Doug Brunk

LAS VEGAS – Between 2010 and 2017, the proportion of newly diagnosed cases of acute hepatitis C virus infection rose threefold, driven largely by the concomitant opioid epidemic.

Doug Brunk/MDedge News

That makes efforts to screen, diagnose, and cure high-risk populations more important than ever, Stevan A. Gonzalez, MD, said at an annual psychopharmacology update held by the Nevada Psychiatric Association.

About 70% of HCV cases are related to injection drug use,” said Dr. Gonzalez, medical director of liver transplantation at the Baylor Simmons Transplant Institute at the Baylor Scott & White All Saints Medical Center in Fort Worth, Tex. “This is affecting whites as much as blacks and Hispanics, females as much as males, and in nonurban areas as much as in urban areas.”

Data from the Centers for Disease Control and Prevention and the Substance Abuse and Mental Health Services Administration indicate that during 2004-2014, the number of acute HCV cases among those aged 18-29 years increased 400%, and the use of injection opioids rose 600%.

At the same time, the number of HCV cases among those aged 30-39 years increased 325%, and the use of injection opioids rose 83%.

“We’re starting to see a pattern overlapping between HCV exposure and opioid injection,” Dr. Gonzalez said. Other high-risk populations include homeless and incarcerated individuals.

More than 70 million people worldwide have chronic HCV infection, Dr. Gonzalez noted, with possibly as many as 5 million cases in the United States. It remains the nation’s most common blood-borne infection.

Chronic disease develops in up to 85% of people who are exposed, infection is asymptomatic, and HCV remains one of the leading indications for liver transplantation and causes of liver cancer.

From a geographic standpoint, the prevalence of HCV in young adults is eclipsing that of Baby Boomers in several states in the Appalachian region and in Northeast, which have long been trouble spots for opioid use disorder (Gastroenterol. 2018 May;154[6]:1850-1).

Surprising exposure risk

The primary risk of transmission is through contaminated blood and the exposure through needles.

“It really doesn’t matter whether it’s a needle that has a small amount of dead space where a little bit of blood can remain or needles that have a larger amount of blood,” Dr. Gonzalez said.

“I’ve had patients who come to me and say, ‘I can’t believe I have HCV. It’s impossible. I always use my own needles. They’re always brand new; I’ve never shared with anybody,’” he continued.

“This is where education and awareness is so critical, because it’s not just the needles,” Dr. Gonzalez explained. “HCV can survive on inanimate objects. For example, on a tabletop surface or a water container, HCV can remain viable up to 3 weeks. In a syringe, 2 months. For that reason, HCV can also be transmitted through crack pipes and nasal drug use, where the prevalence can be up to 35%.”

The duration of a person’s HCV infection drives the transmission.

“That’s important to think about, because people who have chronic hepatitis C are infectious until they’re treated,” Dr. Gonzalez said. “If they don’t know that they have hepatitis C, they continue to transmit the virus to others.”

One study found that half of people living with HCV are unaware of their infection (PLoS One. 2014 Jul 2;9[7]:e101554). According to Dr. Gonzalez, forthcoming guidelines from the U.S. Preventive Services Task Force are expected to recommend a one-time screening for HCV infection in all adults aged 18-79 years, a Grade B recommendation. “That’s a big deal,” he said. (The draft recommendations are available here.)

HCV infection disproportionately affects individuals in correctional institutions. In fact, an estimated one in three inmates in the United States has chronic HCV.

“This is sort of a forgotten population with a lot of substance use and mental illness,” Dr. Gonzalez said. “Injection drug use in that setting is the most common risk factor: It’s about 60% in terms of the risk of transmission within correctional settings. HCV-associated liver disease has now surpassed HIV as a cause of death within correctional settings.”
 

Weighing treatment options

The most common oral regimens for chronic HCV include sofosbuvir/ledipasvir, sofosbuvir/velpatasvir, and glecaprevir/pibrentasvir. They achieve cure in 93%-100% of cases.

“HCV can be cured; it can be eradicated from the body long term,” Dr. Gonzalez said. “The choice of regimen, treatment duration, and use of ribavirin depends on the presence/absence of cirrhosis, prior treatment experience, and the genotype.”

All six forms of the HCV genotype can be treated with oral medication, he added, and methadone, bupropion, and naloxone are safe to use during therapy.

