displays beyond anything I could describe.

It was all not that long ago that the American Psychiatric Association classified homosexuality as a psychiatric disorder. Now we have Pride celebrations, and I don’t think twice about mentioning my brother-in-law’s husband, or a female colleague’s wife, nor am I shocked when I hear that the children of my friends are in the process of gender transition. Obviously, the idea that people express both their gender and their sexuality in diverse ways is not accepted by everyone, but we’ve come a long way toward acceptance of people who were once stigmatized and pathologized. I’ll also point out that this shift occurred despite the fact that the gay community was affected by AIDS.

There are many other differences – and illnesses – that our society has come to either accept or sympathize with more graciously over time, and yet both mental illness and substance abuse disorders remain stigmatized and punished. To put it bluntly, we have done a terrible job of making these conditions acceptable illnesses to have, even though we have done a reasonably good job of offering effective treatments. Cancer no longer carries the stigma it once did, even though cancer is a leading cause of death, and the treatments are painful, toxic, and may include the loss of body parts and hair. But if you become ill with cancer, your friends bring casseroles (or perhaps rotisserie chickens), and if you’re hospitalized with bipolar disorder or check into a drug treatment center, you’re more likely to be the recipient of judgment and even scorn.

We have to fix this. We talk about the need to destigmatize mental illness and substance use disorders, and to make these illnesses more on par with other diseases. Maybe that is the wrong call: These disorders sometimes cause people to behave in disruptive, dangerous, and illegal ways that we don’t often see with other illnesses. Frankly psychotic people may be seen as “other,” they may smell bad, they may behave in bizarre ways, and they may be frightening. Their rare acts of violence have been publicized so much that “He’s mentally ill” is accepted by the public as a full explanation for why someone would commit a mass shooting. Depression can cause people to be irritable and unpleasant, and our society equates a lack of motivation with laziness. While people may have sympathy for the suicidal thoughts and feelings of others, completed suicide leaves behind devastated survivors. People with substance use problems may become belligerent or commit crimes to support their addictions. In 2018, over 10,500 people were killed by drivers who were impaired by alcohol. I’m not sure how we destigmatize these conditions, but commercials, billboards, and educational programs aren’t doing it.
 

Fears around treatment

Perhaps our efforts need to go toward destigmatizing treatment. It is shocking to me how resistant people are to getting help, or having others know they are getting help, when treatment often renders them free from the psychological agony or misbehaviors caused by their condition.

Since I work in an outpatient setting, I see people who have made it beyond the barrier of seeking help. Almost all of my patients are willing to try medications – there is self-selection among those who chose to see a psychiatrist as opposed to another type of psychotherapist. I also believe that direct-to-consumer advertising has helped normalize the use of psychotropic medications.

When it comes to getting a higher level of care, however, the conversations are so much harder. Many of my patients insist they will never be admitted to a psychiatric unit, and when I ask depressed people if they are having suicidal thoughts, some tell me they are afraid to let me know they are for fear I might hospitalize them. This fear of hospitalization is present in people who have never been in a hospital and have only media depictions or their imaginations to go by, but I also see this with patients who have previously been hospitalized and have emerged from their inpatient stays feeling much better. While we know that any type of hospitalization involves a loss of control, unpleasant moments, and sometimes painful procedures, I have never heard anyone say that, if they were to have a second heart attack, they would refuse an admission to the cardiac care unit.

Discussions about treatment for substance use are even more difficult. People with addictions often don’t want to abstain from the substance they are using, and this is an enormous hurdle. Beyond that, they don’t like the labels that come with acknowledging a problem – words like “junkie,” “addict,” “drunk,” and “alcoholic” are hard to escape.

People fear hospitalization for many reasons: They fear losing control, they don’t recognize that they have a problem, or they rationalize their psychosis or substance use as normal. Most of all, they fear what others will think of them and what repercussions this will have for their futures. Patients would rather continue in a state of agony and dysfunction when inpatient treatment would make them better faster. This is nothing short of tragic.

What can we do? The answer is “a lot.” We need to work harder to make the hospital experience a pleasant one for patients. Inpatient units need to be clean, safe places where patients are treated with kindness, dignity, and respect and activities are appropriate, interesting, and promote healing.

Maria, a Maryland attorney, told me about her experience with inpatient treatment. “I experienced my hospitalization as jailing and acutely felt the loss of liberty, especially in the ER, where I was confined to something I recognized from my time visiting incarcerated and detained people as a holding cell, complete with a uniformed guard. I was scared to engage in any kind of meaningful self-advocacy around leaving out of fear for my license to practice law and of lengthening my time as an inpatient. As a result, I found myself concentrating on getting out, and not on getting well. With the benefit of hindsight, I can say now that my hospitalization was a lost opportunity, and the coercive elements were barriers to accessing the treatment that I needed, both at the time and in the years following the hospitalization.”

We have too many policies in place where infractions are met with force, seclusion, and sometimes restraint, and we need to be more flexible with these policies. If a psychiatric unit requires lab work prior to admission and the patient refuses, should force be used in the emergency department if there is nothing to indicate that the patient’s health is in imminent danger? And if the hospital has a policy that all psychiatric patients must disrobe to be examined for preexisting scars or contraband – this is an admission standard for some hospitals, but not others – and the patient refuses, what then? Typically, inpatients are not allowed access to their cell phones or the Internet (for many good reasons), but patients find this very upsetting; might it make sense to allow periods where they can use devices with supervision? Hospitals often forbid smoking, and people with psychiatric disorders may smoke – while it is a wonderful health ideal, is it reasonable to forbid smoking for the course of a hospitalization? Rigid adherence to policies does not always serve our patients well, and it sometimes creates dangerous situations for everyone.

We must work to get questions about psychiatric and substance use disorders removed from any job- or licensure-related forms. There is no reason to believe that people answer these forms truthfully or that including these questions protects the public in any way. What we do know is that people don’t seek help because they, like Maria, are afraid of the consequences of getting care. It doesn’t matter if a surgeon’s abilities are limited because he has episodes of hypoglycemia or past episodes of mania, and the only question on licensing forms should be about current conditions that impair the ability to work. Every district branch of the American Psychiatric Association should be actively speaking with their state professional licensing boards about the harm these questions do.

We need better treatments that have fewer side effects, and we need to acknowledge that, while getting help is the right thing to do, not everyone finds the right treatment with the first attempt and not everyone gets better. Our party line to those who feel suicidal has been “Get Help,” often with a phone number for the National Suicide Prevention Lifeline. While this is an important resource to have readily available, many of the people who die of suicide are already in active treatment. Our party line needs to change to “Get Help, and if it isn’t working, Get Different Help.” We want to be careful that our messaging does not foster a sense of hopelessness in those who have sought care and still suffer.

It’s good to talk about the potential benefits of treatment, but we don’t have enough beds and we don’t have enough mental health clinicians. There are states where psychiatric patients who have committed no crime are held in jail cells while they wait for beds to open – that we allow this is nothing short of a disgrace. The sickest patients with treatment-resistant conditions need access to the best care, and that access should not be limited by finances or networks. And while I’m here: We need our mental health professionals to spend their time working with patients, not computer screens, check boxes, and prior authorization protocols.

Finally, we need to work with the media to show positive and accurate depictions of psychiatric treatment as something that helps. We are still undoing the harm of Nurse Ratched and the depiction of electroconvulsive therapy in the 1975 film “One Flew Over the Cuckoo’s Nest,” and the current focus on mental illness and violence does nothing to help people feel comfortable seeking care.

I’ll end with one more thought from Maria: “Mental health professionals need to talk about hospitalization up front, no matter how uncomfortable, and encourage patients to think about hospitalization as a treatment option on a continuum before it is needed, so they are not approaching hospitalization as an abstract concept, often with a lot of fear and stigma attached to it, but rather as an option that they might explore in a fact-based way.”
 

Dr. Miller is coauthor with Annette Hanson, MD, of “Committed: The Battle Over Involuntary Psychiatric Care” (Baltimore: Johns Hopkins University, 2016). She has a private practice and is assistant professor of psychiatry and behavioral sciences at Johns Hopkins University, both in Baltimore. She reported having nothing to disclose.

One of the hottest topics now in psychiatry is the possibility of repurposing long-established cardiovascular medications for treatment of patients with serious mental illness, Livia De Picker, MD, PhD, said at the virtual congress of the European College of Neuropsychopharmacology.

Courtesy Dr. Livia De Picker

The appeal is multifold. A huge unmet need exists in psychiatry for new and better treatments with novel mechanisms of action. Many guideline-recommended cardiovascular medications have a long track record, including a well-established safety profile with no surprises, and are available in generic versions. They can be developed for a new indication at minimal cost, noted Dr. De Picker, a psychiatrist at the University of Antwerp (Belgium).

The idea of psychiatric repurposing of drugs originally developed for nonpsychiatric indications is nothing new, she added. Examples include lithium for gout, valproate for epilepsy, and ketamine for anesthesiology.

One hitch in efforts to repurpose cardiovascular medications is that, when psychiatric patients have been included in randomized trials of the drugs’ cardiovascular effects, the psychiatric outcomes often went untallied.

Indeed, the only high-quality randomized trial evidence of psychiatric benefits for any class of cardiovascular medications is for statins, where a modest-sized meta-analysis of six placebo-controlled trials in 339 patients with schizophrenia showed the lipid-lowering agents had benefit for both positive and negative symptoms (Psychiatry Res. 2018 Apr;262:84-93). But that’s not a body of data of sufficient size to be definitive, in Dr. De Picker’s view.

Much of the recent enthusiasm for exploring the potential of cardiovascular drugs for psychiatric conditions comes from hypothesis-generating big data analyses drawn from Scandinavian national patient registries. Danish investigators scrutinized all 1.6 million Danes exposed to six classes of drugs of interest during 2005-2015 and determined that those on long-term statins, low-dose aspirin, ACE inhibitors, angiotensin receptor blockers, or allopurinol were associated with a decreased rate of new-onset depression, while high-dose aspirin and non-aspirin NSAIDs were associated with an increased rate, compared with a 30% random sample of the country’s population (Acta Psychiatr Scand. 2019 Jan;1391:68-77).

Similarly, the Danish group found that continued use of statins, angiotensin agents, or low-dose aspirin was associated with a decreased rate of new-onset bipolar disorder, while high-dose aspirin and other NSAIDs were linked to increased risk (Bipolar Disord. 2019 Aug;[15]:410-8). What these agents have in common, the investigators observed, is that they act on inflammation and potentially on the stress response system.

Meanwhile, Swedish investigators examined the course of 142,691 Swedes with a diagnosis of bipolar disorder, schizophrenia, or nonaffective psychosis during 2005-2016. They determined that, during periods when those individuals were on a statin, calcium channel blocker, or metformin, they had reduced rates of psychiatric hospitalization and self-harm (JAMA Psychiatry. 2019 Apr 1;76[4]:382-90).

Scottish researchers analyzed the health records of 144,066 patients placed on monotherapy for hypertension and determined that the lowest risk for hospitalization for a mood disorder during follow-up was in those prescribed an ACE inhibitor or angiotensin receptor blocker. The risk was significantly higher in patients on a beta-blocker or calcium channel blocker, and intermediate in those on a thiazide diuretic (Hypertension. 2016 Nov;68[5:1132-8).

“Obviously, this is all at a very macro scale and we have no idea whatsoever what this means for individual patients, number needed to treat, or which type of patients would benefit, but it does provide us with some guidance for future research,” according to Dr. De Picker.

In the meantime, while physicians await definitive evidence of any impact of cardiovascular drugs might have on psychiatric outcomes, abundant data exist underscoring what she called “shockingly high levels” of inadequate management of cardiovascular risk factors in patients with serious mental illness. That problem needs to be addressed, and Dr. De Picker offered her personal recommendations for doing so in a manner consistent with the evidence to date suggestive of potential mental health benefits of some cardiovascular medications.

She advised that, for treatment of hypertension in patients with bipolar disorder or major depression, an ACE inhibitor or angiotensin-converting enzyme inhibitor is preferred as first-line. There is some evidence to suggest lipophilic beta-blockers, which cross the blood-brain barrier, improve anxiety symptoms and panic attacks, and prevent memory consolidation in patients with posttraumatic stress disorder. But the Scottish data suggest that they may worsen mood disorders.

“I would be careful in using beta-blockers as first-line treatment for hypertension. They’re not in the guidelines for anxiety disorders. British guidelines recommend them to prevent memory consolidation in PTSD, but do not use them as first-line in patients with major depressive disorder or bipolar disorder,” she said. As for calcium channel blockers, the jury is still out, with mixed and inconsistent evidence to date as to the impact of this drug class on mental illness outcomes.

She recommended a very low threshold for prescribing statin therapy in patients with serious mental illness in light of the superb risk/benefit ratio for this drug class. She makes sure a statin is onboard in her patients with schizophrenia, major depressive disorder, or bipolar disorder who are over age 60. In her younger patients, she turns for guidance to an online calculator of an individual’s 10-year risk of a first acute MI or stroke.

Metformin has been shown to be beneficial for addressing the weight gain and other adverse metabolic effects caused by antipsychotic agents, and there is some preliminary evidence of improved psychiatric outcomes in patients with serious mental illness.

Christian Otte, MD, who also spoke at the session, noted that not only do emerging data point to the possibility that cardiovascular drugs might have benefit in terms of psychiatric outcomes, there is also some evidence, albeit mixed, that the converse is true: that is, psychiatric drugs may have cardiovascular benefits. He pointed to a South Korean trial in which 300 patients with a recent acute coronary syndrome and major depression were randomized to 24 weeks of escitalopram or placebo. At median 8.1 years of follow-up, the group that received the SSRI had a 31% relative risk reduction in the primary composite endpoint of all-cause mortality, acute MI, or percutaneous coronary intervention (JAMA. 2018 Jul 24; 320[4]:350–7).

“Potentially independent of their antidepressant effects, some SSRIs’ antiplatelet effects could be beneficial for patients with coronary heart disease, although the jury is still open regarding this question, with evidence in both directions,” said Dr. Otte, professor of psychiatry at Charite University Medical Center in Berlin.

Dr. De Picker offered an example as well: Finnish psychiatrists recently reported that cardiovascular mortality was reduced by an adjusted 38% during periods when 62,250 Finnish schizophrenia patients were on antipsychotic agents, compared with periods of nonuse of the drugs in a national study with a median 14.1 years of follow-up (World Psychiatry. 2020 Feb;19[1]:61-8).

“What they discovered – and this is quite contrary to what we are used to hearing about antipsychotic medication and cardiovascular risk – is that while the number of cardiovascular hospitalizations was not different in periods with or without antipsychotic use, the cardiovascular mortality was quite strikingly reduced when patients were on antipsychotic medication,” she said.

Asked by an audience member whether she personally prescribes metformin, Dr. De Picker replied: “Well, yes, why not? One of the very nice things about metformin is that it is actually a very safe drug, even in the hands of nonspecialists.

“I understand that maybe psychiatrists may not feel very comfortable in starting patients on metformin due to a lack of experience. But there are really only two things you need to take into account. About one-quarter of patients will experience GI side effects – nausea, vomiting, abdominal discomfort – and this can be reduced by gradually uptitrating the dose, dosing at mealtime, and using an extended-release formulation. And the second thing is that metformin can impair vitamin B₁₂ absorption, so I think, especially in psychiatric patients, it would be good to do an annual measurement of vitamin B₁₂ level and, if necessary, administer intramuscular supplements,” Dr. De Picker said.

She reported having no financial conflicts regarding her presentation.

[email protected]

SOURCE: De Picker L. ECNP 2020. Session EDU.05.

One of the hottest topics now in psychiatry is the possibility of repurposing long-established cardiovascular medications for treatment of patients with serious mental illness, Livia De Picker, MD, PhD, said at the virtual congress of the European College of Neuropsychopharmacology.

Courtesy Dr. Livia De Picker

The appeal is multifold. A huge unmet need exists in psychiatry for new and better treatments with novel mechanisms of action. Many guideline-recommended cardiovascular medications have a long track record, including a well-established safety profile with no surprises, and are available in generic versions. They can be developed for a new indication at minimal cost, noted Dr. De Picker, a psychiatrist at the University of Antwerp (Belgium).

The idea of psychiatric repurposing of drugs originally developed for nonpsychiatric indications is nothing new, she added. Examples include lithium for gout, valproate for epilepsy, and ketamine for anesthesiology.

One hitch in efforts to repurpose cardiovascular medications is that, when psychiatric patients have been included in randomized trials of the drugs’ cardiovascular effects, the psychiatric outcomes often went untallied.

Indeed, the only high-quality randomized trial evidence of psychiatric benefits for any class of cardiovascular medications is for statins, where a modest-sized meta-analysis of six placebo-controlled trials in 339 patients with schizophrenia showed the lipid-lowering agents had benefit for both positive and negative symptoms (Psychiatry Res. 2018 Apr;262:84-93). But that’s not a body of data of sufficient size to be definitive, in Dr. De Picker’s view.

Much of the recent enthusiasm for exploring the potential of cardiovascular drugs for psychiatric conditions comes from hypothesis-generating big data analyses drawn from Scandinavian national patient registries. Danish investigators scrutinized all 1.6 million Danes exposed to six classes of drugs of interest during 2005-2015 and determined that those on long-term statins, low-dose aspirin, ACE inhibitors, angiotensin receptor blockers, or allopurinol were associated with a decreased rate of new-onset depression, while high-dose aspirin and non-aspirin NSAIDs were associated with an increased rate, compared with a 30% random sample of the country’s population (Acta Psychiatr Scand. 2019 Jan;1391:68-77).

Similarly, the Danish group found that continued use of statins, angiotensin agents, or low-dose aspirin was associated with a decreased rate of new-onset bipolar disorder, while high-dose aspirin and other NSAIDs were linked to increased risk (Bipolar Disord. 2019 Aug;[15]:410-8). What these agents have in common, the investigators observed, is that they act on inflammation and potentially on the stress response system.

Meanwhile, Swedish investigators examined the course of 142,691 Swedes with a diagnosis of bipolar disorder, schizophrenia, or nonaffective psychosis during 2005-2016. They determined that, during periods when those individuals were on a statin, calcium channel blocker, or metformin, they had reduced rates of psychiatric hospitalization and self-harm (JAMA Psychiatry. 2019 Apr 1;76[4]:382-90).

Scottish researchers analyzed the health records of 144,066 patients placed on monotherapy for hypertension and determined that the lowest risk for hospitalization for a mood disorder during follow-up was in those prescribed an ACE inhibitor or angiotensin receptor blocker. The risk was significantly higher in patients on a beta-blocker or calcium channel blocker, and intermediate in those on a thiazide diuretic (Hypertension. 2016 Nov;68[5:1132-8).

“Obviously, this is all at a very macro scale and we have no idea whatsoever what this means for individual patients, number needed to treat, or which type of patients would benefit, but it does provide us with some guidance for future research,” according to Dr. De Picker.

In the meantime, while physicians await definitive evidence of any impact of cardiovascular drugs might have on psychiatric outcomes, abundant data exist underscoring what she called “shockingly high levels” of inadequate management of cardiovascular risk factors in patients with serious mental illness. That problem needs to be addressed, and Dr. De Picker offered her personal recommendations for doing so in a manner consistent with the evidence to date suggestive of potential mental health benefits of some cardiovascular medications.

She advised that, for treatment of hypertension in patients with bipolar disorder or major depression, an ACE inhibitor or angiotensin-converting enzyme inhibitor is preferred as first-line. There is some evidence to suggest lipophilic beta-blockers, which cross the blood-brain barrier, improve anxiety symptoms and panic attacks, and prevent memory consolidation in patients with posttraumatic stress disorder. But the Scottish data suggest that they may worsen mood disorders.

“I would be careful in using beta-blockers as first-line treatment for hypertension. They’re not in the guidelines for anxiety disorders. British guidelines recommend them to prevent memory consolidation in PTSD, but do not use them as first-line in patients with major depressive disorder or bipolar disorder,” she said. As for calcium channel blockers, the jury is still out, with mixed and inconsistent evidence to date as to the impact of this drug class on mental illness outcomes.

She recommended a very low threshold for prescribing statin therapy in patients with serious mental illness in light of the superb risk/benefit ratio for this drug class. She makes sure a statin is onboard in her patients with schizophrenia, major depressive disorder, or bipolar disorder who are over age 60. In her younger patients, she turns for guidance to an online calculator of an individual’s 10-year risk of a first acute MI or stroke.

Metformin has been shown to be beneficial for addressing the weight gain and other adverse metabolic effects caused by antipsychotic agents, and there is some preliminary evidence of improved psychiatric outcomes in patients with serious mental illness.

Christian Otte, MD, who also spoke at the session, noted that not only do emerging data point to the possibility that cardiovascular drugs might have benefit in terms of psychiatric outcomes, there is also some evidence, albeit mixed, that the converse is true: that is, psychiatric drugs may have cardiovascular benefits. He pointed to a South Korean trial in which 300 patients with a recent acute coronary syndrome and major depression were randomized to 24 weeks of escitalopram or placebo. At median 8.1 years of follow-up, the group that received the SSRI had a 31% relative risk reduction in the primary composite endpoint of all-cause mortality, acute MI, or percutaneous coronary intervention (JAMA. 2018 Jul 24; 320[4]:350–7).

“Potentially independent of their antidepressant effects, some SSRIs’ antiplatelet effects could be beneficial for patients with coronary heart disease, although the jury is still open regarding this question, with evidence in both directions,” said Dr. Otte, professor of psychiatry at Charite University Medical Center in Berlin.

Dr. De Picker offered an example as well: Finnish psychiatrists recently reported that cardiovascular mortality was reduced by an adjusted 38% during periods when 62,250 Finnish schizophrenia patients were on antipsychotic agents, compared with periods of nonuse of the drugs in a national study with a median 14.1 years of follow-up (World Psychiatry. 2020 Feb;19[1]:61-8).

“What they discovered – and this is quite contrary to what we are used to hearing about antipsychotic medication and cardiovascular risk – is that while the number of cardiovascular hospitalizations was not different in periods with or without antipsychotic use, the cardiovascular mortality was quite strikingly reduced when patients were on antipsychotic medication,” she said.

Asked by an audience member whether she personally prescribes metformin, Dr. De Picker replied: “Well, yes, why not? One of the very nice things about metformin is that it is actually a very safe drug, even in the hands of nonspecialists.

“I understand that maybe psychiatrists may not feel very comfortable in starting patients on metformin due to a lack of experience. But there are really only two things you need to take into account. About one-quarter of patients will experience GI side effects – nausea, vomiting, abdominal discomfort – and this can be reduced by gradually uptitrating the dose, dosing at mealtime, and using an extended-release formulation. And the second thing is that metformin can impair vitamin B₁₂ absorption, so I think, especially in psychiatric patients, it would be good to do an annual measurement of vitamin B₁₂ level and, if necessary, administer intramuscular supplements,” Dr. De Picker said.

She reported having no financial conflicts regarding her presentation.

[email protected]

SOURCE: De Picker L. ECNP 2020. Session EDU.05.

One of the hottest topics now in psychiatry is the possibility of repurposing long-established cardiovascular medications for treatment of patients with serious mental illness, Livia De Picker, MD, PhD, said at the virtual congress of the European College of Neuropsychopharmacology.

Courtesy Dr. Livia De Picker

The appeal is multifold. A huge unmet need exists in psychiatry for new and better treatments with novel mechanisms of action. Many guideline-recommended cardiovascular medications have a long track record, including a well-established safety profile with no surprises, and are available in generic versions. They can be developed for a new indication at minimal cost, noted Dr. De Picker, a psychiatrist at the University of Antwerp (Belgium).

The idea of psychiatric repurposing of drugs originally developed for nonpsychiatric indications is nothing new, she added. Examples include lithium for gout, valproate for epilepsy, and ketamine for anesthesiology.

One hitch in efforts to repurpose cardiovascular medications is that, when psychiatric patients have been included in randomized trials of the drugs’ cardiovascular effects, the psychiatric outcomes often went untallied.

Indeed, the only high-quality randomized trial evidence of psychiatric benefits for any class of cardiovascular medications is for statins, where a modest-sized meta-analysis of six placebo-controlled trials in 339 patients with schizophrenia showed the lipid-lowering agents had benefit for both positive and negative symptoms (Psychiatry Res. 2018 Apr;262:84-93). But that’s not a body of data of sufficient size to be definitive, in Dr. De Picker’s view.

Much of the recent enthusiasm for exploring the potential of cardiovascular drugs for psychiatric conditions comes from hypothesis-generating big data analyses drawn from Scandinavian national patient registries. Danish investigators scrutinized all 1.6 million Danes exposed to six classes of drugs of interest during 2005-2015 and determined that those on long-term statins, low-dose aspirin, ACE inhibitors, angiotensin receptor blockers, or allopurinol were associated with a decreased rate of new-onset depression, while high-dose aspirin and non-aspirin NSAIDs were associated with an increased rate, compared with a 30% random sample of the country’s population (Acta Psychiatr Scand. 2019 Jan;1391:68-77).

Similarly, the Danish group found that continued use of statins, angiotensin agents, or low-dose aspirin was associated with a decreased rate of new-onset bipolar disorder, while high-dose aspirin and other NSAIDs were linked to increased risk (Bipolar Disord. 2019 Aug;[15]:410-8). What these agents have in common, the investigators observed, is that they act on inflammation and potentially on the stress response system.

Meanwhile, Swedish investigators examined the course of 142,691 Swedes with a diagnosis of bipolar disorder, schizophrenia, or nonaffective psychosis during 2005-2016. They determined that, during periods when those individuals were on a statin, calcium channel blocker, or metformin, they had reduced rates of psychiatric hospitalization and self-harm (JAMA Psychiatry. 2019 Apr 1;76[4]:382-90).

Scottish researchers analyzed the health records of 144,066 patients placed on monotherapy for hypertension and determined that the lowest risk for hospitalization for a mood disorder during follow-up was in those prescribed an ACE inhibitor or angiotensin receptor blocker. The risk was significantly higher in patients on a beta-blocker or calcium channel blocker, and intermediate in those on a thiazide diuretic (Hypertension. 2016 Nov;68[5:1132-8).

“Obviously, this is all at a very macro scale and we have no idea whatsoever what this means for individual patients, number needed to treat, or which type of patients would benefit, but it does provide us with some guidance for future research,” according to Dr. De Picker.

In the meantime, while physicians await definitive evidence of any impact of cardiovascular drugs might have on psychiatric outcomes, abundant data exist underscoring what she called “shockingly high levels” of inadequate management of cardiovascular risk factors in patients with serious mental illness. That problem needs to be addressed, and Dr. De Picker offered her personal recommendations for doing so in a manner consistent with the evidence to date suggestive of potential mental health benefits of some cardiovascular medications.

She advised that, for treatment of hypertension in patients with bipolar disorder or major depression, an ACE inhibitor or angiotensin-converting enzyme inhibitor is preferred as first-line. There is some evidence to suggest lipophilic beta-blockers, which cross the blood-brain barrier, improve anxiety symptoms and panic attacks, and prevent memory consolidation in patients with posttraumatic stress disorder. But the Scottish data suggest that they may worsen mood disorders.

“I would be careful in using beta-blockers as first-line treatment for hypertension. They’re not in the guidelines for anxiety disorders. British guidelines recommend them to prevent memory consolidation in PTSD, but do not use them as first-line in patients with major depressive disorder or bipolar disorder,” she said. As for calcium channel blockers, the jury is still out, with mixed and inconsistent evidence to date as to the impact of this drug class on mental illness outcomes.

She recommended a very low threshold for prescribing statin therapy in patients with serious mental illness in light of the superb risk/benefit ratio for this drug class. She makes sure a statin is onboard in her patients with schizophrenia, major depressive disorder, or bipolar disorder who are over age 60. In her younger patients, she turns for guidance to an online calculator of an individual’s 10-year risk of a first acute MI or stroke.

Metformin has been shown to be beneficial for addressing the weight gain and other adverse metabolic effects caused by antipsychotic agents, and there is some preliminary evidence of improved psychiatric outcomes in patients with serious mental illness.

Christian Otte, MD, who also spoke at the session, noted that not only do emerging data point to the possibility that cardiovascular drugs might have benefit in terms of psychiatric outcomes, there is also some evidence, albeit mixed, that the converse is true: that is, psychiatric drugs may have cardiovascular benefits. He pointed to a South Korean trial in which 300 patients with a recent acute coronary syndrome and major depression were randomized to 24 weeks of escitalopram or placebo. At median 8.1 years of follow-up, the group that received the SSRI had a 31% relative risk reduction in the primary composite endpoint of all-cause mortality, acute MI, or percutaneous coronary intervention (JAMA. 2018 Jul 24; 320[4]:350–7).

“Potentially independent of their antidepressant effects, some SSRIs’ antiplatelet effects could be beneficial for patients with coronary heart disease, although the jury is still open regarding this question, with evidence in both directions,” said Dr. Otte, professor of psychiatry at Charite University Medical Center in Berlin.

Dr. De Picker offered an example as well: Finnish psychiatrists recently reported that cardiovascular mortality was reduced by an adjusted 38% during periods when 62,250 Finnish schizophrenia patients were on antipsychotic agents, compared with periods of nonuse of the drugs in a national study with a median 14.1 years of follow-up (World Psychiatry. 2020 Feb;19[1]:61-8).

“What they discovered – and this is quite contrary to what we are used to hearing about antipsychotic medication and cardiovascular risk – is that while the number of cardiovascular hospitalizations was not different in periods with or without antipsychotic use, the cardiovascular mortality was quite strikingly reduced when patients were on antipsychotic medication,” she said.

Asked by an audience member whether she personally prescribes metformin, Dr. De Picker replied: “Well, yes, why not? One of the very nice things about metformin is that it is actually a very safe drug, even in the hands of nonspecialists.

“I understand that maybe psychiatrists may not feel very comfortable in starting patients on metformin due to a lack of experience. But there are really only two things you need to take into account. About one-quarter of patients will experience GI side effects – nausea, vomiting, abdominal discomfort – and this can be reduced by gradually uptitrating the dose, dosing at mealtime, and using an extended-release formulation. And the second thing is that metformin can impair vitamin B₁₂ absorption, so I think, especially in psychiatric patients, it would be good to do an annual measurement of vitamin B₁₂ level and, if necessary, administer intramuscular supplements,” Dr. De Picker said.

She reported having no financial conflicts regarding her presentation.

[email protected]

SOURCE: De Picker L. ECNP 2020. Session EDU.05.

Deep brain stimulation (DBS) may be an effective option for patients with treatment-resistant schizophrenia (TRS), new research suggests. However, until further studies are conducted, the treatment should only be considered for the most severe cases.

ipopba/Getty Images

The first clinical trial to assess DBS in this challenging patient population included eight patients initially randomly assigned to receive electrode placement in one of two locations in the brain. Once a clinical response was achieved and participants were stabilized, they were randomly assigned to a second crossover phase.

Preliminary findings from the first phase of the DBS-SCHIZO pilot study, which were reported in 2017, showed promising efficacy.

The newly released final results revealed an association between DBS and significant improvements in Positive and Negative Symptoms Scale (PANSS) scores, as well as reductions in doses of antipsychotic medication. Moreover, the effect reversed when the electrode was switched off.

“DBS may be a potential option for severe treatment-resistant schizophrenia patients,” lead investigator Iluminada Corripio, MD, PhD, department of psychiatry, Hospital de la Santa Creu i Sant Pau, Barcelona, said during her presentation at the virtual congress of the European College of Neuropsychopharmacology. The new data were updated results of a study published in EBioMedicine earlier this year.

Dr. Corripio underlined that it is important to balance the risks and benefits of the intervention. DBS is “not useful for all phenotypes,” and benefits have been seen in patients with hallucinations but not in those with a disorganized phenotype, she added.
 

High economic burden

Managing TRS is challenging and is associated with a high clinical and economic burden, Corripio noted. Relapse rates can reach 80%, increasing resource use by between 200% and 900%.

There is a strong rationale for studying the use of DBS in schizophrenia, because schizophrenia shares a neurologic basis with other neurologic and psychiatric disorders centered around the cortical-striatal-thalamic-cortical circuit, said Dr. Corripio.

The study included eight patients with a DSM-IV-TR diagnosis of schizophrenia whose conditions were resistant to at least two different atypical antipsychotics and who had not responded to clozapine monotherapy, combination therapy, or electroconvulsive therapy.

All were randomly assigned in a 1:1 ratio to DBS electrode implantation in one of two locations. Investigators chose the nucleus accumbens (NAcc), because recent studies have shown that DBS can increase dopamine levels there, and the subgenual anterior cingulate cortex (ACC). Deactivation failure in the ACC region has been observed in patients with schizophrenia and other mental illnesses.

Stimulation began 48-72 hours postoperatively with unilateral left stimulation at 2.5 volts. It was increased in 0.5 volt increments to a maximum of 7.5 volts. Patients who did not respond were switched to bilateral stimulation.

Follow-up was conducted every 2 weeks for up to 20 months. The study’s primary outcome was a symptomatic response, defined as an improvement of at least 25% on the PANSS.

Once that was achieved, patients could enter a second randomization phase in which they were assigned, in a 24-week, double-blind crossover design, to on- or off-treatment DBS arms such that patients received stimulation for 12 weeks before the device was turned off for 12 weeks, or vice versa.

Those who experienced relapse while off treatment were crossed over to the on-treatment arm; those who experienced relapsed while on treatment were withdrawn from the study. The patients’ average age was 42.5 years, and 50% were women. All were taking clozapine in combination with another antipsychotic.
 

 

Adverse events

Five patients experienced adverse events during the first phase, four of which were associated with rechargeable battery replacement. One experienced akathisia, another experienced behavioral changes, and a third experienced electrical disturbances.

A fourth patient experienced postsurgical hemorrhage of the right internal capsule on day 4, followed by encephalitis at week 8. He had a clinical improvement but experienced relapsed during follow-up.

The fifth patient accidentally switched off the device and withdrew from the study.

During the first randomization phase, DBS was associated with significant improvements on total, positive, and negative PANSS scores in comparison with the postoperative baseline measure in the seven remaining patients (P < .001).

When the team compared the baseline measure with the last observation, the improvement in PANSS scores remained significant for total scores (P = .007) and positive scores (P = .002), but not for negative scores (P = .18).

Three patients entered the second crossover phase of the study. Two began in the off-treatment arm and experienced relapsed within 1 and 2 weeks, respectively. Total PANSS scores increased from 79 to 98 for the first patient and from 47 to 93 for the second patient.

Neuroimaging showed that, among patients who responded to DBS, brain metabolism increased in some brain areas and decreased in others. Dr. Corripio said this suggests a “rebalancing” of neural circuits.

As of July 2020, one of three patients with an electrode placed in the NAcc had experienced remission of positive symptoms and now has predominant negative symptoms. Another experienced significant improvements in negative symptoms. Two patients currently require psychosocial rehabilitation.

Patients for whom an electrode was placed in the ACC required higher voltages and more time to achieve an effect in comparison with those for whom an electrode was placed in the NAcc. Two patients required bilateral stimulation.

However, for all three patients who remained in the study, their clozapine dose was reduced.

Dr. Corripio reported that the team has observed negative thoughts and obsessive symptoms in patients with electrodes in the ACC, and all have needed either psychosocial rehabilitation or cognitive-behavioral therapy.

The investigators are now planning another DBS study involving patients with TRS, although this one will include a clinical recovery program focusing on family interventions and cognitive-behavioral therapy.
 

“Last-resort” treatment

In the postpresentation debate, Damiaan Denys, PhD, professor and chair of the department of psychiatry at the Academic Medical Canter, University of Amsterdam, said that DBS remains a treatment of “last resort” in TRS.

This is because it is both costly and invasive, and although the associated risk of bleeding and infection is low, he noted that the consequences are significant.

Dr. Denys added that patients need to have the potential for improvement; electrodes can be easily implanted, and the approach may tempt clinicians who sometimes “struggle with a huge amount of treatment-refractory cases.”

He also pointed to results achieved in studies of obsessive-compulsive disorder and depression, in which around 50% of patients responded to DBS.

“I think that’s the reason why we should be reluctant and not treat anyone at any stage, but first look for the more severe cases,” Dr. Denys said.
 

 

Unmet need

Judith M. Gault, PhD, associate research professor of neurosurgery at the University of Colorado at Denver, Aurora, also took part in the debate.

She said in an interview that patients with TRS have a lot of unmet needs and that DBS is worth trying in this patient population, with the goal being to “conduct a really good clinical trial” similar to the current study.

Antipsychotic drugs work well in responsive patients, but “in some cases the person is treatment refractory ... and in other cases the patient relapses,” Dr. Gault said.

She believes that DBS has the “potential to be more potent than antipsychotics in modulating the circuit of interest” and so fulfills the unmet needs of these patients while alleviating their symptoms.

Dr. Gault added that some patients experience “breakthrough symptoms” even while they are medication adherent. “That is a call for an intervention that is more potent” and suggests another potential role for DBS.

Overall, there are “a lot of really compelling reasons to pursue” DBS. However, there are also questions about how motivated patients with TRS are to participate in a clinical trial, Dr. Gault noted.

Patients with schizophrenia “tend not to be very motivated, especially if they have negative symptoms.” However, “if you were able to consider more of the population and not just the most severely affected, eventually you would find more people who are interested,” she said.

Still, it will take a better understanding of the efficacy and safety of the intervention for more people to be interested in trying it, said Dr. Gault.

“I think it’s hard early on, when you don’t actually know what the outcomes would be, if it’s even effective at all. But as you get more and more data in the population and at the different targets, people would be more open to it,” she said.

Another issue in generating interest among patients with schizophrenia is that many have not considered DBS as an option.

“It takes a while to think about it,” she noted. “You don’t want to rush into something that you just heard about, and so part of it is just education.”

The study was funded by Instituto Carlos III. Dr. Corripio reported having received research grants and conducting consultancy for Otsuka, Ferrer, Janssen, and Lilly. No other relevant financial relationships were reported.

A version of this article originally appeared on Medscape.com.

Deep brain stimulation (DBS) may be an effective option for patients with treatment-resistant schizophrenia (TRS), new research suggests. However, until further studies are conducted, the treatment should only be considered for the most severe cases.

ipopba/Getty Images

The first clinical trial to assess DBS in this challenging patient population included eight patients initially randomly assigned to receive electrode placement in one of two locations in the brain. Once a clinical response was achieved and participants were stabilized, they were randomly assigned to a second crossover phase.

Preliminary findings from the first phase of the DBS-SCHIZO pilot study, which were reported in 2017, showed promising efficacy.

The newly released final results revealed an association between DBS and significant improvements in Positive and Negative Symptoms Scale (PANSS) scores, as well as reductions in doses of antipsychotic medication. Moreover, the effect reversed when the electrode was switched off.

“DBS may be a potential option for severe treatment-resistant schizophrenia patients,” lead investigator Iluminada Corripio, MD, PhD, department of psychiatry, Hospital de la Santa Creu i Sant Pau, Barcelona, said during her presentation at the virtual congress of the European College of Neuropsychopharmacology. The new data were updated results of a study published in EBioMedicine earlier this year.

Dr. Corripio underlined that it is important to balance the risks and benefits of the intervention. DBS is “not useful for all phenotypes,” and benefits have been seen in patients with hallucinations but not in those with a disorganized phenotype, she added.
 

High economic burden

Managing TRS is challenging and is associated with a high clinical and economic burden, Corripio noted. Relapse rates can reach 80%, increasing resource use by between 200% and 900%.

There is a strong rationale for studying the use of DBS in schizophrenia, because schizophrenia shares a neurologic basis with other neurologic and psychiatric disorders centered around the cortical-striatal-thalamic-cortical circuit, said Dr. Corripio.

The study included eight patients with a DSM-IV-TR diagnosis of schizophrenia whose conditions were resistant to at least two different atypical antipsychotics and who had not responded to clozapine monotherapy, combination therapy, or electroconvulsive therapy.

All were randomly assigned in a 1:1 ratio to DBS electrode implantation in one of two locations. Investigators chose the nucleus accumbens (NAcc), because recent studies have shown that DBS can increase dopamine levels there, and the subgenual anterior cingulate cortex (ACC). Deactivation failure in the ACC region has been observed in patients with schizophrenia and other mental illnesses.

Stimulation began 48-72 hours postoperatively with unilateral left stimulation at 2.5 volts. It was increased in 0.5 volt increments to a maximum of 7.5 volts. Patients who did not respond were switched to bilateral stimulation.

Follow-up was conducted every 2 weeks for up to 20 months. The study’s primary outcome was a symptomatic response, defined as an improvement of at least 25% on the PANSS.

Once that was achieved, patients could enter a second randomization phase in which they were assigned, in a 24-week, double-blind crossover design, to on- or off-treatment DBS arms such that patients received stimulation for 12 weeks before the device was turned off for 12 weeks, or vice versa.

Those who experienced relapse while off treatment were crossed over to the on-treatment arm; those who experienced relapsed while on treatment were withdrawn from the study. The patients’ average age was 42.5 years, and 50% were women. All were taking clozapine in combination with another antipsychotic.
 

 

Adverse events

Five patients experienced adverse events during the first phase, four of which were associated with rechargeable battery replacement. One experienced akathisia, another experienced behavioral changes, and a third experienced electrical disturbances.

A fourth patient experienced postsurgical hemorrhage of the right internal capsule on day 4, followed by encephalitis at week 8. He had a clinical improvement but experienced relapsed during follow-up.

The fifth patient accidentally switched off the device and withdrew from the study.

During the first randomization phase, DBS was associated with significant improvements on total, positive, and negative PANSS scores in comparison with the postoperative baseline measure in the seven remaining patients (P < .001).

When the team compared the baseline measure with the last observation, the improvement in PANSS scores remained significant for total scores (P = .007) and positive scores (P = .002), but not for negative scores (P = .18).

Three patients entered the second crossover phase of the study. Two began in the off-treatment arm and experienced relapsed within 1 and 2 weeks, respectively. Total PANSS scores increased from 79 to 98 for the first patient and from 47 to 93 for the second patient.

Neuroimaging showed that, among patients who responded to DBS, brain metabolism increased in some brain areas and decreased in others. Dr. Corripio said this suggests a “rebalancing” of neural circuits.

As of July 2020, one of three patients with an electrode placed in the NAcc had experienced remission of positive symptoms and now has predominant negative symptoms. Another experienced significant improvements in negative symptoms. Two patients currently require psychosocial rehabilitation.

Patients for whom an electrode was placed in the ACC required higher voltages and more time to achieve an effect in comparison with those for whom an electrode was placed in the NAcc. Two patients required bilateral stimulation.