Reinfection following HCV treatment occurs infrequently. Dr. Gonzalez cited a randomized, controlled trial presented as an abstract at the 2018 annual meeting of the American Association for the Study of Liver Diseases. That study’s researchers found that – among 199 patients on opioid-replacement therapy who were receiving direct-acting antiviral therapy, in whom greater than 50% were actively using drugs – the rate of reinfection at 3 years was 1.8 reinfections/100 person-years.

“That’s lower than people expect,” Dr. Gonzalez said.
 

How to boost screening

Electronic health record systems can be used as an important tool to increase HCV screening in health care settings.

In 2017, researchers published an analysis of three randomized trials carried out at three separate primary care settings to improve screening for HCV: repeated mailings, an EHR best practice alert (BPA), and patient solicitation (Hepatology 2017 Jan;65[1]:44-53). They evaluated HCV antibody testing, diagnosis, and costs for each of the interventions, compared with standard-of-care testing.

The investigators found that the BPA intervention had the lowest incremental cost per completed test – $24 with fixed start-up costs, including technical design and development of the BPA system; $3 without fixed start-up costs. The BPA intervention also had the lowest incremental cost per new case identified.

Other efforts to expand access to screening and treatment are underway.

In 2019, Louisiana health officials negotiated a one-time fee for unlimited access for 5 years to sofosbuvir/velpatasvir (Epclusa) to treat the estimated 30,000 patients on Louisiana Medicaid and in that state’s department of corrections who have HCV.

“The goal is 90% cure; the burden is on the state health department to screen, diagnose, and dispense medication,” Dr. Gonzalez said.

Also in 2019, the state of Washington used an open bidding process to negotiate access to glecaprevir/pibrentasvir (Mavyret) for the state’s Medicaid population who have HCV.

“Those states are setting the pace,” Dr. Gonzalez said. “They are showing examples of how we can start implementing a process to treat these vulnerable populations.”

Meanwhile, the World Health Organization set a goal of eliminating viral hepatitis as a major public health threat by 2030.

“That sounds ambitious, but I think it’s possible,” Dr. Gonzalez said. “It’s important to address these high-risk populations: the incarcerated, people who use drugs, and the homeless, because those are the groups that have a high prevalence of HCV – mainly through injection drug use.

“If we don’t address that population, and we only target the general population, we’re going to have a continual source of transmission,” Dr. Gonzalez warned. “In that case, we would never be able to achieve elimination.”

Dr. Gonzalez disclosed that he is a member of the speakers bureau for AbbVie and Salix.

[email protected]

LAS VEGAS – Between 2010 and 2017, the proportion of newly diagnosed cases of acute hepatitis C virus infection rose threefold, driven largely by the concomitant opioid epidemic.

Doug Brunk/MDedge News

That makes efforts to screen, diagnose, and cure high-risk populations more important than ever, Stevan A. Gonzalez, MD, said at an annual psychopharmacology update held by the Nevada Psychiatric Association.

About 70% of HCV cases are related to injection drug use,” said Dr. Gonzalez, medical director of liver transplantation at the Baylor Simmons Transplant Institute at the Baylor Scott & White All Saints Medical Center in Fort Worth, Tex. “This is affecting whites as much as blacks and Hispanics, females as much as males, and in nonurban areas as much as in urban areas.”

Data from the Centers for Disease Control and Prevention and the Substance Abuse and Mental Health Services Administration indicate that during 2004-2014, the number of acute HCV cases among those aged 18-29 years increased 400%, and the use of injection opioids rose 600%.

At the same time, the number of HCV cases among those aged 30-39 years increased 325%, and the use of injection opioids rose 83%.

“We’re starting to see a pattern overlapping between HCV exposure and opioid injection,” Dr. Gonzalez said. Other high-risk populations include homeless and incarcerated individuals.

More than 70 million people worldwide have chronic HCV infection, Dr. Gonzalez noted, with possibly as many as 5 million cases in the United States. It remains the nation’s most common blood-borne infection.

Chronic disease develops in up to 85% of people who are exposed, infection is asymptomatic, and HCV remains one of the leading indications for liver transplantation and causes of liver cancer.

From a geographic standpoint, the prevalence of HCV in young adults is eclipsing that of Baby Boomers in several states in the Appalachian region and in Northeast, which have long been trouble spots for opioid use disorder (Gastroenterol. 2018 May;154[6]:1850-1).

Surprising exposure risk

The primary risk of transmission is through contaminated blood and the exposure through needles.

“It really doesn’t matter whether it’s a needle that has a small amount of dead space where a little bit of blood can remain or needles that have a larger amount of blood,” Dr. Gonzalez said.