However, for all three patients who remained in the study, their clozapine dose was reduced.

Dr. Corripio reported that the team has observed negative thoughts and obsessive symptoms in patients with electrodes in the ACC, and all have needed either psychosocial rehabilitation or cognitive-behavioral therapy.

The investigators are now planning another DBS study involving patients with TRS, although this one will include a clinical recovery program focusing on family interventions and cognitive-behavioral therapy.
 

“Last-resort” treatment

In the postpresentation debate, Damiaan Denys, PhD, professor and chair of the department of psychiatry at the Academic Medical Canter, University of Amsterdam, said that DBS remains a treatment of “last resort” in TRS.

This is because it is both costly and invasive, and although the associated risk of bleeding and infection is low, he noted that the consequences are significant.

Dr. Denys added that patients need to have the potential for improvement; electrodes can be easily implanted, and the approach may tempt clinicians who sometimes “struggle with a huge amount of treatment-refractory cases.”

He also pointed to results achieved in studies of obsessive-compulsive disorder and depression, in which around 50% of patients responded to DBS.

“I think that’s the reason why we should be reluctant and not treat anyone at any stage, but first look for the more severe cases,” Dr. Denys said.
 

 

Unmet need

Judith M. Gault, PhD, associate research professor of neurosurgery at the University of Colorado at Denver, Aurora, also took part in the debate.

She said in an interview that patients with TRS have a lot of unmet needs and that DBS is worth trying in this patient population, with the goal being to “conduct a really good clinical trial” similar to the current study.

Antipsychotic drugs work well in responsive patients, but “in some cases the person is treatment refractory ... and in other cases the patient relapses,” Dr. Gault said.

She believes that DBS has the “potential to be more potent than antipsychotics in modulating the circuit of interest” and so fulfills the unmet needs of these patients while alleviating their symptoms.

Dr. Gault added that some patients experience “breakthrough symptoms” even while they are medication adherent. “That is a call for an intervention that is more potent” and suggests another potential role for DBS.

Overall, there are “a lot of really compelling reasons to pursue” DBS. However, there are also questions about how motivated patients with TRS are to participate in a clinical trial, Dr. Gault noted.

Patients with schizophrenia “tend not to be very motivated, especially if they have negative symptoms.” However, “if you were able to consider more of the population and not just the most severely affected, eventually you would find more people who are interested,” she said.

Still, it will take a better understanding of the efficacy and safety of the intervention for more people to be interested in trying it, said Dr. Gault.

“I think it’s hard early on, when you don’t actually know what the outcomes would be, if it’s even effective at all. But as you get more and more data in the population and at the different targets, people would be more open to it,” she said.

Another issue in generating interest among patients with schizophrenia is that many have not considered DBS as an option.

“It takes a while to think about it,” she noted. “You don’t want to rush into something that you just heard about, and so part of it is just education.”

The study was funded by Instituto Carlos III. Dr. Corripio reported having received research grants and conducting consultancy for Otsuka, Ferrer, Janssen, and Lilly. No other relevant financial relationships were reported.

A version of this article originally appeared on Medscape.com.

Deep brain stimulation (DBS) may be an effective option for patients with treatment-resistant schizophrenia (TRS), new research suggests. However, until further studies are conducted, the treatment should only be considered for the most severe cases.

ipopba/Getty Images

The first clinical trial to assess DBS in this challenging patient population included eight patients initially randomly assigned to receive electrode placement in one of two locations in the brain. Once a clinical response was achieved and participants were stabilized, they were randomly assigned to a second crossover phase.

Preliminary findings from the first phase of the DBS-SCHIZO pilot study, which were reported in 2017, showed promising efficacy.

The newly released final results revealed an association between DBS and significant improvements in Positive and Negative Symptoms Scale (PANSS) scores, as well as reductions in doses of antipsychotic medication. Moreover, the effect reversed when the electrode was switched off.

“DBS may be a potential option for severe treatment-resistant schizophrenia patients,” lead investigator Iluminada Corripio, MD, PhD, department of psychiatry, Hospital de la Santa Creu i Sant Pau, Barcelona, said during her presentation at the virtual congress of the European College of Neuropsychopharmacology. The new data were updated results of a study published in EBioMedicine earlier this year.

Dr. Corripio underlined that it is important to balance the risks and benefits of the intervention. DBS is “not useful for all phenotypes,” and benefits have been seen in patients with hallucinations but not in those with a disorganized phenotype, she added.
 

High economic burden

Managing TRS is challenging and is associated with a high clinical and economic burden, Corripio noted. Relapse rates can reach 80%, increasing resource use by between 200% and 900%.

There is a strong rationale for studying the use of DBS in schizophrenia, because schizophrenia shares a neurologic basis with other neurologic and psychiatric disorders centered around the cortical-striatal-thalamic-cortical circuit, said Dr. Corripio.

The study included eight patients with a DSM-IV-TR diagnosis of schizophrenia whose conditions were resistant to at least two different atypical antipsychotics and who had not responded to clozapine monotherapy, combination therapy, or electroconvulsive therapy.

All were randomly assigned in a 1:1 ratio to DBS electrode implantation in one of two locations. Investigators chose the nucleus accumbens (NAcc), because recent studies have shown that DBS can increase dopamine levels there, and the subgenual anterior cingulate cortex (ACC). Deactivation failure in the ACC region has been observed in patients with schizophrenia and other mental illnesses.

Stimulation began 48-72 hours postoperatively with unilateral left stimulation at 2.5 volts. It was increased in 0.5 volt increments to a maximum of 7.5 volts. Patients who did not respond were switched to bilateral stimulation.

Follow-up was conducted every 2 weeks for up to 20 months. The study’s primary outcome was a symptomatic response, defined as an improvement of at least 25% on the PANSS.

Once that was achieved, patients could enter a second randomization phase in which they were assigned, in a 24-week, double-blind crossover design, to on- or off-treatment DBS arms such that patients received stimulation for 12 weeks before the device was turned off for 12 weeks, or vice versa.

Those who experienced relapse while off treatment were crossed over to the on-treatment arm; those who experienced relapsed while on treatment were withdrawn from the study. The patients’ average age was 42.5 years, and 50% were women. All were taking clozapine in combination with another antipsychotic.
 

 

Adverse events

Five patients experienced adverse events during the first phase, four of which were associated with rechargeable battery replacement. One experienced akathisia, another experienced behavioral changes, and a third experienced electrical disturbances.

A fourth patient experienced postsurgical hemorrhage of the right internal capsule on day 4, followed by encephalitis at week 8. He had a clinical improvement but experienced relapsed during follow-up.

The fifth patient accidentally switched off the device and withdrew from the study.

During the first randomization phase, DBS was associated with significant improvements on total, positive, and negative PANSS scores in comparison with the postoperative baseline measure in the seven remaining patients (P < .001).

When the team compared the baseline measure with the last observation, the improvement in PANSS scores remained significant for total scores (P = .007) and positive scores (P = .002), but not for negative scores (P = .18).

Three patients entered the second crossover phase of the study. Two began in the off-treatment arm and experienced relapsed within 1 and 2 weeks, respectively. Total PANSS scores increased from 79 to 98 for the first patient and from 47 to 93 for the second patient.

Neuroimaging showed that, among patients who responded to DBS, brain metabolism increased in some brain areas and decreased in others. Dr. Corripio said this suggests a “rebalancing” of neural circuits.

As of July 2020, one of three patients with an electrode placed in the NAcc had experienced remission of positive symptoms and now has predominant negative symptoms. Another experienced significant improvements in negative symptoms. Two patients currently require psychosocial rehabilitation.

Patients for whom an electrode was placed in the ACC required higher voltages and more time to achieve an effect in comparison with those for whom an electrode was placed in the NAcc. Two patients required bilateral stimulation.

However, for all three patients who remained in the study, their clozapine dose was reduced.

Dr. Corripio reported that the team has observed negative thoughts and obsessive symptoms in patients with electrodes in the ACC, and all have needed either psychosocial rehabilitation or cognitive-behavioral therapy.

The investigators are now planning another DBS study involving patients with TRS, although this one will include a clinical recovery program focusing on family interventions and cognitive-behavioral therapy.
 

“Last-resort” treatment

In the postpresentation debate, Damiaan Denys, PhD, professor and chair of the department of psychiatry at the Academic Medical Canter, University of Amsterdam, said that DBS remains a treatment of “last resort” in TRS.

This is because it is both costly and invasive, and although the associated risk of bleeding and infection is low, he noted that the consequences are significant.

Dr. Denys added that patients need to have the potential for improvement; electrodes can be easily implanted, and the approach may tempt clinicians who sometimes “struggle with a huge amount of treatment-refractory cases.”

He also pointed to results achieved in studies of obsessive-compulsive disorder and depression, in which around 50% of patients responded to DBS.

“I think that’s the reason why we should be reluctant and not treat anyone at any stage, but first look for the more severe cases,” Dr. Denys said.
 

 

Unmet need

Judith M. Gault, PhD, associate research professor of neurosurgery at the University of Colorado at Denver, Aurora, also took part in the debate.

She said in an interview that patients with TRS have a lot of unmet needs and that DBS is worth trying in this patient population, with the goal being to “conduct a really good clinical trial” similar to the current study.

Antipsychotic drugs work well in responsive patients, but “in some cases the person is treatment refractory ... and in other cases the patient relapses,” Dr. Gault said.

She believes that DBS has the “potential to be more potent than antipsychotics in modulating the circuit of interest” and so fulfills the unmet needs of these patients while alleviating their symptoms.

Dr. Gault added that some patients experience “breakthrough symptoms” even while they are medication adherent. “That is a call for an intervention that is more potent” and suggests another potential role for DBS.

Overall, there are “a lot of really compelling reasons to pursue” DBS. However, there are also questions about how motivated patients with TRS are to participate in a clinical trial, Dr. Gault noted.

Patients with schizophrenia “tend not to be very motivated, especially if they have negative symptoms.” However, “if you were able to consider more of the population and not just the most severely affected, eventually you would find more people who are interested,” she said.

Still, it will take a better understanding of the efficacy and safety of the intervention for more people to be interested in trying it, said Dr. Gault.

“I think it’s hard early on, when you don’t actually know what the outcomes would be, if it’s even effective at all. But as you get more and more data in the population and at the different targets, people would be more open to it,” she said.

Another issue in generating interest among patients with schizophrenia is that many have not considered DBS as an option.

“It takes a while to think about it,” she noted. “You don’t want to rush into something that you just heard about, and so part of it is just education.”

The study was funded by Instituto Carlos III. Dr. Corripio reported having received research grants and conducting consultancy for Otsuka, Ferrer, Janssen, and Lilly. No other relevant financial relationships were reported.

A version of this article originally appeared on Medscape.com.

A psychiatric diagnosis for patients hospitalized with COVID-19 is linked to a significantly increased risk for death, new research shows.

Investigators found that patients who were hospitalized with COVID-19 and who had been diagnosed with a psychiatric disorder had a 50% increased risk for a COVID-related death in comparison with COVID-19 patients who had not received a psychiatric diagnosis.

“Pay attention and potentially address/treat a prior psychiatric diagnosis if a patient is hospitalized for COVID-19, as this risk factor can impact the patient’s outcome – death – while in the hospital,” lead investigator Luming Li, MD, assistant professor of psychiatry and associate medical director of quality improvement, Yale New Haven Psychiatric Hospital, New Haven, Conn., said in an interview.

The study was published Sept. 30 in JAMA Network Open.
 

Negative impact

“We were interested to learn more about the impact of psychiatric diagnoses on COVID-19 mortality, as prior large cohort studies included neurological and other medical conditions but did not assess for a priori psychiatric diagnoses,” said Dr. Li.

“We know from the literature that prior psychiatric diagnoses can have a negative impact on the outcomes of medical conditions, and therefore we tested our hypothesis on a cohort of patients who were hospitalized with COVID-19,” she added.

To investigate, the researchers analyzed data on 1,685 patients hospitalized with COVID-19 between Feb. 15 and April 25, 2020, and whose cases were followed to May 27, 2020. The patients (mean age, 65.2 years; 52.6% men) were drawn from the Yale New Haven Health System.

The median follow-up period was 8 days (interquartile range, 4-16 days) .

Of these patients, 28% had received a psychiatric diagnosis prior to hospitalization. The patients with psychiatric disorders were significantly older and were more likely to be women, White, non-Hispanic, and to have medical comorbidities (i.e., cancer, cerebrovascular disease, heart failure, diabetes, kidney disease, liver disease, MI, and/or HIV).

Psychiatric diagnoses were defined in accordance with ICD codes that included mental and behavioral health, Alzheimer’s disease, and self-injury.
 

Vulnerability to stress

In the unadjusted model, the risk for COVID-19–related hospital death was greater for those who had received any psychiatric diagnosis, compared with those had not (hazard ratio, 2.3; 95% CI, 1.8-2.9; P < .001).

In the adjusted model that controlled for demographic characteristics, other medical comorbidities, and hospital location, the mortality risk somewhat decreased but still remained significantly higher (HR, 1.5; 95% CI, 1.1-1.9; P = .003).

Dr. Li noted a number of factors that might account for the higher mortality rate among psychiatric patients who had COVID-19 in comparison with COVD-19 patients who did not have a psychiatric disorder. These included “potential inflammatory and stress responses that the body experiences related to prior psychiatric conditions,” she said.

Having been previously diagnosed with a psychiatric disorder may also “reflect existing neurochemical differences, compared to those who do not have a prior psychiatric diagnosis, [and] these differences may make the population with the prior psychiatric diagnosis more vulnerable to respond to an acute stressor such as COVID-19,” she said.
 

 

Quality care

Harold Pincus, MD, professor and vice chair of the department of psychiatry at Columbia University, New York, said it “adds to the fairly well-known and well-established phenomenon that people with mental illnesses have a high risk of all sorts of morbidity and mortality for non–mental health conditions.”

The researchers “adjusted for various expected [mortality] risks that would be independent of the presence of COVID-19,” so “there was something else going on associated with mortality,” said Dr. Pincus, who is also codirector of the Irving Institute for Clinical and Translation Research. He was not involved with the study.

Beyond the possibility of “some basic immunologic process affected by the presence of a mental disorder,” it is possible that the vulnerability is “related to access to quality care for the comorbid general condition that is not being effectively treated,” he said.

“The take-home message is that people with mental disorders are at higher risk for death, and we need to make sure that, irrespective of COVID-19, they get adequate preventive and chronic-disease care, which would be the most effective way to intervene and protect the impact of a serious disease like COVID-19,” he noted. This would include being appropriately vaccinated and receiving preventive healthcare to reduce smoking and encourage weight loss.

No source of funding for the study was provided. Dr. Li reported receiving grants from a Health and Aging Policy Fellowship during the conduct of the study. Dr. Pincus reported no relevant financial relationships.

A psychiatric diagnosis for patients hospitalized with COVID-19 is linked to a significantly increased risk for death, new research shows.

Investigators found that patients who were hospitalized with COVID-19 and who had been diagnosed with a psychiatric disorder had a 50% increased risk for a COVID-related death in comparison with COVID-19 patients who had not received a psychiatric diagnosis.

“Pay attention and potentially address/treat a prior psychiatric diagnosis if a patient is hospitalized for COVID-19, as this risk factor can impact the patient’s outcome – death – while in the hospital,” lead investigator Luming Li, MD, assistant professor of psychiatry and associate medical director of quality improvement, Yale New Haven Psychiatric Hospital, New Haven, Conn., said in an interview.

The study was published Sept. 30 in JAMA Network Open.
 

Negative impact

“We were interested to learn more about the impact of psychiatric diagnoses on COVID-19 mortality, as prior large cohort studies included neurological and other medical conditions but did not assess for a priori psychiatric diagnoses,” said Dr. Li.

“We know from the literature that prior psychiatric diagnoses can have a negative impact on the outcomes of medical conditions, and therefore we tested our hypothesis on a cohort of patients who were hospitalized with COVID-19,” she added.

To investigate, the researchers analyzed data on 1,685 patients hospitalized with COVID-19 between Feb. 15 and April 25, 2020, and whose cases were followed to May 27, 2020. The patients (mean age, 65.2 years; 52.6% men) were drawn from the Yale New Haven Health System.

The median follow-up period was 8 days (interquartile range, 4-16 days) .

Of these patients, 28% had received a psychiatric diagnosis prior to hospitalization. The patients with psychiatric disorders were significantly older and were more likely to be women, White, non-Hispanic, and to have medical comorbidities (i.e., cancer, cerebrovascular disease, heart failure, diabetes, kidney disease, liver disease, MI, and/or HIV).

Psychiatric diagnoses were defined in accordance with ICD codes that included mental and behavioral health, Alzheimer’s disease, and self-injury.
 

Vulnerability to stress

In the unadjusted model, the risk for COVID-19–related hospital death was greater for those who had received any psychiatric diagnosis, compared with those had not (hazard ratio, 2.3; 95% CI, 1.8-2.9; P < .001).

In the adjusted model that controlled for demographic characteristics, other medical comorbidities, and hospital location, the mortality risk somewhat decreased but still remained significantly higher (HR, 1.5; 95% CI, 1.1-1.9; P = .003).

Dr. Li noted a number of factors that might account for the higher mortality rate among psychiatric patients who had COVID-19 in comparison with COVD-19 patients who did not have a psychiatric disorder. These included “potential inflammatory and stress responses that the body experiences related to prior psychiatric conditions,” she said.

Having been previously diagnosed with a psychiatric disorder may also “reflect existing neurochemical differences, compared to those who do not have a prior psychiatric diagnosis, [and] these differences may make the population with the prior psychiatric diagnosis more vulnerable to respond to an acute stressor such as COVID-19,” she said.
 

 

Quality care

Harold Pincus, MD, professor and vice chair of the department of psychiatry at Columbia University, New York, said it “adds to the fairly well-known and well-established phenomenon that people with mental illnesses have a high risk of all sorts of morbidity and mortality for non–mental health conditions.”

The researchers “adjusted for various expected [mortality] risks that would be independent of the presence of COVID-19,” so “there was something else going on associated with mortality,” said Dr. Pincus, who is also codirector of the Irving Institute for Clinical and Translation Research. He was not involved with the study.

Beyond the possibility of “some basic immunologic process affected by the presence of a mental disorder,” it is possible that the vulnerability is “related to access to quality care for the comorbid general condition that is not being effectively treated,” he said.

“The take-home message is that people with mental disorders are at higher risk for death, and we need to make sure that, irrespective of COVID-19, they get adequate preventive and chronic-disease care, which would be the most effective way to intervene and protect the impact of a serious disease like COVID-19,” he noted. This would include being appropriately vaccinated and receiving preventive healthcare to reduce smoking and encourage weight loss.

No source of funding for the study was provided. Dr. Li reported receiving grants from a Health and Aging Policy Fellowship during the conduct of the study. Dr. Pincus reported no relevant financial relationships.

A psychiatric diagnosis for patients hospitalized with COVID-19 is linked to a significantly increased risk for death, new research shows.

Investigators found that patients who were hospitalized with COVID-19 and who had been diagnosed with a psychiatric disorder had a 50% increased risk for a COVID-related death in comparison with COVID-19 patients who had not received a psychiatric diagnosis.

“Pay attention and potentially address/treat a prior psychiatric diagnosis if a patient is hospitalized for COVID-19, as this risk factor can impact the patient’s outcome – death – while in the hospital,” lead investigator Luming Li, MD, assistant professor of psychiatry and associate medical director of quality improvement, Yale New Haven Psychiatric Hospital, New Haven, Conn., said in an interview.

The study was published Sept. 30 in JAMA Network Open.
 

Negative impact

“We were interested to learn more about the impact of psychiatric diagnoses on COVID-19 mortality, as prior large cohort studies included neurological and other medical conditions but did not assess for a priori psychiatric diagnoses,” said Dr. Li.

“We know from the literature that prior psychiatric diagnoses can have a negative impact on the outcomes of medical conditions, and therefore we tested our hypothesis on a cohort of patients who were hospitalized with COVID-19,” she added.

To investigate, the researchers analyzed data on 1,685 patients hospitalized with COVID-19 between Feb. 15 and April 25, 2020, and whose cases were followed to May 27, 2020. The patients (mean age, 65.2 years; 52.6% men) were drawn from the Yale New Haven Health System.

The median follow-up period was 8 days (interquartile range, 4-16 days) .

Of these patients, 28% had received a psychiatric diagnosis prior to hospitalization. The patients with psychiatric disorders were significantly older and were more likely to be women, White, non-Hispanic, and to have medical comorbidities (i.e., cancer, cerebrovascular disease, heart failure, diabetes, kidney disease, liver disease, MI, and/or HIV).

Psychiatric diagnoses were defined in accordance with ICD codes that included mental and behavioral health, Alzheimer’s disease, and self-injury.
 

Vulnerability to stress

In the unadjusted model, the risk for COVID-19–related hospital death was greater for those who had received any psychiatric diagnosis, compared with those had not (hazard ratio, 2.3; 95% CI, 1.8-2.9; P < .001).

In the adjusted model that controlled for demographic characteristics, other medical comorbidities, and hospital location, the mortality risk somewhat decreased but still remained significantly higher (HR, 1.5; 95% CI, 1.1-1.9; P = .003).

Dr. Li noted a number of factors that might account for the higher mortality rate among psychiatric patients who had COVID-19 in comparison with COVD-19 patients who did not have a psychiatric disorder. These included “potential inflammatory and stress responses that the body experiences related to prior psychiatric conditions,” she said.

Having been previously diagnosed with a psychiatric disorder may also “reflect existing neurochemical differences, compared to those who do not have a prior psychiatric diagnosis, [and] these differences may make the population with the prior psychiatric diagnosis more vulnerable to respond to an acute stressor such as COVID-19,” she said.
 

 

Quality care

Harold Pincus, MD, professor and vice chair of the department of psychiatry at Columbia University, New York, said it “adds to the fairly well-known and well-established phenomenon that people with mental illnesses have a high risk of all sorts of morbidity and mortality for non–mental health conditions.”

The researchers “adjusted for various expected [mortality] risks that would be independent of the presence of COVID-19,” so “there was something else going on associated with mortality,” said Dr. Pincus, who is also codirector of the Irving Institute for Clinical and Translation Research. He was not involved with the study.

Beyond the possibility of “some basic immunologic process affected by the presence of a mental disorder,” it is possible that the vulnerability is “related to access to quality care for the comorbid general condition that is not being effectively treated,” he said.

“The take-home message is that people with mental disorders are at higher risk for death, and we need to make sure that, irrespective of COVID-19, they get adequate preventive and chronic-disease care, which would be the most effective way to intervene and protect the impact of a serious disease like COVID-19,” he noted. This would include being appropriately vaccinated and receiving preventive healthcare to reduce smoking and encourage weight loss.

No source of funding for the study was provided. Dr. Li reported receiving grants from a Health and Aging Policy Fellowship during the conduct of the study. Dr. Pincus reported no relevant financial relationships.

The negative symptoms of schizophrenia have been recognized for 100 years. Characterized by a loss of a function that should be present, negative symptoms include anhedonia, asociality, amotivation, and affective blunting. Individuals with schizophrenia who have a preponderance of negative symptoms (“deficit syndrome”) may comprise a special subset of patients. Compared with positive symptoms, negative symptoms are associated with worse global functioning and worse response to antipsychotic medication. Treatment of negative symptoms is challenging. Secondary negative symptoms—those that simulate or resemble primary negative symptoms but are attributable to another cause, such as major depressive disorder or the adverse effects of antipsychotic medication—need to be ruled out. Emerging evidence suggests that newer antipsychotics with novel mechanisms might be effective in treating negative symptoms. Antidepressants might also play a role.

This article describes types of negative symptoms, their clinical relevance, neuroanatomical and neurotransmission factors associated with negative symptoms, and current and future treatment options.

Modest improvements with antipsychotics

Schizophrenia affects an estimated 1% of the population.¹ Antipsychotic medication has been the mainstay of schizophrenia treatment since chlorpromazine was introduced in the 1950s; it was soon followed by many other antipsychotics. These first-generation antipsychotics (FGAs) were joined by second-generation antipsychotics (SGAs) in the 1990s. While SGAs are better tolerated and less likely to induce extrapyramidal side effects (EPS) than FGAs, they also are associated with troubling metabolic adverse effects (eg, impaired glucose tolerance).¹

All antipsychotics are believed to exert their therapeutic effects by blocking dopamine (D2) receptors and are effective in ameliorating the positive symptoms of schizophrenia, including hallucinations, delusions, bizarre behavior, disordered thinking, and agitation.¹ Early research had suggested that SGAs might also reduce the negative symptoms of schizophrenia, perhaps because they also block serotonin 2A receptors, a property thought to broaden their therapeutic profile. Over time, it became clear that neither FGAs nor SGAs conferred an advantage in treating negative symptoms, and that the observed improvements were modest.^2-5 However, recent research suggests that several newer antipsychotics might be effective in targeting negative symptoms.^2,6,7

History of negative symptoms

In the early 20th century, Swiss psychiatrist Eugen Bleuler coined the term schizophrenia to emphasize the cognitive impairment that occurs in patients with this illness, and which he conceptualized as a fragmenting of the psychic process.⁸ He believed that certain symptoms were fundamental to the illness, and described affective blunting, disturbance of association (ie, distorted thinking) autism (ie, impaired relationships), and ambivalence (ie, fragmented emotional responses). He viewed hallucinations and delusions as accessory symptoms because they were not unique to schizophrenia but were also found in other disorders (eg, mood disorders). Bleuler’s ideas took root, and generations of psychiatrists were taught his fundamental symptoms (“the 4 A’s”), the forerunner of today’s negative symptoms. Later, other experts chose to emphasize psychotic symptoms as most characteristic of schizophrenia, including Schneider’s “first-rank symptoms,” such as voices conversing or delusions of passivity.⁹

Negative symptoms were rediscovered in the 1970s and 1980s by psychiatric researchers interested in descriptive phenomenology.^10,11 Research confirmed the presence of a positive dimension in schizophrenia characterized by the loss of boundaries between the patient and the real world (eg, hallucinations, delusions), and a negative dimension characterized by the loss of a function that should be present, such as alogia and asociality. These experts carefully described negative symptoms and created scales to measure them, including the Scale for the Assessment of Negative Symptoms (SANS),¹² the Positive and Negative Syndrome Scale (PANSS),¹³ the Brief Negative Symptom Scale (BNSS),¹⁴ and the 16-item Negative Symptom Assessment (NSA-16).¹⁵ Contemporaneous to this work, a “deficit syndrome” was identified among patients with schizophrenia with prominent negative symptoms. The deficit syndrome is found in 25% to 30% of chronic cases.¹⁶ Negative symptoms are very common in patients with schizophrenia (Table 1⁹).^8,17

Early editions of the DSM defined schizophrenia mainly on the basis of disturbance of cognition, mood, and behavior, and a retreat from reality. With the publication of DSM-III in 1980, and in subsequent editions, schizophrenia was redefined as a relatively severe psychotic illness in which positive and negative symptoms were present, thereby acknowledging the importance of Bleuler’s fundamental symptoms. In DSM-5, negative symptoms are described as accounting for “a substantial portion of the morbidity associated with schizophrenia but are less prominent in other psychotic disorders.”¹⁸

Continue to: Types of negative symptoms

 

Types of negative symptoms

The following symptoms fall within the negative dimension¹⁹:

Alogia refers to the impoverished thinking and cognition that often occur in patients with schizophrenia. The patient’s thinking processes seem empty, turgid, or slow, as inferred from the patient’s speech. The 2 major manifestations of alogia are poverty of speech (nonfluent empty speech) and poverty of content of speech (fluent but empty speech). Examples of each appear in Table 2.¹⁹

Affective flattening or blunting manifests as a general impoverishment of emotional expression, reactivity, and feeling. Affective flattening can be assessed through observing a patient’s behavior and responsiveness during the interview.

Avolition-apathy manifests itself as a lack of energy and drive. Patients become inert and are unable to mobilize themselves to initiate or persist in completing many kinds of tasks.

Anhedonia-asociality encompasses the patient’s difficulties in experiencing interest or pleasure. It may express itself as a loss of interest in pleasurable activities, an inability to experience pleasure when participating in activities normally considered pleasurable, or a lack of involvement in social relationships.

Continue to: Attention

 

Attention is often poor in patients with severe mental illnesses. The patient may have trouble focusing his/her attention or may be able to focus only sporadically and erratically. He/she may ignore attempts to converse with him/her, wander away during an activity or a task, or appear to be inattentive when engaged in formal testing or interviewing.

Clinical relevance of negative symptoms

According to DSM-5, “Negative symptoms are more closely related to prognosis than are positive symptoms and tend to be the most persistent.”¹⁸ Research has shown that, compared with positive symptoms, negative symptoms are associated with greater impairment in overall functioning, social interaction, interpersonal relationships, economic functioning, and recreational activities.^1,3,5 Negative symptoms also are associated with poorer response to medication and a positive family history of schizophrenia. Research shows that negative symptoms are persistent over time, and, in fact, become more prominent as the patient ages, whereas positive symptoms become less prominent.²⁰

Secondary negative symptoms

Potential secondary causes of negative symptoms should be ruled out before concluding that the negative symptoms are due to schizophrenia.³ What might appear to be a negative symptom of schizophrenia, such as poor motivation or flattened affect, could be due to the presence of major depressive disorder. Such symptoms might resolve with treatment. Alternatively, a patient could have developed pseudoparkinsonism from antipsychotic medication and display unchanging facial expression and decreased spontaneous movements. These symptoms could resolve by adding benztropine or a similar medication to the treatment regimen. Other potential causes of secondary negative symptoms range from chronic substance abuse (eg, leading to poor grooming and hygiene), to paranoia and hallucinations, to sleep apnea inducing anergia and impersistence at work. Causes of secondary negative symptoms are outlined in Table 3.³

The neuroanatomy of negative symptoms

Although the neuroanatomical basis of negative symptoms has not been determined, neuroimaging studies have provided important clues.³ Structural brain imaging has consistently shown that negative symptoms in patients with schizophrenia correlate with decreased prefrontal white matter volume, anterior cingulate volume, insular cortex volume, left temporal cortex volume, and ventricular enlargement. Interestingly, volume loss starts before the appearance of negative symptoms.^21,22 Functional imaging has shown that negative symptoms correlate with reduced cerebral blood perfusion in frontal, prefrontal, posterior cingulate, thalamus, parietal, and striatal regions.^21,22 These findings may help explain the apathy, failure to initiate activities, and impaired social relatedness in patients with schizophrenia.

Neurotransmission and negative symptoms

Some experts have hypothesized that lowered cortical dopamine transmission in mesocortical pathways could give rise to negative symptoms, whereas excess transmission in subcortical structures leads to positive symptoms.²³ There is also evidence for a noradrenalin deficiency based on the finding that low levels of cerebrospinal fluid 3-methoxy-4-hydroxyphenylglycol (MHPG), a noradrenaline metabolite, correlates with greater negative symptom severity.²⁴ The presence of a serotonin deficiency has been proposed based on evidence that negative symptoms might be mitigated by serotonergic agents.²⁵ More recently, some experts have posited that the dopamine D3 receptor might be involved in the etiology of negative symptoms. The dopamine D3 receptor activity is expressed in brain regions thought to control reward, emotions, and motivation.² Newer medications with novel mechanisms suggest that other neuro­transmitter pathways could be involved.^6,7

Continue to: Treatment options

 

 

Treatment options

Treating negative symptoms remains challenging and there are no clear answers. When they were introduced in the 1990s, SGAs were initially thought to be superior to FGAs in targeting negative symptoms. Subsequent research, including recent reviews and meta-analyses, has shown that SGAs are not superior to FGAs in treating negative symptoms, and the effect of either medication class on negative symptoms is modest.^2-5 One exception is amisulpride (not available in the United States), which is known to antagonize D2 and D3 receptors. A meta-analysis of the efficacy of antipsychotics in schizophrenia showed that amisulpride was significantly more effective than placebo in treating negative symptoms in 590 patients who received the medication.²⁶ The authors suggested that amisulpride was effective due to its binding to presynaptic receptors in the frontal cortex, thereby enhancing dopamine transmission in this region.

Cariprazine, which acts as a partial agonist at the D2 and D3 receptors, with a 10-fold affinity for the D3 receptor, also has shown promise in treating negative symptoms.² In a clinical trial of 460 patients with predominant negative symptoms, treatment with cariprazine led to a greater reduction in negative symptoms than risperidone, although the effect size was small.²⁷ In this study, cariprazine produced greater improvement in personal and social performance than risperidone. Animal data supports the possible use of cariprazine in treating negative symptoms.²⁸

Other promising agentsinclude roluperidone (MIN-101), in phase 3 of development, and SEP-363856, an investigational antipsychotic agent that is in phase 2 of development. Interestingly, roluperidone acts on serotonin 2A and sigma2 receptors and does not target dopamine receptors, whereas SEP-363856 is thought to activate trace amine-associated receptor 1 (TAAR1) in addition to serotonin 1A receptors.^6,7

Antidepressants also could be effective in reducing negative symptoms.³ A meta-analysis of randomized controlled trials evaluating the use of antidepressants as adjuncts to antipsychotic medications showed that adding an antidepressant was effective in reducing negative symptoms.²⁹ The mechanism by which an antidepressant might cause a reduction in negative symptoms is uncertain, and it is possible that the antidepressant might treat depressive symptoms that are causing or contributing to the negative symptoms.

Bottom Line

Negative symptoms in patients with schizophrenia are associated with a worse functional outcome and poorer response to antipsychotic medication than positive symptoms. First- and second-generation antipsychotics are largely ineffective in consistently treating negative symptoms. Antipsychotic medications that target the D3 receptor might be more effective. Roluperidone, which targets serotonin 2A and sigma receptors, and SEP-363856, which targets TAAR1 and serotonin 1A receptors, are being studied for their effects on negative symptoms.

Continue to: Related Resources

 

 

Related Resources

• Galderisi S, Färden A, Kaiser S. Dissecting negative symptoms of schizophrenia: History, assessment, pathophysiological mechanisms and treatment. Schizophr Res. 2017;186:1-2.
• Rabinowitz J. Treating negative symptoms of schizophrenia. Current Psychiatry. 2018;17(12):19-23.

Drug Brand Names

Benztropine • Cogentin
Cariprazine • Vraylar
Chlorpromazine • Promapar, Thorazine
Risperidone • Risperdal

The negative symptoms of schizophrenia have been recognized for 100 years. Characterized by a loss of a function that should be present, negative symptoms include anhedonia, asociality, amotivation, and affective blunting. Individuals with schizophrenia who have a preponderance of negative symptoms (“deficit syndrome”) may comprise a special subset of patients. Compared with positive symptoms, negative symptoms are associated with worse global functioning and worse response to antipsychotic medication. Treatment of negative symptoms is challenging. Secondary negative symptoms—those that simulate or resemble primary negative symptoms but are attributable to another cause, such as major depressive disorder or the adverse effects of antipsychotic medication—need to be ruled out. Emerging evidence suggests that newer antipsychotics with novel mechanisms might be effective in treating negative symptoms. Antidepressants might also play a role.

This article describes types of negative symptoms, their clinical relevance, neuroanatomical and neurotransmission factors associated with negative symptoms, and current and future treatment options.

Modest improvements with antipsychotics

Schizophrenia affects an estimated 1% of the population.¹ Antipsychotic medication has been the mainstay of schizophrenia treatment since chlorpromazine was introduced in the 1950s; it was soon followed by many other antipsychotics. These first-generation antipsychotics (FGAs) were joined by second-generation antipsychotics (SGAs) in the 1990s. While SGAs are better tolerated and less likely to induce extrapyramidal side effects (EPS) than FGAs, they also are associated with troubling metabolic adverse effects (eg, impaired glucose tolerance).¹

All antipsychotics are believed to exert their therapeutic effects by blocking dopamine (D2) receptors and are effective in ameliorating the positive symptoms of schizophrenia, including hallucinations, delusions, bizarre behavior, disordered thinking, and agitation.¹ Early research had suggested that SGAs might also reduce the negative symptoms of schizophrenia, perhaps because they also block serotonin 2A receptors, a property thought to broaden their therapeutic profile. Over time, it became clear that neither FGAs nor SGAs conferred an advantage in treating negative symptoms, and that the observed improvements were modest.^2-5 However, recent research suggests that several newer antipsychotics might be effective in targeting negative symptoms.^2,6,7

History of negative symptoms

In the early 20th century, Swiss psychiatrist Eugen Bleuler coined the term schizophrenia to emphasize the cognitive impairment that occurs in patients with this illness, and which he conceptualized as a fragmenting of the psychic process.⁸ He believed that certain symptoms were fundamental to the illness, and described affective blunting, disturbance of association (ie, distorted thinking) autism (ie, impaired relationships), and ambivalence (ie, fragmented emotional responses). He viewed hallucinations and delusions as accessory symptoms because they were not unique to schizophrenia but were also found in other disorders (eg, mood disorders). Bleuler’s ideas took root, and generations of psychiatrists were taught his fundamental symptoms (“the 4 A’s”), the forerunner of today’s negative symptoms. Later, other experts chose to emphasize psychotic symptoms as most characteristic of schizophrenia, including Schneider’s “first-rank symptoms,” such as voices conversing or delusions of passivity.⁹

Negative symptoms were rediscovered in the 1970s and 1980s by psychiatric researchers interested in descriptive phenomenology.^10,11 Research confirmed the presence of a positive dimension in schizophrenia characterized by the loss of boundaries between the patient and the real world (eg, hallucinations, delusions), and a negative dimension characterized by the loss of a function that should be present, such as alogia and asociality. These experts carefully described negative symptoms and created scales to measure them, including the Scale for the Assessment of Negative Symptoms (SANS),¹² the Positive and Negative Syndrome Scale (PANSS),¹³ the Brief Negative Symptom Scale (BNSS),¹⁴ and the 16-item Negative Symptom Assessment (NSA-16).¹⁵ Contemporaneous to this work, a “deficit syndrome” was identified among patients with schizophrenia with prominent negative symptoms. The deficit syndrome is found in 25% to 30% of chronic cases.¹⁶ Negative symptoms are very common in patients with schizophrenia (Table 1⁹).^8,17

Early editions of the DSM defined schizophrenia mainly on the basis of disturbance of cognition, mood, and behavior, and a retreat from reality. With the publication of DSM-III in 1980, and in subsequent editions, schizophrenia was redefined as a relatively severe psychotic illness in which positive and negative symptoms were present, thereby acknowledging the importance of Bleuler’s fundamental symptoms. In DSM-5, negative symptoms are described as accounting for “a substantial portion of the morbidity associated with schizophrenia but are less prominent in other psychotic disorders.”¹⁸

Continue to: Types of negative symptoms

 

Types of negative symptoms

The following symptoms fall within the negative dimension¹⁹:

Alogia refers to the impoverished thinking and cognition that often occur in patients with schizophrenia. The patient’s thinking processes seem empty, turgid, or slow, as inferred from the patient’s speech. The 2 major manifestations of alogia are poverty of speech (nonfluent empty speech) and poverty of content of speech (fluent but empty speech). Examples of each appear in Table 2.¹⁹

Affective flattening or blunting manifests as a general impoverishment of emotional expression, reactivity, and feeling. Affective flattening can be assessed through observing a patient’s behavior and responsiveness during the interview.

Avolition-apathy manifests itself as a lack of energy and drive. Patients become inert and are unable to mobilize themselves to initiate or persist in completing many kinds of tasks.

Anhedonia-asociality encompasses the patient’s difficulties in experiencing interest or pleasure. It may express itself as a loss of interest in pleasurable activities, an inability to experience pleasure when participating in activities normally considered pleasurable, or a lack of involvement in social relationships.

Continue to: Attention

 

Attention is often poor in patients with severe mental illnesses. The patient may have trouble focusing his/her attention or may be able to focus only sporadically and erratically. He/she may ignore attempts to converse with him/her, wander away during an activity or a task, or appear to be inattentive when engaged in formal testing or interviewing.

Clinical relevance of negative symptoms

According to DSM-5, “Negative symptoms are more closely related to prognosis than are positive symptoms and tend to be the most persistent.”¹⁸ Research has shown that, compared with positive symptoms, negative symptoms are associated with greater impairment in overall functioning, social interaction, interpersonal relationships, economic functioning, and recreational activities.^1,3,5 Negative symptoms also are associated with poorer response to medication and a positive family history of schizophrenia. Research shows that negative symptoms are persistent over time, and, in fact, become more prominent as the patient ages, whereas positive symptoms become less prominent.²⁰

Secondary negative symptoms

Potential secondary causes of negative symptoms should be ruled out before concluding that the negative symptoms are due to schizophrenia.³ What might appear to be a negative symptom of schizophrenia, such as poor motivation or flattened affect, could be due to the presence of major depressive disorder. Such symptoms might resolve with treatment. Alternatively, a patient could have developed pseudoparkinsonism from antipsychotic medication and display unchanging facial expression and decreased spontaneous movements. These symptoms could resolve by adding benztropine or a similar medication to the treatment regimen. Other potential causes of secondary negative symptoms range from chronic substance abuse (eg, leading to poor grooming and hygiene), to paranoia and hallucinations, to sleep apnea inducing anergia and impersistence at work. Causes of secondary negative symptoms are outlined in Table 3.³

The neuroanatomy of negative symptoms

Although the neuroanatomical basis of negative symptoms has not been determined, neuroimaging studies have provided important clues.³ Structural brain imaging has consistently shown that negative symptoms in patients with schizophrenia correlate with decreased prefrontal white matter volume, anterior cingulate volume, insular cortex volume, left temporal cortex volume, and ventricular enlargement. Interestingly, volume loss starts before the appearance of negative symptoms.^21,22 Functional imaging has shown that negative symptoms correlate with reduced cerebral blood perfusion in frontal, prefrontal, posterior cingulate, thalamus, parietal, and striatal regions.^21,22 These findings may help explain the apathy, failure to initiate activities, and impaired social relatedness in patients with schizophrenia.

Neurotransmission and negative symptoms

Some experts have hypothesized that lowered cortical dopamine transmission in mesocortical pathways could give rise to negative symptoms, whereas excess transmission in subcortical structures leads to positive symptoms.²³ There is also evidence for a noradrenalin deficiency based on the finding that low levels of cerebrospinal fluid 3-methoxy-4-hydroxyphenylglycol (MHPG), a noradrenaline metabolite, correlates with greater negative symptom severity.²⁴ The presence of a serotonin deficiency has been proposed based on evidence that negative symptoms might be mitigated by serotonergic agents.²⁵ More recently, some experts have posited that the dopamine D3 receptor might be involved in the etiology of negative symptoms. The dopamine D3 receptor activity is expressed in brain regions thought to control reward, emotions, and motivation.² Newer medications with novel mechanisms suggest that other neuro­transmitter pathways could be involved.^6,7

Continue to: Treatment options

 

 

Treatment options

Treating negative symptoms remains challenging and there are no clear answers. When they were introduced in the 1990s, SGAs were initially thought to be superior to FGAs in targeting negative symptoms. Subsequent research, including recent reviews and meta-analyses, has shown that SGAs are not superior to FGAs in treating negative symptoms, and the effect of either medication class on negative symptoms is modest.^2-5 One exception is amisulpride (not available in the United States), which is known to antagonize D2 and D3 receptors. A meta-analysis of the efficacy of antipsychotics in schizophrenia showed that amisulpride was significantly more effective than placebo in treating negative symptoms in 590 patients who received the medication.²⁶ The authors suggested that amisulpride was effective due to its binding to presynaptic receptors in the frontal cortex, thereby enhancing dopamine transmission in this region.

Cariprazine, which acts as a partial agonist at the D2 and D3 receptors, with a 10-fold affinity for the D3 receptor, also has shown promise in treating negative symptoms.² In a clinical trial of 460 patients with predominant negative symptoms, treatment with cariprazine led to a greater reduction in negative symptoms than risperidone, although the effect size was small.²⁷ In this study, cariprazine produced greater improvement in personal and social performance than risperidone. Animal data supports the possible use of cariprazine in treating negative symptoms.²⁸

Other promising agentsinclude roluperidone (MIN-101), in phase 3 of development, and SEP-363856, an investigational antipsychotic agent that is in phase 2 of development. Interestingly, roluperidone acts on serotonin 2A and sigma2 receptors and does not target dopamine receptors, whereas SEP-363856 is thought to activate trace amine-associated receptor 1 (TAAR1) in addition to serotonin 1A receptors.^6,7

Antidepressants also could be effective in reducing negative symptoms.³ A meta-analysis of randomized controlled trials evaluating the use of antidepressants as adjuncts to antipsychotic medications showed that adding an antidepressant was effective in reducing negative symptoms.²⁹ The mechanism by which an antidepressant might cause a reduction in negative symptoms is uncertain, and it is possible that the antidepressant might treat depressive symptoms that are causing or contributing to the negative symptoms.

Bottom Line

Negative symptoms in patients with schizophrenia are associated with a worse functional outcome and poorer response to antipsychotic medication than positive symptoms. First- and second-generation antipsychotics are largely ineffective in consistently treating negative symptoms. Antipsychotic medications that target the D3 receptor might be more effective. Roluperidone, which targets serotonin 2A and sigma receptors, and SEP-363856, which targets TAAR1 and serotonin 1A receptors, are being studied for their effects on negative symptoms.

Continue to: Related Resources

 

 

Related Resources

• Galderisi S, Färden A, Kaiser S. Dissecting negative symptoms of schizophrenia: History, assessment, pathophysiological mechanisms and treatment. Schizophr Res. 2017;186:1-2.
• Rabinowitz J. Treating negative symptoms of schizophrenia. Current Psychiatry. 2018;17(12):19-23.

Drug Brand Names

Benztropine • Cogentin
Cariprazine • Vraylar
Chlorpromazine • Promapar, Thorazine
Risperidone • Risperdal

The negative symptoms of schizophrenia have been recognized for 100 years. Characterized by a loss of a function that should be present, negative symptoms include anhedonia, asociality, amotivation, and affective blunting. Individuals with schizophrenia who have a preponderance of negative symptoms (“deficit syndrome”) may comprise a special subset of patients. Compared with positive symptoms, negative symptoms are associated with worse global functioning and worse response to antipsychotic medication. Treatment of negative symptoms is challenging. Secondary negative symptoms—those that simulate or resemble primary negative symptoms but are attributable to another cause, such as major depressive disorder or the adverse effects of antipsychotic medication—need to be ruled out. Emerging evidence suggests that newer antipsychotics with novel mechanisms might be effective in treating negative symptoms. Antidepressants might also play a role.

This article describes types of negative symptoms, their clinical relevance, neuroanatomical and neurotransmission factors associated with negative symptoms, and current and future treatment options.

Modest improvements with antipsychotics

Schizophrenia affects an estimated 1% of the population.¹ Antipsychotic medication has been the mainstay of schizophrenia treatment since chlorpromazine was introduced in the 1950s; it was soon followed by many other antipsychotics. These first-generation antipsychotics (FGAs) were joined by second-generation antipsychotics (SGAs) in the 1990s. While SGAs are better tolerated and less likely to induce extrapyramidal side effects (EPS) than FGAs, they also are associated with troubling metabolic adverse effects (eg, impaired glucose tolerance).¹

All antipsychotics are believed to exert their therapeutic effects by blocking dopamine (D2) receptors and are effective in ameliorating the positive symptoms of schizophrenia, including hallucinations, delusions, bizarre behavior, disordered thinking, and agitation.¹ Early research had suggested that SGAs might also reduce the negative symptoms of schizophrenia, perhaps because they also block serotonin 2A receptors, a property thought to broaden their therapeutic profile. Over time, it became clear that neither FGAs nor SGAs conferred an advantage in treating negative symptoms, and that the observed improvements were modest.^2-5 However, recent research suggests that several newer antipsychotics might be effective in targeting negative symptoms.^2,6,7

History of negative symptoms

In the early 20th century, Swiss psychiatrist Eugen Bleuler coined the term schizophrenia to emphasize the cognitive impairment that occurs in patients with this illness, and which he conceptualized as a fragmenting of the psychic process.⁸ He believed that certain symptoms were fundamental to the illness, and described affective blunting, disturbance of association (ie, distorted thinking) autism (ie, impaired relationships), and ambivalence (ie, fragmented emotional responses). He viewed hallucinations and delusions as accessory symptoms because they were not unique to schizophrenia but were also found in other disorders (eg, mood disorders). Bleuler’s ideas took root, and generations of psychiatrists were taught his fundamental symptoms (“the 4 A’s”), the forerunner of today’s negative symptoms. Later, other experts chose to emphasize psychotic symptoms as most characteristic of schizophrenia, including Schneider’s “first-rank symptoms,” such as voices conversing or delusions of passivity.⁹

Negative symptoms were rediscovered in the 1970s and 1980s by psychiatric researchers interested in descriptive phenomenology.^10,11 Research confirmed the presence of a positive dimension in schizophrenia characterized by the loss of boundaries between the patient and the real world (eg, hallucinations, delusions), and a negative dimension characterized by the loss of a function that should be present, such as alogia and asociality. These experts carefully described negative symptoms and created scales to measure them, including the Scale for the Assessment of Negative Symptoms (SANS),¹² the Positive and Negative Syndrome Scale (PANSS),¹³ the Brief Negative Symptom Scale (BNSS),¹⁴ and the 16-item Negative Symptom Assessment (NSA-16).¹⁵ Contemporaneous to this work, a “deficit syndrome” was identified among patients with schizophrenia with prominent negative symptoms. The deficit syndrome is found in 25% to 30% of chronic cases.¹⁶ Negative symptoms are very common in patients with schizophrenia (Table 1⁹).^8,17

Early editions of the DSM defined schizophrenia mainly on the basis of disturbance of cognition, mood, and behavior, and a retreat from reality. With the publication of DSM-III in 1980, and in subsequent editions, schizophrenia was redefined as a relatively severe psychotic illness in which positive and negative symptoms were present, thereby acknowledging the importance of Bleuler’s fundamental symptoms. In DSM-5, negative symptoms are described as accounting for “a substantial portion of the morbidity associated with schizophrenia but are less prominent in other psychotic disorders.”¹⁸

Continue to: Types of negative symptoms

 

Types of negative symptoms

The following symptoms fall within the negative dimension¹⁹:

Alogia refers to the impoverished thinking and cognition that often occur in patients with schizophrenia. The patient’s thinking processes seem empty, turgid, or slow, as inferred from the patient’s speech. The 2 major manifestations of alogia are poverty of speech (nonfluent empty speech) and poverty of content of speech (fluent but empty speech). Examples of each appear in Table 2.¹⁹

Affective flattening or blunting manifests as a general impoverishment of emotional expression, reactivity, and feeling. Affective flattening can be assessed through observing a patient’s behavior and responsiveness during the interview.

Avolition-apathy manifests itself as a lack of energy and drive. Patients become inert and are unable to mobilize themselves to initiate or persist in completing many kinds of tasks.

Anhedonia-asociality encompasses the patient’s difficulties in experiencing interest or pleasure. It may express itself as a loss of interest in pleasurable activities, an inability to experience pleasure when participating in activities normally considered pleasurable, or a lack of involvement in social relationships.

Continue to: Attention

 

Attention is often poor in patients with severe mental illnesses. The patient may have trouble focusing his/her attention or may be able to focus only sporadically and erratically. He/she may ignore attempts to converse with him/her, wander away during an activity or a task, or appear to be inattentive when engaged in formal testing or interviewing.

Clinical relevance of negative symptoms

According to DSM-5, “Negative symptoms are more closely related to prognosis than are positive symptoms and tend to be the most persistent.”¹⁸ Research has shown that, compared with positive symptoms, negative symptoms are associated with greater impairment in overall functioning, social interaction, interpersonal relationships, economic functioning, and recreational activities.^1,3,5 Negative symptoms also are associated with poorer response to medication and a positive family history of schizophrenia. Research shows that negative symptoms are persistent over time, and, in fact, become more prominent as the patient ages, whereas positive symptoms become less prominent.²⁰

Secondary negative symptoms

Potential secondary causes of negative symptoms should be ruled out before concluding that the negative symptoms are due to schizophrenia.³ What might appear to be a negative symptom of schizophrenia, such as poor motivation or flattened affect, could be due to the presence of major depressive disorder. Such symptoms might resolve with treatment. Alternatively, a patient could have developed pseudoparkinsonism from antipsychotic medication and display unchanging facial expression and decreased spontaneous movements. These symptoms could resolve by adding benztropine or a similar medication to the treatment regimen. Other potential causes of secondary negative symptoms range from chronic substance abuse (eg, leading to poor grooming and hygiene), to paranoia and hallucinations, to sleep apnea inducing anergia and impersistence at work. Causes of secondary negative symptoms are outlined in Table 3.³

The neuroanatomy of negative symptoms

Although the neuroanatomical basis of negative symptoms has not been determined, neuroimaging studies have provided important clues.³ Structural brain imaging has consistently shown that negative symptoms in patients with schizophrenia correlate with decreased prefrontal white matter volume, anterior cingulate volume, insular cortex volume, left temporal cortex volume, and ventricular enlargement. Interestingly, volume loss starts before the appearance of negative symptoms.^21,22 Functional imaging has shown that negative symptoms correlate with reduced cerebral blood perfusion in frontal, prefrontal, posterior cingulate, thalamus, parietal, and striatal regions.^21,22 These findings may help explain the apathy, failure to initiate activities, and impaired social relatedness in patients with schizophrenia.

Neurotransmission and negative symptoms

Some experts have hypothesized that lowered cortical dopamine transmission in mesocortical pathways could give rise to negative symptoms, whereas excess transmission in subcortical structures leads to positive symptoms.²³ There is also evidence for a noradrenalin deficiency based on the finding that low levels of cerebrospinal fluid 3-methoxy-4-hydroxyphenylglycol (MHPG), a noradrenaline metabolite, correlates with greater negative symptom severity.²⁴ The presence of a serotonin deficiency has been proposed based on evidence that negative symptoms might be mitigated by serotonergic agents.²⁵ More recently, some experts have posited that the dopamine D3 receptor might be involved in the etiology of negative symptoms. The dopamine D3 receptor activity is expressed in brain regions thought to control reward, emotions, and motivation.² Newer medications with novel mechanisms suggest that other neuro­transmitter pathways could be involved.^6,7

Continue to: Treatment options

 

 

Treatment options

Treating negative symptoms remains challenging and there are no clear answers. When they were introduced in the 1990s, SGAs were initially thought to be superior to FGAs in targeting negative symptoms. Subsequent research, including recent reviews and meta-analyses, has shown that SGAs are not superior to FGAs in treating negative symptoms, and the effect of either medication class on negative symptoms is modest.^2-5 One exception is amisulpride (not available in the United States), which is known to antagonize D2 and D3 receptors. A meta-analysis of the efficacy of antipsychotics in schizophrenia showed that amisulpride was significantly more effective than placebo in treating negative symptoms in 590 patients who received the medication.²⁶ The authors suggested that amisulpride was effective due to its binding to presynaptic receptors in the frontal cortex, thereby enhancing dopamine transmission in this region.

Cariprazine, which acts as a partial agonist at the D2 and D3 receptors, with a 10-fold affinity for the D3 receptor, also has shown promise in treating negative symptoms.² In a clinical trial of 460 patients with predominant negative symptoms, treatment with cariprazine led to a greater reduction in negative symptoms than risperidone, although the effect size was small.²⁷ In this study, cariprazine produced greater improvement in personal and social performance than risperidone. Animal data supports the possible use of cariprazine in treating negative symptoms.²⁸

Other promising agentsinclude roluperidone (MIN-101), in phase 3 of development, and SEP-363856, an investigational antipsychotic agent that is in phase 2 of development. Interestingly, roluperidone acts on serotonin 2A and sigma2 receptors and does not target dopamine receptors, whereas SEP-363856 is thought to activate trace amine-associated receptor 1 (TAAR1) in addition to serotonin 1A receptors.^6,7

Antidepressants also could be effective in reducing negative symptoms.³ A meta-analysis of randomized controlled trials evaluating the use of antidepressants as adjuncts to antipsychotic medications showed that adding an antidepressant was effective in reducing negative symptoms.²⁹ The mechanism by which an antidepressant might cause a reduction in negative symptoms is uncertain, and it is possible that the antidepressant might treat depressive symptoms that are causing or contributing to the negative symptoms.

Bottom Line

Negative symptoms in patients with schizophrenia are associated with a worse functional outcome and poorer response to antipsychotic medication than positive symptoms. First- and second-generation antipsychotics are largely ineffective in consistently treating negative symptoms. Antipsychotic medications that target the D3 receptor might be more effective. Roluperidone, which targets serotonin 2A and sigma receptors, and SEP-363856, which targets TAAR1 and serotonin 1A receptors, are being studied for their effects on negative symptoms.

Continue to: Related Resources

 

 

Related Resources

• Galderisi S, Färden A, Kaiser S. Dissecting negative symptoms of schizophrenia: History, assessment, pathophysiological mechanisms and treatment. Schizophr Res. 2017;186:1-2.
• Rabinowitz J. Treating negative symptoms of schizophrenia. Current Psychiatry. 2018;17(12):19-23.

Drug Brand Names

Benztropine • Cogentin
Cariprazine • Vraylar
Chlorpromazine • Promapar, Thorazine
Risperidone • Risperdal

CASE Drooling, unsteady, and not himself

B, age 10, who is left handed and has autism spectrum disorder, is brought to the emergency department (ED) with a 1-day history of drooling, unsteady gait, and left wrist in sustained flexion. His parents report that for the past week, B has had cold symptoms, including rhinorrhea, a low-grade fever (100.0°F), and cough. Earlier in the day, he was seen at his pediatrician’s office, where he was diagnosed with an acute respiratory infection and started on amoxicillin, 500 mg twice daily for 7 days.

At baseline, B is nonverbal. He requires some assistance with his activities of daily living. He usually is able to walk without assistance and dress himself, but he is not toilet trained. His parents report that in the past day, he has had significant difficulties with tasks involving his left hand. Normally, B is able to feed himself “finger foods” but has been unable to do so today. His parents say that he has been unsteady on his feet, and has been “falling forward” when he tries to walk.

Two years ago, B was started on risperidone, 0.5 mg nightly, for behavioral aggression and self-mutilation. Over the next 12 months, the dosage was steadily increased to 1 mg twice daily, with good response. He has been taking his current dosage, 1 mg twice daily, for the past 12 months without adjustment. His parents report there have been no other medication changes, other than starting amoxicillin earlier that day.

As part of his initial ED evaluation, B is found to be mildly dehydrated, with an elevated sedimentation rate on urinalysis. His complete blood count (CBC) with differential is within normal limits. A comprehensive metabolic panel shows a slight increase in his creatinine level, indicating dehydration. B is administered IV fluid replacement because he is having difficulty drinking due to excessive drooling.

The ED physician is concerned that B may be experiencing an acute dystonic reaction from risperidone, so the team holds this medication, and gives B a one-time dose of IV diphenhydramine, 25 mg, for presumptive acute dystonic reaction. After several minutes, there is no improvement in the sustained flexion of his left wrist.

[polldaddy:10615848]

The authors’ observations

B presented with new-onset neurologic findings after a recently diagnosed upper respiratory viral illness. His symptoms appeared to be confined to his left upper extremity, specifically demonstrating left arm extension at the elbow with flexion of the left wrist. He also had new-onset unsteady gait with a stooped forward posture and required assistance with walking. Interestingly, despite B’s history of antipsychotic use, administering an anticholinergic agent did not lessen the dystonic posturing at his wrist and elbow.

EVALUATION Laboratory results reveal new clues

While in the ED, B undergoes MRI of the brain and spinal cord to rule out any mass lesions that could be impinging upon the motor pathways. Both brain and spinal cord imaging appear to be essentially normal, without evidence of impingement of the spinal nerves or lesions involving the brainstem or cerebellum.

Continue to: Due to concerns...

 

Due to concerns of possible airway obstruction, a CT scan of the neck is obtained to rule out any acute pathology, such as epiglottitis compromising his airway. The scan shows some inflammation and edema in the soft tissues that is thought to be secondary to his acute viral illness. B is able to maintain his airway and oxygenation, so intubation is not necessary.

A CPK test is ordered because there are concerns of sustained muscle contraction of B’s left wrist and elbow. The CPK level is 884 U/L (reference range 26 to 192 U/L). The elevation in CPK is consistent with prior laboratory findings of dehydration and indicating skeletal muscle breakdown from sustained muscle contraction. All other laboratory results, including a comprehensive metabolic panel, urine drug screen, and thyroid screening panel, are within normal limits.

[polldaddy:10615850]

EVALUATION No variation in facial expression

B is admitted to the general pediatrics service. Maintenance IV fluids are started due to concerns of dehydration and possible rhabdomyolysis due to his elevated CPK level. Risperidone is held throughout the hospital course due to concerns for an acute dystonic reaction. B is monitored for several days without clinical improvement and eventually discharged home with a diagnosis of inflammatory mononeuropathy due to viral infection. The patient is told to discontinue risperidone as part of discharge instructions.

Five days later, B returns to the hospital because there was no improvement in his left extremity or walking. His left elbow remains extended with left wrist in flexion. Psychiatry is consulted for further diagnostic clarity and evaluation.

On physical examination, B’s left arm remains unchanged. Despite discontinuing risperidone, there is evidence of cogwheel rigidity of the left wrist joint. Reflexes in the upper and lower extremities are 2+ and symmetrical bilaterally, suggesting intact upper and lower motor pathways. Babinski sign is absent bilaterally, which is a normal finding in B’s age group. B continues to have difficulty with ambulating and appears to “fall forward” while trying to walk with assistance. His parents also say that B is not laughing, smiling, or showing any variation in facial expression.

Continue to: Additional family history...

 

Additional family history is gathered from B’s parents for possible hereditary movement disorders such as Wilson’s disease. They report that no family members have developed involuntary movements or other neurologic syndromes. Additional considerations on the differential diagnosis for B include juvenile ALS or mononeuropathy involving the C5 and C6 nerve roots. B’s parents deny any recent shoulder trauma, and radiographic studies did not demonstrate any involvement of the nerve roots.

TREATMENT A trial of bromocriptine

At this point, B’s neurologic workup is essentially normal, and he is given a provisional diagnosis of antipsychotic-induced tardive dystonia vs tardive parkinsonism. Risperidone continues to be held, and B is monitored for clinical improvement. B is administered a one-time dose of diphenhydramine, 25 mg, for dystonia with no improvement in symptoms. He is then started on bromocriptine, 1.25 mg twice daily with meals, for parkinsonian symptoms secondary to antipsychotic medication use. After 1 day of treatment, B shows less sustained flexion of his left wrist. He is able to relax his left arm, shows improvements in ambulation, and requires less assistance. B continues to be observed closely and continues to improve toward his baseline.

At Day 4, he is discharged. B is able to walk mostly without assistance and demonstrates improvement in left wrist flexion. He is scheduled to see a movement disorders specialist a week after discharge. The initial diagnosis given by the movement disorder specialist is tardive dystonia.

The authors’ observations

Tardive dyskinesia is a well-known iatrogenic effect of antipsychotic medications that are commonly used to manage conditions such as schizophrenia or behavioral agitation associated with autism spectrum disorder. Symptoms of tardive dyskinesia typically emerge after 1 to 2 years of continuous exposure to dopamine receptor blocking agents (DRBAs). Tardive dyskinesia symptoms include involuntary, repetitive, purposeless movements of the tongue, jaw, lips, face, trunk, and upper and lower extremities, with significant functional impairment.¹

Tardive syndromes refer to a diverse array of hyperkinetic, hypokinetic, and sensory movement disorders resulting from at least 3 months of continuous DRBA therapy.² Tardive dyskinesia is perhaps the most well-known of the tardive syndromes, but is not the only one to consider when assessing for antipsychotic-induced movement disorders. A key feature differentiating a tardive syndrome is the persistence of the movement disorder after the DRBA is discontinued. In this case, B had been receiving a stable dose of risperidone for >1 year. He developed dystonic posturing of his left wrist and elbow that was both unresponsive to anticholinergic medication and persisted after risperidone was discontinued. The term “tardive” emphasizes the delay in development of abnormal involuntary movement symptoms after initiating antipsychotic medications.³ Table 1² shows a comparison of tardive dystonia vs an acute dystonic reaction.

Continue to: Other tardive syndromes include...

 

Other tardive syndromes include:

• tardive tics
• tardive parkinsonism
• tardive pain
• tardive myoclonus
• tardive akathisia
• tardive tremors.

The incidence of tardive syndromes increases 5% annually for the first 5 years of treatment. At 10 years of treatment, the annual incidence is thought to be 49%, and at 25 years of treatment, 68%.⁴ The predominant theory of the pathophysiology of tardive syndromes is that the chronic use of DRBAs causes a gradual hypersensitization of dopamine receptors.⁴ The diagnosis of a tardive syndrome is based on history of exposure to a DRBA as well as clinical observation of symptoms.

Compared with classic tardive dyskinesia, tardive dystonia is more common among younger patients. The mean age of onset of tardive dystonia is 40, and it typically affects young males.⁵ Typical posturing observed in cases of tardive dystonia include extension of the arms and flexion at the wrists.⁶ In contrast to cases of primary dystonia, tardive dystonia is typically associated with stereotypies, akathisia, or other movement disorders. Anticholinergic agents, such as benztropine or trihexyphenidyl, may or may not alleviate symptoms of tardive dystonia but can worsen tardive dyskinesia, so careful delineation between the 2 syndromes is important.⁶

The American Psychiatric Association has issued guidelines on screening for involuntary movement syndromes by using the Abnormal Involuntary Movement Scale (AIMS).⁷ The current recommendations include assessment every 6 months for patients receiving first-generation antipsychotics, and every 12 months for those receiving second-generation antipsychotics.⁷ Prescribers should also carefully assess for any pre-existing involuntary movements before prescribing a DRBA.⁷

[polldaddy:10615855]

The authors’ observations

In 2013, the American Academy of Neurology (AAN) published guidelines on the treatment of tardive dyskinesia. According to these guidelines, at that time, the treatments with the most evidence supporting their use were clonazepam, ginkgo biloba, amantadine, and tetrabenazine.⁸ Other medications, including bromocriptine, baclofen, botulinum toxin, and vitamin E, did not show sufficient evidence to be recommended or refuted as treatment options.⁸ Botulinum toxin has long been utilized to treat focal and cervical dystonias, although there is no clear consensus on its role in treating tardive syndromes because of the conflicting results of prior studies.⁸Table 2⁸ outlines the AAN guidelines for treating tardive dyskinesia.

Continue to: In 2017, valbenazine and deutetrabenazine...

 

In 2017, valbenazine and deutetrabenazine became the first FDA-approved treatments for tardive dyskinesia in adults. Both medications block the vesicular monoamine transporter 2 (VMAT2) system, which results in decreased synaptic dopamine and dopamine receptor stimulation. Both VMAT2 inhibitor medications have a category level A supporting their use for treating tardive dyskinesia.^8-10

Currently, there are no published treatment guidelines on pharmacologic management of tardive dystonia. In B’s case, bromocriptine, a dopamine agonist, was used to counter the dopamine-blocking effects of risperidone on the nigrostriatal pathway and improve parkinsonian features of B’s presentation, including bradykinesia, stooped forward posture, and masked facies. Bromocriptine was found to be effective in alleviating parkinsonian features; however, to date there is no evidence demonstrating its effectiveness in countering delayed dystonic effects of DRBAs.

OUTCOME Improvement of dystonia symptoms

One week after discharge, B is seen for a follow-up visit. He continues taking bromocriptine, 1.25 mg twice daily, with meals after discharge. On examination, he has some evidence of tardive dystonia, including flexion of left wrist and posturing while ambulating. B’s parkinsonian features, including stooped forward posture, masked facies, and cogwheel rigidity of the left wrist muscle, have resolved. B is now able to walk on his own without unsteadiness. Bromocriptine is discontinued after 1 month, and his symptoms of dystonia continue to improve.

Two months after hospitalization, B is started on quetiapine, 25 mg twice daily, for behavioral aggression. Quetiapine is chosen because it has a lower dopamine receptor affinity compared with risperidone, and theoretically, quetiapine is associated with a lower risk of developing tardive symptoms. During the next 6 months, B is monitored closely for recurrence of tardive symptoms. Quetiapine is slowly titrated to 25 mg in the morning, and 50 mg at bedtime. His behavioral agitation improves significantly and he does not have a recurrence of tardive symptoms.

Bottom Line

Tardive dystonia is a possible iatrogenic adverse effect for patients receiving long-term dopamine receptor blocking agent (DRBA) therapy. Tardive syndromes encompass delayed-onset movement disorders caused by long-term blockade of the dopamine receptor by antipsychotic agents. Tardive dystonia can be contrasted from acute dystonic reaction based on the time course of development as well as by the persistence of symptoms after DRBAs are withheld.

Continue to: Related Resources

 

 

Related Resources

• American Academy of Neurology. Summary of evidence-based guideline for clinicians: treatment of tardive syndromes. https://www.aan.com/Guidelines/Home/GetGuidelineContent/613. Published 2013.
• Dystonia Medical Research Foundation. https://dystonia-foundation.org/.

Drug Brand Names

Amantadine • Gocovri, Symmetrel
Amoxicillin • Amoxil
Baclofen • Kemstro, Liroesal
Benztropine • Cogentin
Bromocriptine • Parlodel
Clonazepam • Klonopin
Deutetrabenazine • Austedo
Galantamine • Razadyne
Quetiapine • Seroquel
Risperidone • Risperdal
Tetrabenazine • Xenazine
Trihexyphenidyl • Artane, Tremin
Valbenazine • Ingrezza

CASE Drooling, unsteady, and not himself

B, age 10, who is left handed and has autism spectrum disorder, is brought to the emergency department (ED) with a 1-day history of drooling, unsteady gait, and left wrist in sustained flexion. His parents report that for the past week, B has had cold symptoms, including rhinorrhea, a low-grade fever (100.0°F), and cough. Earlier in the day, he was seen at his pediatrician’s office, where he was diagnosed with an acute respiratory infection and started on amoxicillin, 500 mg twice daily for 7 days.

At baseline, B is nonverbal. He requires some assistance with his activities of daily living. He usually is able to walk without assistance and dress himself, but he is not toilet trained. His parents report that in the past day, he has had significant difficulties with tasks involving his left hand. Normally, B is able to feed himself “finger foods” but has been unable to do so today. His parents say that he has been unsteady on his feet, and has been “falling forward” when he tries to walk.

Two years ago, B was started on risperidone, 0.5 mg nightly, for behavioral aggression and self-mutilation. Over the next 12 months, the dosage was steadily increased to 1 mg twice daily, with good response. He has been taking his current dosage, 1 mg twice daily, for the past 12 months without adjustment. His parents report there have been no other medication changes, other than starting amoxicillin earlier that day.

As part of his initial ED evaluation, B is found to be mildly dehydrated, with an elevated sedimentation rate on urinalysis. His complete blood count (CBC) with differential is within normal limits. A comprehensive metabolic panel shows a slight increase in his creatinine level, indicating dehydration. B is administered IV fluid replacement because he is having difficulty drinking due to excessive drooling.

The ED physician is concerned that B may be experiencing an acute dystonic reaction from risperidone, so the team holds this medication, and gives B a one-time dose of IV diphenhydramine, 25 mg, for presumptive acute dystonic reaction. After several minutes, there is no improvement in the sustained flexion of his left wrist.

[polldaddy:10615848]

The authors’ observations

B presented with new-onset neurologic findings after a recently diagnosed upper respiratory viral illness. His symptoms appeared to be confined to his left upper extremity, specifically demonstrating left arm extension at the elbow with flexion of the left wrist. He also had new-onset unsteady gait with a stooped forward posture and required assistance with walking. Interestingly, despite B’s history of antipsychotic use, administering an anticholinergic agent did not lessen the dystonic posturing at his wrist and elbow.

EVALUATION Laboratory results reveal new clues

While in the ED, B undergoes MRI of the brain and spinal cord to rule out any mass lesions that could be impinging upon the motor pathways. Both brain and spinal cord imaging appear to be essentially normal, without evidence of impingement of the spinal nerves or lesions involving the brainstem or cerebellum.

Continue to: Due to concerns...

 

Due to concerns of possible airway obstruction, a CT scan of the neck is obtained to rule out any acute pathology, such as epiglottitis compromising his airway. The scan shows some inflammation and edema in the soft tissues that is thought to be secondary to his acute viral illness. B is able to maintain his airway and oxygenation, so intubation is not necessary.

A CPK test is ordered because there are concerns of sustained muscle contraction of B’s left wrist and elbow. The CPK level is 884 U/L (reference range 26 to 192 U/L). The elevation in CPK is consistent with prior laboratory findings of dehydration and indicating skeletal muscle breakdown from sustained muscle contraction. All other laboratory results, including a comprehensive metabolic panel, urine drug screen, and thyroid screening panel, are within normal limits.

[polldaddy:10615850]

EVALUATION No variation in facial expression

B is admitted to the general pediatrics service. Maintenance IV fluids are started due to concerns of dehydration and possible rhabdomyolysis due to his elevated CPK level. Risperidone is held throughout the hospital course due to concerns for an acute dystonic reaction. B is monitored for several days without clinical improvement and eventually discharged home with a diagnosis of inflammatory mononeuropathy due to viral infection. The patient is told to discontinue risperidone as part of discharge instructions.

Five days later, B returns to the hospital because there was no improvement in his left extremity or walking. His left elbow remains extended with left wrist in flexion. Psychiatry is consulted for further diagnostic clarity and evaluation.

On physical examination, B’s left arm remains unchanged. Despite discontinuing risperidone, there is evidence of cogwheel rigidity of the left wrist joint. Reflexes in the upper and lower extremities are 2+ and symmetrical bilaterally, suggesting intact upper and lower motor pathways. Babinski sign is absent bilaterally, which is a normal finding in B’s age group. B continues to have difficulty with ambulating and appears to “fall forward” while trying to walk with assistance. His parents also say that B is not laughing, smiling, or showing any variation in facial expression.

Continue to: Additional family history...

 

Additional family history is gathered from B’s parents for possible hereditary movement disorders such as Wilson’s disease. They report that no family members have developed involuntary movements or other neurologic syndromes. Additional considerations on the differential diagnosis for B include juvenile ALS or mononeuropathy involving the C5 and C6 nerve roots. B’s parents deny any recent shoulder trauma, and radiographic studies did not demonstrate any involvement of the nerve roots.

TREATMENT A trial of bromocriptine

At this point, B’s neurologic workup is essentially normal, and he is given a provisional diagnosis of antipsychotic-induced tardive dystonia vs tardive parkinsonism. Risperidone continues to be held, and B is monitored for clinical improvement. B is administered a one-time dose of diphenhydramine, 25 mg, for dystonia with no improvement in symptoms. He is then started on bromocriptine, 1.25 mg twice daily with meals, for parkinsonian symptoms secondary to antipsychotic medication use. After 1 day of treatment, B shows less sustained flexion of his left wrist. He is able to relax his left arm, shows improvements in ambulation, and requires less assistance. B continues to be observed closely and continues to improve toward his baseline.

At Day 4, he is discharged. B is able to walk mostly without assistance and demonstrates improvement in left wrist flexion. He is scheduled to see a movement disorders specialist a week after discharge. The initial diagnosis given by the movement disorder specialist is tardive dystonia.

The authors’ observations

Tardive dyskinesia is a well-known iatrogenic effect of antipsychotic medications that are commonly used to manage conditions such as schizophrenia or behavioral agitation associated with autism spectrum disorder. Symptoms of tardive dyskinesia typically emerge after 1 to 2 years of continuous exposure to dopamine receptor blocking agents (DRBAs). Tardive dyskinesia symptoms include involuntary, repetitive, purposeless movements of the tongue, jaw, lips, face, trunk, and upper and lower extremities, with significant functional impairment.¹

Tardive syndromes refer to a diverse array of hyperkinetic, hypokinetic, and sensory movement disorders resulting from at least 3 months of continuous DRBA therapy.² Tardive dyskinesia is perhaps the most well-known of the tardive syndromes, but is not the only one to consider when assessing for antipsychotic-induced movement disorders. A key feature differentiating a tardive syndrome is the persistence of the movement disorder after the DRBA is discontinued. In this case, B had been receiving a stable dose of risperidone for >1 year. He developed dystonic posturing of his left wrist and elbow that was both unresponsive to anticholinergic medication and persisted after risperidone was discontinued. The term “tardive” emphasizes the delay in development of abnormal involuntary movement symptoms after initiating antipsychotic medications.³ Table 1² shows a comparison of tardive dystonia vs an acute dystonic reaction.

Continue to: Other tardive syndromes include...

 

Other tardive syndromes include:

• tardive tics
• tardive parkinsonism
• tardive pain
• tardive myoclonus
• tardive akathisia
• tardive tremors.

The incidence of tardive syndromes increases 5% annually for the first 5 years of treatment. At 10 years of treatment, the annual incidence is thought to be 49%, and at 25 years of treatment, 68%.⁴ The predominant theory of the pathophysiology of tardive syndromes is that the chronic use of DRBAs causes a gradual hypersensitization of dopamine receptors.⁴ The diagnosis of a tardive syndrome is based on history of exposure to a DRBA as well as clinical observation of symptoms.

Compared with classic tardive dyskinesia, tardive dystonia is more common among younger patients. The mean age of onset of tardive dystonia is 40, and it typically affects young males.⁵ Typical posturing observed in cases of tardive dystonia include extension of the arms and flexion at the wrists.⁶ In contrast to cases of primary dystonia, tardive dystonia is typically associated with stereotypies, akathisia, or other movement disorders. Anticholinergic agents, such as benztropine or trihexyphenidyl, may or may not alleviate symptoms of tardive dystonia but can worsen tardive dyskinesia, so careful delineation between the 2 syndromes is important.⁶

The American Psychiatric Association has issued guidelines on screening for involuntary movement syndromes by using the Abnormal Involuntary Movement Scale (AIMS).⁷ The current recommendations include assessment every 6 months for patients receiving first-generation antipsychotics, and every 12 months for those receiving second-generation antipsychotics.⁷ Prescribers should also carefully assess for any pre-existing involuntary movements before prescribing a DRBA.⁷

[polldaddy:10615855]

The authors’ observations

In 2013, the American Academy of Neurology (AAN) published guidelines on the treatment of tardive dyskinesia. According to these guidelines, at that time, the treatments with the most evidence supporting their use were clonazepam, ginkgo biloba, amantadine, and tetrabenazine.⁸ Other medications, including bromocriptine, baclofen, botulinum toxin, and vitamin E, did not show sufficient evidence to be recommended or refuted as treatment options.⁸ Botulinum toxin has long been utilized to treat focal and cervical dystonias, although there is no clear consensus on its role in treating tardive syndromes because of the conflicting results of prior studies.⁸Table 2⁸ outlines the AAN guidelines for treating tardive dyskinesia.

Continue to: In 2017, valbenazine and deutetrabenazine...

 

In 2017, valbenazine and deutetrabenazine became the first FDA-approved treatments for tardive dyskinesia in adults. Both medications block the vesicular monoamine transporter 2 (VMAT2) system, which results in decreased synaptic dopamine and dopamine receptor stimulation. Both VMAT2 inhibitor medications have a category level A supporting their use for treating tardive dyskinesia.^8-10

Currently, there are no published treatment guidelines on pharmacologic management of tardive dystonia. In B’s case, bromocriptine, a dopamine agonist, was used to counter the dopamine-blocking effects of risperidone on the nigrostriatal pathway and improve parkinsonian features of B’s presentation, including bradykinesia, stooped forward posture, and masked facies. Bromocriptine was found to be effective in alleviating parkinsonian features; however, to date there is no evidence demonstrating its effectiveness in countering delayed dystonic effects of DRBAs.

OUTCOME Improvement of dystonia symptoms

One week after discharge, B is seen for a follow-up visit. He continues taking bromocriptine, 1.25 mg twice daily, with meals after discharge. On examination, he has some evidence of tardive dystonia, including flexion of left wrist and posturing while ambulating. B’s parkinsonian features, including stooped forward posture, masked facies, and cogwheel rigidity of the left wrist muscle, have resolved. B is now able to walk on his own without unsteadiness. Bromocriptine is discontinued after 1 month, and his symptoms of dystonia continue to improve.

Two months after hospitalization, B is started on quetiapine, 25 mg twice daily, for behavioral aggression. Quetiapine is chosen because it has a lower dopamine receptor affinity compared with risperidone, and theoretically, quetiapine is associated with a lower risk of developing tardive symptoms. During the next 6 months, B is monitored closely for recurrence of tardive symptoms. Quetiapine is slowly titrated to 25 mg in the morning, and 50 mg at bedtime. His behavioral agitation improves significantly and he does not have a recurrence of tardive symptoms.

Bottom Line

Tardive dystonia is a possible iatrogenic adverse effect for patients receiving long-term dopamine receptor blocking agent (DRBA) therapy. Tardive syndromes encompass delayed-onset movement disorders caused by long-term blockade of the dopamine receptor by antipsychotic agents. Tardive dystonia can be contrasted from acute dystonic reaction based on the time course of development as well as by the persistence of symptoms after DRBAs are withheld.

Continue to: Related Resources

 

 

Related Resources

• American Academy of Neurology. Summary of evidence-based guideline for clinicians: treatment of tardive syndromes. https://www.aan.com/Guidelines/Home/GetGuidelineContent/613. Published 2013.
• Dystonia Medical Research Foundation. https://dystonia-foundation.org/.

Drug Brand Names

Amantadine • Gocovri, Symmetrel
Amoxicillin • Amoxil
Baclofen • Kemstro, Liroesal
Benztropine • Cogentin
Bromocriptine • Parlodel
Clonazepam • Klonopin
Deutetrabenazine • Austedo
Galantamine • Razadyne
Quetiapine • Seroquel
Risperidone • Risperdal
Tetrabenazine • Xenazine
Trihexyphenidyl • Artane, Tremin
Valbenazine • Ingrezza

CASE Drooling, unsteady, and not himself

B, age 10, who is left handed and has autism spectrum disorder, is brought to the emergency department (ED) with a 1-day history of drooling, unsteady gait, and left wrist in sustained flexion. His parents report that for the past week, B has had cold symptoms, including rhinorrhea, a low-grade fever (100.0°F), and cough. Earlier in the day, he was seen at his pediatrician’s office, where he was diagnosed with an acute respiratory infection and started on amoxicillin, 500 mg twice daily for 7 days.

At baseline, B is nonverbal. He requires some assistance with his activities of daily living. He usually is able to walk without assistance and dress himself, but he is not toilet trained. His parents report that in the past day, he has had significant difficulties with tasks involving his left hand. Normally, B is able to feed himself “finger foods” but has been unable to do so today. His parents say that he has been unsteady on his feet, and has been “falling forward” when he tries to walk.

Two years ago, B was started on risperidone, 0.5 mg nightly, for behavioral aggression and self-mutilation. Over the next 12 months, the dosage was steadily increased to 1 mg twice daily, with good response. He has been taking his current dosage, 1 mg twice daily, for the past 12 months without adjustment. His parents report there have been no other medication changes, other than starting amoxicillin earlier that day.

As part of his initial ED evaluation, B is found to be mildly dehydrated, with an elevated sedimentation rate on urinalysis. His complete blood count (CBC) with differential is within normal limits. A comprehensive metabolic panel shows a slight increase in his creatinine level, indicating dehydration. B is administered IV fluid replacement because he is having difficulty drinking due to excessive drooling.

The ED physician is concerned that B may be experiencing an acute dystonic reaction from risperidone, so the team holds this medication, and gives B a one-time dose of IV diphenhydramine, 25 mg, for presumptive acute dystonic reaction. After several minutes, there is no improvement in the sustained flexion of his left wrist.

[polldaddy:10615848]

The authors’ observations

B presented with new-onset neurologic findings after a recently diagnosed upper respiratory viral illness. His symptoms appeared to be confined to his left upper extremity, specifically demonstrating left arm extension at the elbow with flexion of the left wrist. He also had new-onset unsteady gait with a stooped forward posture and required assistance with walking. Interestingly, despite B’s history of antipsychotic use, administering an anticholinergic agent did not lessen the dystonic posturing at his wrist and elbow.

EVALUATION Laboratory results reveal new clues

While in the ED, B undergoes MRI of the brain and spinal cord to rule out any mass lesions that could be impinging upon the motor pathways. Both brain and spinal cord imaging appear to be essentially normal, without evidence of impingement of the spinal nerves or lesions involving the brainstem or cerebellum.

Continue to: Due to concerns...

 

Due to concerns of possible airway obstruction, a CT scan of the neck is obtained to rule out any acute pathology, such as epiglottitis compromising his airway. The scan shows some inflammation and edema in the soft tissues that is thought to be secondary to his acute viral illness. B is able to maintain his airway and oxygenation, so intubation is not necessary.

A CPK test is ordered because there are concerns of sustained muscle contraction of B’s left wrist and elbow. The CPK level is 884 U/L (reference range 26 to 192 U/L). The elevation in CPK is consistent with prior laboratory findings of dehydration and indicating skeletal muscle breakdown from sustained muscle contraction. All other laboratory results, including a comprehensive metabolic panel, urine drug screen, and thyroid screening panel, are within normal limits.

[polldaddy:10615850]

EVALUATION No variation in facial expression

B is admitted to the general pediatrics service. Maintenance IV fluids are started due to concerns of dehydration and possible rhabdomyolysis due to his elevated CPK level. Risperidone is held throughout the hospital course due to concerns for an acute dystonic reaction. B is monitored for several days without clinical improvement and eventually discharged home with a diagnosis of inflammatory mononeuropathy due to viral infection. The patient is told to discontinue risperidone as part of discharge instructions.

Five days later, B returns to the hospital because there was no improvement in his left extremity or walking. His left elbow remains extended with left wrist in flexion. Psychiatry is consulted for further diagnostic clarity and evaluation.

On physical examination, B’s left arm remains unchanged. Despite discontinuing risperidone, there is evidence of cogwheel rigidity of the left wrist joint. Reflexes in the upper and lower extremities are 2+ and symmetrical bilaterally, suggesting intact upper and lower motor pathways. Babinski sign is absent bilaterally, which is a normal finding in B’s age group. B continues to have difficulty with ambulating and appears to “fall forward” while trying to walk with assistance. His parents also say that B is not laughing, smiling, or showing any variation in facial expression.

Continue to: Additional family history...

 

Additional family history is gathered from B’s parents for possible hereditary movement disorders such as Wilson’s disease. They report that no family members have developed involuntary movements or other neurologic syndromes. Additional considerations on the differential diagnosis for B include juvenile ALS or mononeuropathy involving the C5 and C6 nerve roots. B’s parents deny any recent shoulder trauma, and radiographic studies did not demonstrate any involvement of the nerve roots.

TREATMENT A trial of bromocriptine

At this point, B’s neurologic workup is essentially normal, and he is given a provisional diagnosis of antipsychotic-induced tardive dystonia vs tardive parkinsonism. Risperidone continues to be held, and B is monitored for clinical improvement. B is administered a one-time dose of diphenhydramine, 25 mg, for dystonia with no improvement in symptoms. He is then started on bromocriptine, 1.25 mg twice daily with meals, for parkinsonian symptoms secondary to antipsychotic medication use. After 1 day of treatment, B shows less sustained flexion of his left wrist. He is able to relax his left arm, shows improvements in ambulation, and requires less assistance. B continues to be observed closely and continues to improve toward his baseline.

At Day 4, he is discharged. B is able to walk mostly without assistance and demonstrates improvement in left wrist flexion. He is scheduled to see a movement disorders specialist a week after discharge. The initial diagnosis given by the movement disorder specialist is tardive dystonia.

The authors’ observations

Tardive dyskinesia is a well-known iatrogenic effect of antipsychotic medications that are commonly used to manage conditions such as schizophrenia or behavioral agitation associated with autism spectrum disorder. Symptoms of tardive dyskinesia typically emerge after 1 to 2 years of continuous exposure to dopamine receptor blocking agents (DRBAs). Tardive dyskinesia symptoms include involuntary, repetitive, purposeless movements of the tongue, jaw, lips, face, trunk, and upper and lower extremities, with significant functional impairment.¹

Tardive syndromes refer to a diverse array of hyperkinetic, hypokinetic, and sensory movement disorders resulting from at least 3 months of continuous DRBA therapy.² Tardive dyskinesia is perhaps the most well-known of the tardive syndromes, but is not the only one to consider when assessing for antipsychotic-induced movement disorders. A key feature differentiating a tardive syndrome is the persistence of the movement disorder after the DRBA is discontinued. In this case, B had been receiving a stable dose of risperidone for >1 year. He developed dystonic posturing of his left wrist and elbow that was both unresponsive to anticholinergic medication and persisted after risperidone was discontinued. The term “tardive” emphasizes the delay in development of abnormal involuntary movement symptoms after initiating antipsychotic medications.³ Table 1² shows a comparison of tardive dystonia vs an acute dystonic reaction.

Continue to: Other tardive syndromes include...

 

Other tardive syndromes include:

• tardive tics
• tardive parkinsonism
• tardive pain
• tardive myoclonus
• tardive akathisia
• tardive tremors.

The incidence of tardive syndromes increases 5% annually for the first 5 years of treatment. At 10 years of treatment, the annual incidence is thought to be 49%, and at 25 years of treatment, 68%.⁴ The predominant theory of the pathophysiology of tardive syndromes is that the chronic use of DRBAs causes a gradual hypersensitization of dopamine receptors.⁴ The diagnosis of a tardive syndrome is based on history of exposure to a DRBA as well as clinical observation of symptoms.

Compared with classic tardive dyskinesia, tardive dystonia is more common among younger patients. The mean age of onset of tardive dystonia is 40, and it typically affects young males.⁵ Typical posturing observed in cases of tardive dystonia include extension of the arms and flexion at the wrists.⁶ In contrast to cases of primary dystonia, tardive dystonia is typically associated with stereotypies, akathisia, or other movement disorders. Anticholinergic agents, such as benztropine or trihexyphenidyl, may or may not alleviate symptoms of tardive dystonia but can worsen tardive dyskinesia, so careful delineation between the 2 syndromes is important.⁶

The American Psychiatric Association has issued guidelines on screening for involuntary movement syndromes by using the Abnormal Involuntary Movement Scale (AIMS).⁷ The current recommendations include assessment every 6 months for patients receiving first-generation antipsychotics, and every 12 months for those receiving second-generation antipsychotics.⁷ Prescribers should also carefully assess for any pre-existing involuntary movements before prescribing a DRBA.⁷

[polldaddy:10615855]

The authors’ observations

In 2013, the American Academy of Neurology (AAN) published guidelines on the treatment of tardive dyskinesia. According to these guidelines, at that time, the treatments with the most evidence supporting their use were clonazepam, ginkgo biloba, amantadine, and tetrabenazine.⁸ Other medications, including bromocriptine, baclofen, botulinum toxin, and vitamin E, did not show sufficient evidence to be recommended or refuted as treatment options.⁸ Botulinum toxin has long been utilized to treat focal and cervical dystonias, although there is no clear consensus on its role in treating tardive syndromes because of the conflicting results of prior studies.⁸Table 2⁸ outlines the AAN guidelines for treating tardive dyskinesia.

Continue to: In 2017, valbenazine and deutetrabenazine...

 

In 2017, valbenazine and deutetrabenazine became the first FDA-approved treatments for tardive dyskinesia in adults. Both medications block the vesicular monoamine transporter 2 (VMAT2) system, which results in decreased synaptic dopamine and dopamine receptor stimulation. Both VMAT2 inhibitor medications have a category level A supporting their use for treating tardive dyskinesia.^8-10

Currently, there are no published treatment guidelines on pharmacologic management of tardive dystonia. In B’s case, bromocriptine, a dopamine agonist, was used to counter the dopamine-blocking effects of risperidone on the nigrostriatal pathway and improve parkinsonian features of B’s presentation, including bradykinesia, stooped forward posture, and masked facies. Bromocriptine was found to be effective in alleviating parkinsonian features; however, to date there is no evidence demonstrating its effectiveness in countering delayed dystonic effects of DRBAs.

OUTCOME Improvement of dystonia symptoms

One week after discharge, B is seen for a follow-up visit. He continues taking bromocriptine, 1.25 mg twice daily, with meals after discharge. On examination, he has some evidence of tardive dystonia, including flexion of left wrist and posturing while ambulating. B’s parkinsonian features, including stooped forward posture, masked facies, and cogwheel rigidity of the left wrist muscle, have resolved. B is now able to walk on his own without unsteadiness. Bromocriptine is discontinued after 1 month, and his symptoms of dystonia continue to improve.

Two months after hospitalization, B is started on quetiapine, 25 mg twice daily, for behavioral aggression. Quetiapine is chosen because it has a lower dopamine receptor affinity compared with risperidone, and theoretically, quetiapine is associated with a lower risk of developing tardive symptoms. During the next 6 months, B is monitored closely for recurrence of tardive symptoms. Quetiapine is slowly titrated to 25 mg in the morning, and 50 mg at bedtime. His behavioral agitation improves significantly and he does not have a recurrence of tardive symptoms.

Bottom Line

Tardive dystonia is a possible iatrogenic adverse effect for patients receiving long-term dopamine receptor blocking agent (DRBA) therapy. Tardive syndromes encompass delayed-onset movement disorders caused by long-term blockade of the dopamine receptor by antipsychotic agents. Tardive dystonia can be contrasted from acute dystonic reaction based on the time course of development as well as by the persistence of symptoms after DRBAs are withheld.

Continue to: Related Resources

 

 

Related Resources

• American Academy of Neurology. Summary of evidence-based guideline for clinicians: treatment of tardive syndromes. https://www.aan.com/Guidelines/Home/GetGuidelineContent/613. Published 2013.
• Dystonia Medical Research Foundation. https://dystonia-foundation.org/.

Drug Brand Names

Amantadine • Gocovri, Symmetrel
Amoxicillin • Amoxil
Baclofen • Kemstro, Liroesal
Benztropine • Cogentin
Bromocriptine • Parlodel
Clonazepam • Klonopin
Deutetrabenazine • Austedo
Galantamine • Razadyne
Quetiapine • Seroquel
Risperidone • Risperdal
Tetrabenazine • Xenazine
Trihexyphenidyl • Artane, Tremin
Valbenazine • Ingrezza

 

Two oral agents with novel mechanisms of action in schizophrenia generated considerable audience interest after acing large phase 2 clinical trials presented at the virtual congress of the European College of Neuropsychopharmacology.

The two successful drugs moving on to definitive phase 3 studies after their performance at ECNP 2020 are KarXT, a proprietary combination of xanomeline and trospium chloride, and an inhibitor of glycine transporter 1 (Gly-T1) known for now as BI 425809.

Pimavanserin, an oral selective serotonin inverse agonist with a high affinity for 5-HT2A receptors and low affinity for 5-HT2C receptors, has taken a more convoluted path through the developmental pipeline for schizophrenia. It recently failed to outperform placebo as adjunctive treatment for schizophrenia on the primary endpoint of improvement in Positive And Negative Syndrome Scale (PANSS) total score in the 6-week, phase 3 ENHANCE (Efficacy and Safety of Adjunctive Pimavanserin for the Treatment of Schizophrenia) study. The drug did, however, show significant benefit on secondary endpoints involving negative symptoms.

And in the 400-patient, 26-week, placebo-controlled, phase 2 ADVANCE trial, adjunctive pimavanserin was positive for the primary endpoint of improvement in the Negative Symptom Assessment-16 (NSA-16) score. A phase 3 program evaluating the drug specifically for negative symptoms is underway.

Another novel therapy, an investigational selective estrogen receptor beta agonist, proved reassuringly safe but completely ineffective in men with schizophrenia in a study presented at ECNP 2020.

“The results, unfortunately, were disappointing. We saw no signal on cognition, no change on brain imaging with fMRI, and no improvement in negative symptoms or PANSS total score,” reported Alan Breier, MD, professor and vice chair of the department of psychiatry at Indiana University in Indianapolis.

The congress session on new medications with novel mechanisms was a meeting highlight. Broad agreement exists that current antipsychotics targeting D2 dopamine and serotonin receptors in schizophrenia leave much to be desired. They’re ineffective for two of the three major symptom categories that define schizophrenia: cognitive impairment and negative symptoms, such as apathy and social withdrawal. And even for the current antipsychotics’ forte – treatment of positive symptoms, including hallucinations and delusions – effectiveness is often only modest to moderate and accompanied by limiting side effects.

KarXT

KarXT combines xanomeline, a selective M1/M4 muscarinic receptor agonist exclusively licensed from Lilly to Karuna Therapeutics, with trospium chloride, a muscarinic antagonist approved for more than a decade in the United States and Europe for treatment of overactive bladder. Xanomeline was synthesized in the 1990s. It showed promising evidence of antipsychotic efficacy in schizophrenia and Alzheimer’s disease in yearlong clinical trials totaling more than 800 patients, but interest in further developing the drug cooled because of limiting GI and other cholinergic adverse events. KarXT, Karuna’s lead product candidate, is designed to maintain the efficacy of xanomeline while trospium, which doesn’t cross the blood-brain barrier, cancels out its side effects, explained Stephen Brannan, MD, a psychiatrist and chief medical officer at the company.

He presented the results of the phase 2 study, a multicenter, randomized, double-blind, placebo-controlled, 5-week trial conducted with 182 schizophrenia inpatients experiencing an acute psychotic exacerbation. All other antipsychotics were washed out before randomization to KarXT at 50 mg xanomeline/20 mg trospium twice daily, titrated to 100/20 twice daily on days 3-7 and 100/20 b.i.d. thereafter, with an optional increase to 125/30 twice daily.

The primary study endpoint was change from baseline to week 5 in PANSS total score. The results were positive at the P < .0001 level, with a mean 17.4-point reduction in the KarXT group, compared with a 5.9-point improvement in placebo-treated controls. The between-group difference was significant by the first assessment at week 2.

Four of five prespecified secondary endpoints were also positive in rapid and sustained fashion: improvement in the PANSS positive subscore, PANSS negative subscore, Marder PANSS negative subscore, and Clinical Global Impressions-Severity. The fifth secondary endpoint – the proportion of patients with a Clinical Global Impressions rating of 1 or 2, meaning normal or only mildly mentally ill – wasn’t significantly different with KarXT, compared with placebo, but Dr. Brannan shrugged that off.

“In hindsight, it was probably a little overly optimistic to think that after 5 weeks [patients with schizophrenia] would be either well or almost well,” he quipped.

An exploratory analysis of participants’ before-and-after scores on a battery of six cognitive tests showed an encouraging trend: Patients on KarXT performed numerically better than did controls on five of the six tests, albeit not significantly so. Moreover, in a further analysis stratified by baseline impairment, patients in the most impaired tertile showed a larger, statistically significant benefit in response to KarXT.

“We’re interested enough that we plan to continue to look at this in our upcoming larger and longer-term trials,” Dr. Brannan said.

As for safety and tolerability, he continued: “We were pleasantly surprised. We certainly see more side effects with KarXT than with placebo, but not by that much, and they’re much, much better than with xanomeline alone.”

The side effects, mostly cholinergic and anticholinergic, occurred 2-4 times more frequently than in controls. Notably, the rates of nausea, vomiting, and dry mouth – three of the five most common treatment-related adverse events in patients on KarXT – decreased over time to levels similar to placebo by week 5. In contrast, rates of constipation and dyspepsia remained stable over time. All side effects were mild to moderate, and none led to study discontinuation.

A key point was that the KarXT-related side effects were not the same ones that are commonly problematic and limiting with current antipsychotics. There was no weight gain or other metabolic changes, sleepiness or sedation, or extrapyramidal symptoms.

“These results show KarXT has the potential to offer patients a novel mechanism-of-action antipsychotic with a different efficacy and/or tolerability profile than current antipsychotic medications,” Dr. Brannan said.

 

BI 425809

BI 425809 is a once-daily oral inhibitor of glycine transporter 1 (Gly-T1) specifically designed to alleviate cognitive impairment in people with schizophrenia. Underactivity by the NMDA (N-methyl-D-aspartic acid) receptor has been implicated in this cognitive dysfunction. Glycine is an NMDA cotransmitter. By blocking glutamatergic presynaptic and astrocyte reuptake of glycine, BI 425809 results in increased glycine levels in the synaptic cleft, facilitating neurotransmission, explained W. Wolfgang Fleischhacker, MD, president of the Medical University of Innsbruck (Austria), where he is also professor of psychiatry.

He presented the results of a phase 2, randomized, double-blind, 11-country study in which 509 adults with stable schizophrenia on no more than two antipsychotics were placed on add-on BI 425809 at 2, 5, 10, or 25 mg once daily or placebo for 12 weeks.

The primary endpoint was change from baseline to 12 weeks in the MATRICS (Measurement and Treatment Research to Improve Cognition in Schizophrenia) Consensus Cognitive Battery (MCCB) score. The results were strongly positive, with patients on the two top doses of BI 425809 – 10 and 25 mg/day – showing roughly a 2-point greater improvement in MCCB overall composite T-score compared with controls. Dr. Fleischhacker drew attention to the high study completion rates in the various study arms, ranging from a low of 91% to 97.6% in the 25 mg/day group.

“That’s a very nice but also an unusual finding for a trial of this length,” he observed.

The high study completion rate was a reflection of the drug’s high-level tolerability. Indeed, the rate of adverse events leading to treatment discontinuation was 0% with BI 425809 at 10 mg/day, 2.4% at 25 mg/day, and identical at 2.4% with placebo. No increase was found in psychiatric adverse events such as suicidal ideation or behavior.

“This is a first very promising result,” Dr. Fleischhacker concluded. “Basically, this is the first study that has really shown in a convincing fashion an effect of any novel compound on cognitive impairment in people suffering from schizophrenia.”

A separate ongoing phase 2 study is evaluating BI 425809 in combination with adjunctive computerized cognitive training in an effort to increase cognitive stimulation. The company is awaiting those study results before designing its phase 3 program.
 

Pimavanserin

It has been a busy year for pimavanserin, with both successes and disappointments in clinical trials addressing a range of psychotic disorders, according to Dragana Bugarski-Kirola, MD, MBA, MSc, vice president for clinical development at Acadia Pharmaceuticals in San Diego.

At present, pimavanserin is Food and Drug Administration–approved as Nuplazid only for treatment of hallucinations and delusions associated with Parkinson’s disease psychosis. But in July 2020, on the strength of the positive results of the pivotal phase 3 HARMONY trial, Acadia filed an application with the FDA for marketing approval of the drug for treatment of dementia-related psychosis. In HARMONY, patients on placebo proved to be 2.8-fold more likely to experience a relapse of delusions or hallucinations than with pimavanserin.

A big recent disappointment was that pimavanserin failed to meet its primary endpoint in the phase 3 CLARITY I and CLARITY II trials as adjunctive therapy for major depressive disorder inadequately responsive to a selective serotonin reuptake inhibitor or serotonin norepinephrine reuptake inhibitor. The change in Hamilton Depression Rating Scale–17 scores in patients on the atypical antipsychotic wasn’t significantly better than with placebo. However, pimavanserin did outperform placebo on the secondary endpoint of Clinical Global Impression–Severity. Additional clinical trials of the drug for treatment of major depression are planned, Dr. Bugarski-Kirola said.
 

 

LY500307

Although schizophrenia is equally common in men and women, the disease has a later onset and more benign course in women. This suggests a possible protective effect of estrogen, and indeed, extensive literature supports the use of exogenous estrogen in schizophrenia, where it reduces relapses and improves cognitive impairment and negative symptoms.

“We have no other agents that do that,” noted Dr. Breier, also chief of the psychotic disorders program and director of the Prevention and Recovery Center at Indiana University.

What he considers the best-executed clinical trial of estradiol in schizophrenia, an 8-week, double-blind, randomized study of a 200-mcg estradiol patch or placebo in 200 women aged 19-46 on antipsychotics, was published last year (JAMA Psychiatry. 2019 Jul 31;76[10]:1-9).

The results were impressive. However, estrogen may not be a viable treatment for men and premenopausal women because of its side effects, including feminization, and increased thrombotic and malignancy risks.

This was the impetus for the placebo-controlled randomized trial of LY500307, a highly selective estrogen receptor beta agonist originally developed by Eli Lilly as a potential treatment for benign prostatic hypertrophy, for which it proved ineffective. In animal models, estrogen receptor beta is responsible for a range of effects, including enhanced cognition, social behavior, and an anxiolytic action, whereas the alpha receptor affects the sex organs, skeletal and metabolic homeostasis, and is responsible for estrogen’s problematic side effects.

All three doses studied in the phase 2 randomized trial, which included 94 men with schizophrenia, proved safe, well-tolerated – and ineffective.

“I think one potential conclusion one could consider from these data is that estrogen receptor alpha engagement may be necessary for the estrogenic therapeutics in schizophrenia,” Dr. Breier said.

He reported having no financial conflicts regarding the trial, funded by Indiana University. Outside the scope of the study, he serves as a consultant to Karuna Therapeutics, BioXcel, and Perception Neuroscience.

Dr. Fleischhacker serves as a consultant to Boehringer Ingelheim, which sponsored the phase 2 study of BI 425809, as well as to Angelini, Richter, and Recordati.
 

[email protected]

SOURCE: ECNP 2020, Session S.12.

 

Two oral agents with novel mechanisms of action in schizophrenia generated considerable audience interest after acing large phase 2 clinical trials presented at the virtual congress of the European College of Neuropsychopharmacology.

The two successful drugs moving on to definitive phase 3 studies after their performance at ECNP 2020 are KarXT, a proprietary combination of xanomeline and trospium chloride, and an inhibitor of glycine transporter 1 (Gly-T1) known for now as BI 425809.

Pimavanserin, an oral selective serotonin inverse agonist with a high affinity for 5-HT2A receptors and low affinity for 5-HT2C receptors, has taken a more convoluted path through the developmental pipeline for schizophrenia. It recently failed to outperform placebo as adjunctive treatment for schizophrenia on the primary endpoint of improvement in Positive And Negative Syndrome Scale (PANSS) total score in the 6-week, phase 3 ENHANCE (Efficacy and Safety of Adjunctive Pimavanserin for the Treatment of Schizophrenia) study. The drug did, however, show significant benefit on secondary endpoints involving negative symptoms.

And in the 400-patient, 26-week, placebo-controlled, phase 2 ADVANCE trial, adjunctive pimavanserin was positive for the primary endpoint of improvement in the Negative Symptom Assessment-16 (NSA-16) score. A phase 3 program evaluating the drug specifically for negative symptoms is underway.

Another novel therapy, an investigational selective estrogen receptor beta agonist, proved reassuringly safe but completely ineffective in men with schizophrenia in a study presented at ECNP 2020.

“The results, unfortunately, were disappointing. We saw no signal on cognition, no change on brain imaging with fMRI, and no improvement in negative symptoms or PANSS total score,” reported Alan Breier, MD, professor and vice chair of the department of psychiatry at Indiana University in Indianapolis.

The congress session on new medications with novel mechanisms was a meeting highlight. Broad agreement exists that current antipsychotics targeting D2 dopamine and serotonin receptors in schizophrenia leave much to be desired. They’re ineffective for two of the three major symptom categories that define schizophrenia: cognitive impairment and negative symptoms, such as apathy and social withdrawal. And even for the current antipsychotics’ forte – treatment of positive symptoms, including hallucinations and delusions – effectiveness is often only modest to moderate and accompanied by limiting side effects.

KarXT

KarXT combines xanomeline, a selective M1/M4 muscarinic receptor agonist exclusively licensed from Lilly to Karuna Therapeutics, with trospium chloride, a muscarinic antagonist approved for more than a decade in the United States and Europe for treatment of overactive bladder. Xanomeline was synthesized in the 1990s. It showed promising evidence of antipsychotic efficacy in schizophrenia and Alzheimer’s disease in yearlong clinical trials totaling more than 800 patients, but interest in further developing the drug cooled because of limiting GI and other cholinergic adverse events. KarXT, Karuna’s lead product candidate, is designed to maintain the efficacy of xanomeline while trospium, which doesn’t cross the blood-brain barrier, cancels out its side effects, explained Stephen Brannan, MD, a psychiatrist and chief medical officer at the company.

He presented the results of the phase 2 study, a multicenter, randomized, double-blind, placebo-controlled, 5-week trial conducted with 182 schizophrenia inpatients experiencing an acute psychotic exacerbation. All other antipsychotics were washed out before randomization to KarXT at 50 mg xanomeline/20 mg trospium twice daily, titrated to 100/20 twice daily on days 3-7 and 100/20 b.i.d. thereafter, with an optional increase to 125/30 twice daily.

The primary study endpoint was change from baseline to week 5 in PANSS total score. The results were positive at the P < .0001 level, with a mean 17.4-point reduction in the KarXT group, compared with a 5.9-point improvement in placebo-treated controls. The between-group difference was significant by the first assessment at week 2.

Four of five prespecified secondary endpoints were also positive in rapid and sustained fashion: improvement in the PANSS positive subscore, PANSS negative subscore, Marder PANSS negative subscore, and Clinical Global Impressions-Severity. The fifth secondary endpoint – the proportion of patients with a Clinical Global Impressions rating of 1 or 2, meaning normal or only mildly mentally ill – wasn’t significantly different with KarXT, compared with placebo, but Dr. Brannan shrugged that off.

“In hindsight, it was probably a little overly optimistic to think that after 5 weeks [patients with schizophrenia] would be either well or almost well,” he quipped.

An exploratory analysis of participants’ before-and-after scores on a battery of six cognitive tests showed an encouraging trend: Patients on KarXT performed numerically better than did controls on five of the six tests, albeit not significantly so. Moreover, in a further analysis stratified by baseline impairment, patients in the most impaired tertile showed a larger, statistically significant benefit in response to KarXT.

“We’re interested enough that we plan to continue to look at this in our upcoming larger and longer-term trials,” Dr. Brannan said.

As for safety and tolerability, he continued: “We were pleasantly surprised. We certainly see more side effects with KarXT than with placebo, but not by that much, and they’re much, much better than with xanomeline alone.”

The side effects, mostly cholinergic and anticholinergic, occurred 2-4 times more frequently than in controls. Notably, the rates of nausea, vomiting, and dry mouth – three of the five most common treatment-related adverse events in patients on KarXT – decreased over time to levels similar to placebo by week 5. In contrast, rates of constipation and dyspepsia remained stable over time. All side effects were mild to moderate, and none led to study discontinuation.

A key point was that the KarXT-related side effects were not the same ones that are commonly problematic and limiting with current antipsychotics. There was no weight gain or other metabolic changes, sleepiness or sedation, or extrapyramidal symptoms.

“These results show KarXT has the potential to offer patients a novel mechanism-of-action antipsychotic with a different efficacy and/or tolerability profile than current antipsychotic medications,” Dr. Brannan said.

 

BI 425809

BI 425809 is a once-daily oral inhibitor of glycine transporter 1 (Gly-T1) specifically designed to alleviate cognitive impairment in people with schizophrenia. Underactivity by the NMDA (N-methyl-D-aspartic acid) receptor has been implicated in this cognitive dysfunction. Glycine is an NMDA cotransmitter. By blocking glutamatergic presynaptic and astrocyte reuptake of glycine, BI 425809 results in increased glycine levels in the synaptic cleft, facilitating neurotransmission, explained W. Wolfgang Fleischhacker, MD, president of the Medical University of Innsbruck (Austria), where he is also professor of psychiatry.

He presented the results of a phase 2, randomized, double-blind, 11-country study in which 509 adults with stable schizophrenia on no more than two antipsychotics were placed on add-on BI 425809 at 2, 5, 10, or 25 mg once daily or placebo for 12 weeks.

The primary endpoint was change from baseline to 12 weeks in the MATRICS (Measurement and Treatment Research to Improve Cognition in Schizophrenia) Consensus Cognitive Battery (MCCB) score. The results were strongly positive, with patients on the two top doses of BI 425809 – 10 and 25 mg/day – showing roughly a 2-point greater improvement in MCCB overall composite T-score compared with controls. Dr. Fleischhacker drew attention to the high study completion rates in the various study arms, ranging from a low of 91% to 97.6% in the 25 mg/day group.

“That’s a very nice but also an unusual finding for a trial of this length,” he observed.

The high study completion rate was a reflection of the drug’s high-level tolerability. Indeed, the rate of adverse events leading to treatment discontinuation was 0% with BI 425809 at 10 mg/day, 2.4% at 25 mg/day, and identical at 2.4% with placebo. No increase was found in psychiatric adverse events such as suicidal ideation or behavior.

“This is a first very promising result,” Dr. Fleischhacker concluded. “Basically, this is the first study that has really shown in a convincing fashion an effect of any novel compound on cognitive impairment in people suffering from schizophrenia.”

A separate ongoing phase 2 study is evaluating BI 425809 in combination with adjunctive computerized cognitive training in an effort to increase cognitive stimulation. The company is awaiting those study results before designing its phase 3 program.
 

Pimavanserin

It has been a busy year for pimavanserin, with both successes and disappointments in clinical trials addressing a range of psychotic disorders, according to Dragana Bugarski-Kirola, MD, MBA, MSc, vice president for clinical development at Acadia Pharmaceuticals in San Diego.

At present, pimavanserin is Food and Drug Administration–approved as Nuplazid only for treatment of hallucinations and delusions associated with Parkinson’s disease psychosis. But in July 2020, on the strength of the positive results of the pivotal phase 3 HARMONY trial, Acadia filed an application with the FDA for marketing approval of the drug for treatment of dementia-related psychosis. In HARMONY, patients on placebo proved to be 2.8-fold more likely to experience a relapse of delusions or hallucinations than with pimavanserin.

A big recent disappointment was that pimavanserin failed to meet its primary endpoint in the phase 3 CLARITY I and CLARITY II trials as adjunctive therapy for major depressive disorder inadequately responsive to a selective serotonin reuptake inhibitor or serotonin norepinephrine reuptake inhibitor. The change in Hamilton Depression Rating Scale–17 scores in patients on the atypical antipsychotic wasn’t significantly better than with placebo. However, pimavanserin did outperform placebo on the secondary endpoint of Clinical Global Impression–Severity. Additional clinical trials of the drug for treatment of major depression are planned, Dr. Bugarski-Kirola said.
 

 

LY500307

Although schizophrenia is equally common in men and women, the disease has a later onset and more benign course in women. This suggests a possible protective effect of estrogen, and indeed, extensive literature supports the use of exogenous estrogen in schizophrenia, where it reduces relapses and improves cognitive impairment and negative symptoms.

“We have no other agents that do that,” noted Dr. Breier, also chief of the psychotic disorders program and director of the Prevention and Recovery Center at Indiana University.

What he considers the best-executed clinical trial of estradiol in schizophrenia, an 8-week, double-blind, randomized study of a 200-mcg estradiol patch or placebo in 200 women aged 19-46 on antipsychotics, was published last year (JAMA Psychiatry. 2019 Jul 31;76[10]:1-9).

The results were impressive. However, estrogen may not be a viable treatment for men and premenopausal women because of its side effects, including feminization, and increased thrombotic and malignancy risks.

This was the impetus for the placebo-controlled randomized trial of LY500307, a highly selective estrogen receptor beta agonist originally developed by Eli Lilly as a potential treatment for benign prostatic hypertrophy, for which it proved ineffective. In animal models, estrogen receptor beta is responsible for a range of effects, including enhanced cognition, social behavior, and an anxiolytic action, whereas the alpha receptor affects the sex organs, skeletal and metabolic homeostasis, and is responsible for estrogen’s problematic side effects.

All three doses studied in the phase 2 randomized trial, which included 94 men with schizophrenia, proved safe, well-tolerated – and ineffective.

“I think one potential conclusion one could consider from these data is that estrogen receptor alpha engagement may be necessary for the estrogenic therapeutics in schizophrenia,” Dr. Breier said.

He reported having no financial conflicts regarding the trial, funded by Indiana University. Outside the scope of the study, he serves as a consultant to Karuna Therapeutics, BioXcel, and Perception Neuroscience.

Dr. Fleischhacker serves as a consultant to Boehringer Ingelheim, which sponsored the phase 2 study of BI 425809, as well as to Angelini, Richter, and Recordati.
 

[email protected]

SOURCE: ECNP 2020, Session S.12.

 

Two oral agents with novel mechanisms of action in schizophrenia generated considerable audience interest after acing large phase 2 clinical trials presented at the virtual congress of the European College of Neuropsychopharmacology.

The two successful drugs moving on to definitive phase 3 studies after their performance at ECNP 2020 are KarXT, a proprietary combination of xanomeline and trospium chloride, and an inhibitor of glycine transporter 1 (Gly-T1) known for now as BI 425809.

Pimavanserin, an oral selective serotonin inverse agonist with a high affinity for 5-HT2A receptors and low affinity for 5-HT2C receptors, has taken a more convoluted path through the developmental pipeline for schizophrenia. It recently failed to outperform placebo as adjunctive treatment for schizophrenia on the primary endpoint of improvement in Positive And Negative Syndrome Scale (PANSS) total score in the 6-week, phase 3 ENHANCE (Efficacy and Safety of Adjunctive Pimavanserin for the Treatment of Schizophrenia) study. The drug did, however, show significant benefit on secondary endpoints involving negative symptoms.

And in the 400-patient, 26-week, placebo-controlled, phase 2 ADVANCE trial, adjunctive pimavanserin was positive for the primary endpoint of improvement in the Negative Symptom Assessment-16 (NSA-16) score. A phase 3 program evaluating the drug specifically for negative symptoms is underway.

Another novel therapy, an investigational selective estrogen receptor beta agonist, proved reassuringly safe but completely ineffective in men with schizophrenia in a study presented at ECNP 2020.

“The results, unfortunately, were disappointing. We saw no signal on cognition, no change on brain imaging with fMRI, and no improvement in negative symptoms or PANSS total score,” reported Alan Breier, MD, professor and vice chair of the department of psychiatry at Indiana University in Indianapolis.

The congress session on new medications with novel mechanisms was a meeting highlight. Broad agreement exists that current antipsychotics targeting D2 dopamine and serotonin receptors in schizophrenia leave much to be desired. They’re ineffective for two of the three major symptom categories that define schizophrenia: cognitive impairment and negative symptoms, such as apathy and social withdrawal. And even for the current antipsychotics’ forte – treatment of positive symptoms, including hallucinations and delusions – effectiveness is often only modest to moderate and accompanied by limiting side effects.

KarXT

KarXT combines xanomeline, a selective M1/M4 muscarinic receptor agonist exclusively licensed from Lilly to Karuna Therapeutics, with trospium chloride, a muscarinic antagonist approved for more than a decade in the United States and Europe for treatment of overactive bladder. Xanomeline was synthesized in the 1990s. It showed promising evidence of antipsychotic efficacy in schizophrenia and Alzheimer’s disease in yearlong clinical trials totaling more than 800 patients, but interest in further developing the drug cooled because of limiting GI and other cholinergic adverse events. KarXT, Karuna’s lead product candidate, is designed to maintain the efficacy of xanomeline while trospium, which doesn’t cross the blood-brain barrier, cancels out its side effects, explained Stephen Brannan, MD, a psychiatrist and chief medical officer at the company.

He presented the results of the phase 2 study, a multicenter, randomized, double-blind, placebo-controlled, 5-week trial conducted with 182 schizophrenia inpatients experiencing an acute psychotic exacerbation. All other antipsychotics were washed out before randomization to KarXT at 50 mg xanomeline/20 mg trospium twice daily, titrated to 100/20 twice daily on days 3-7 and 100/20 b.i.d. thereafter, with an optional increase to 125/30 twice daily.

The primary study endpoint was change from baseline to week 5 in PANSS total score. The results were positive at the P < .0001 level, with a mean 17.4-point reduction in the KarXT group, compared with a 5.9-point improvement in placebo-treated controls. The between-group difference was significant by the first assessment at week 2.

Four of five prespecified secondary endpoints were also positive in rapid and sustained fashion: improvement in the PANSS positive subscore, PANSS negative subscore, Marder PANSS negative subscore, and Clinical Global Impressions-Severity. The fifth secondary endpoint – the proportion of patients with a Clinical Global Impressions rating of 1 or 2, meaning normal or only mildly mentally ill – wasn’t significantly different with KarXT, compared with placebo, but Dr. Brannan shrugged that off.

“In hindsight, it was probably a little overly optimistic to think that after 5 weeks [patients with schizophrenia] would be either well or almost well,” he quipped.

An exploratory analysis of participants’ before-and-after scores on a battery of six cognitive tests showed an encouraging trend: Patients on KarXT performed numerically better than did controls on five of the six tests, albeit not significantly so. Moreover, in a further analysis stratified by baseline impairment, patients in the most impaired tertile showed a larger, statistically significant benefit in response to KarXT.

“We’re interested enough that we plan to continue to look at this in our upcoming larger and longer-term trials,” Dr. Brannan said.

As for safety and tolerability, he continued: “We were pleasantly surprised. We certainly see more side effects with KarXT than with placebo, but not by that much, and they’re much, much better than with xanomeline alone.”

The side effects, mostly cholinergic and anticholinergic, occurred 2-4 times more frequently than in controls. Notably, the rates of nausea, vomiting, and dry mouth – three of the five most common treatment-related adverse events in patients on KarXT – decreased over time to levels similar to placebo by week 5. In contrast, rates of constipation and dyspepsia remained stable over time. All side effects were mild to moderate, and none led to study discontinuation.

A key point was that the KarXT-related side effects were not the same ones that are commonly problematic and limiting with current antipsychotics. There was no weight gain or other metabolic changes, sleepiness or sedation, or extrapyramidal symptoms.

“These results show KarXT has the potential to offer patients a novel mechanism-of-action antipsychotic with a different efficacy and/or tolerability profile than current antipsychotic medications,” Dr. Brannan said.

 

BI 425809

BI 425809 is a once-daily oral inhibitor of glycine transporter 1 (Gly-T1) specifically designed to alleviate cognitive impairment in people with schizophrenia. Underactivity by the NMDA (N-methyl-D-aspartic acid) receptor has been implicated in this cognitive dysfunction. Glycine is an NMDA cotransmitter. By blocking glutamatergic presynaptic and astrocyte reuptake of glycine, BI 425809 results in increased glycine levels in the synaptic cleft, facilitating neurotransmission, explained W. Wolfgang Fleischhacker, MD, president of the Medical University of Innsbruck (Austria), where he is also professor of psychiatry.

He presented the results of a phase 2, randomized, double-blind, 11-country study in which 509 adults with stable schizophrenia on no more than two antipsychotics were placed on add-on BI 425809 at 2, 5, 10, or 25 mg once daily or placebo for 12 weeks.

The primary endpoint was change from baseline to 12 weeks in the MATRICS (Measurement and Treatment Research to Improve Cognition in Schizophrenia) Consensus Cognitive Battery (MCCB) score. The results were strongly positive, with patients on the two top doses of BI 425809 – 10 and 25 mg/day – showing roughly a 2-point greater improvement in MCCB overall composite T-score compared with controls. Dr. Fleischhacker drew attention to the high study completion rates in the various study arms, ranging from a low of 91% to 97.6% in the 25 mg/day group.

“That’s a very nice but also an unusual finding for a trial of this length,” he observed.

The high study completion rate was a reflection of the drug’s high-level tolerability. Indeed, the rate of adverse events leading to treatment discontinuation was 0% with BI 425809 at 10 mg/day, 2.4% at 25 mg/day, and identical at 2.4% with placebo. No increase was found in psychiatric adverse events such as suicidal ideation or behavior.

“This is a first very promising result,” Dr. Fleischhacker concluded. “Basically, this is the first study that has really shown in a convincing fashion an effect of any novel compound on cognitive impairment in people suffering from schizophrenia.”

A separate ongoing phase 2 study is evaluating BI 425809 in combination with adjunctive computerized cognitive training in an effort to increase cognitive stimulation. The company is awaiting those study results before designing its phase 3 program.
 

Pimavanserin

It has been a busy year for pimavanserin, with both successes and disappointments in clinical trials addressing a range of psychotic disorders, according to Dragana Bugarski-Kirola, MD, MBA, MSc, vice president for clinical development at Acadia Pharmaceuticals in San Diego.

At present, pimavanserin is Food and Drug Administration–approved as Nuplazid only for treatment of hallucinations and delusions associated with Parkinson’s disease psychosis. But in July 2020, on the strength of the positive results of the pivotal phase 3 HARMONY trial, Acadia filed an application with the FDA for marketing approval of the drug for treatment of dementia-related psychosis. In HARMONY, patients on placebo proved to be 2.8-fold more likely to experience a relapse of delusions or hallucinations than with pimavanserin.

A big recent disappointment was that pimavanserin failed to meet its primary endpoint in the phase 3 CLARITY I and CLARITY II trials as adjunctive therapy for major depressive disorder inadequately responsive to a selective serotonin reuptake inhibitor or serotonin norepinephrine reuptake inhibitor. The change in Hamilton Depression Rating Scale–17 scores in patients on the atypical antipsychotic wasn’t significantly better than with placebo. However, pimavanserin did outperform placebo on the secondary endpoint of Clinical Global Impression–Severity. Additional clinical trials of the drug for treatment of major depression are planned, Dr. Bugarski-Kirola said.
 

 

LY500307

Although schizophrenia is equally common in men and women, the disease has a later onset and more benign course in women. This suggests a possible protective effect of estrogen, and indeed, extensive literature supports the use of exogenous estrogen in schizophrenia, where it reduces relapses and improves cognitive impairment and negative symptoms.

“We have no other agents that do that,” noted Dr. Breier, also chief of the psychotic disorders program and director of the Prevention and Recovery Center at Indiana University.

What he considers the best-executed clinical trial of estradiol in schizophrenia, an 8-week, double-blind, randomized study of a 200-mcg estradiol patch or placebo in 200 women aged 19-46 on antipsychotics, was published last year (JAMA Psychiatry. 2019 Jul 31;76[10]:1-9).

The results were impressive. However, estrogen may not be a viable treatment for men and premenopausal women because of its side effects, including feminization, and increased thrombotic and malignancy risks.

This was the impetus for the placebo-controlled randomized trial of LY500307, a highly selective estrogen receptor beta agonist originally developed by Eli Lilly as a potential treatment for benign prostatic hypertrophy, for which it proved ineffective. In animal models, estrogen receptor beta is responsible for a range of effects, including enhanced cognition, social behavior, and an anxiolytic action, whereas the alpha receptor affects the sex organs, skeletal and metabolic homeostasis, and is responsible for estrogen’s problematic side effects.

All three doses studied in the phase 2 randomized trial, which included 94 men with schizophrenia, proved safe, well-tolerated – and ineffective.

“I think one potential conclusion one could consider from these data is that estrogen receptor alpha engagement may be necessary for the estrogenic therapeutics in schizophrenia,” Dr. Breier said.

He reported having no financial conflicts regarding the trial, funded by Indiana University. Outside the scope of the study, he serves as a consultant to Karuna Therapeutics, BioXcel, and Perception Neuroscience.

Dr. Fleischhacker serves as a consultant to Boehringer Ingelheim, which sponsored the phase 2 study of BI 425809, as well as to Angelini, Richter, and Recordati.
 

[email protected]

SOURCE: ECNP 2020, Session S.12.