“I’ve had patients who come to me and say, ‘I can’t believe I have HCV. It’s impossible. I always use my own needles. They’re always brand new; I’ve never shared with anybody,’” he continued.

“This is where education and awareness is so critical, because it’s not just the needles,” Dr. Gonzalez explained. “HCV can survive on inanimate objects. For example, on a tabletop surface or a water container, HCV can remain viable up to 3 weeks. In a syringe, 2 months. For that reason, HCV can also be transmitted through crack pipes and nasal drug use, where the prevalence can be up to 35%.”

The duration of a person’s HCV infection drives the transmission.

“That’s important to think about, because people who have chronic hepatitis C are infectious until they’re treated,” Dr. Gonzalez said. “If they don’t know that they have hepatitis C, they continue to transmit the virus to others.”

One study found that half of people living with HCV are unaware of their infection (PLoS One. 2014 Jul 2;9[7]:e101554). According to Dr. Gonzalez, forthcoming guidelines from the U.S. Preventive Services Task Force are expected to recommend a one-time screening for HCV infection in all adults aged 18-79 years, a Grade B recommendation. “That’s a big deal,” he said. (The draft recommendations are available here.)

HCV infection disproportionately affects individuals in correctional institutions. In fact, an estimated one in three inmates in the United States has chronic HCV.

“This is sort of a forgotten population with a lot of substance use and mental illness,” Dr. Gonzalez said. “Injection drug use in that setting is the most common risk factor: It’s about 60% in terms of the risk of transmission within correctional settings. HCV-associated liver disease has now surpassed HIV as a cause of death within correctional settings.”
 

Weighing treatment options

The most common oral regimens for chronic HCV include sofosbuvir/ledipasvir, sofosbuvir/velpatasvir, and glecaprevir/pibrentasvir. They achieve cure in 93%-100% of cases.

“HCV can be cured; it can be eradicated from the body long term,” Dr. Gonzalez said. “The choice of regimen, treatment duration, and use of ribavirin depends on the presence/absence of cirrhosis, prior treatment experience, and the genotype.”

All six forms of the HCV genotype can be treated with oral medication, he added, and methadone, bupropion, and naloxone are safe to use during therapy.

Reinfection following HCV treatment occurs infrequently. Dr. Gonzalez cited a randomized, controlled trial presented as an abstract at the 2018 annual meeting of the American Association for the Study of Liver Diseases. That study’s researchers found that – among 199 patients on opioid-replacement therapy who were receiving direct-acting antiviral therapy, in whom greater than 50% were actively using drugs – the rate of reinfection at 3 years was 1.8 reinfections/100 person-years.

“That’s lower than people expect,” Dr. Gonzalez said.
 

How to boost screening

Electronic health record systems can be used as an important tool to increase HCV screening in health care settings.

In 2017, researchers published an analysis of three randomized trials carried out at three separate primary care settings to improve screening for HCV: repeated mailings, an EHR best practice alert (BPA), and patient solicitation (Hepatology 2017 Jan;65[1]:44-53). They evaluated HCV antibody testing, diagnosis, and costs for each of the interventions, compared with standard-of-care testing.

The investigators found that the BPA intervention had the lowest incremental cost per completed test – $24 with fixed start-up costs, including technical design and development of the BPA system; $3 without fixed start-up costs. The BPA intervention also had the lowest incremental cost per new case identified.

Other efforts to expand access to screening and treatment are underway.

In 2019, Louisiana health officials negotiated a one-time fee for unlimited access for 5 years to sofosbuvir/velpatasvir (Epclusa) to treat the estimated 30,000 patients on Louisiana Medicaid and in that state’s department of corrections who have HCV.

“The goal is 90% cure; the burden is on the state health department to screen, diagnose, and dispense medication,” Dr. Gonzalez said.

Also in 2019, the state of Washington used an open bidding process to negotiate access to glecaprevir/pibrentasvir (Mavyret) for the state’s Medicaid population who have HCV.

“Those states are setting the pace,” Dr. Gonzalez said. “They are showing examples of how we can start implementing a process to treat these vulnerable populations.”

Meanwhile, the World Health Organization set a goal of eliminating viral hepatitis as a major public health threat by 2030.

“That sounds ambitious, but I think it’s possible,” Dr. Gonzalez said. “It’s important to address these high-risk populations: the incarcerated, people who use drugs, and the homeless, because those are the groups that have a high prevalence of HCV – mainly through injection drug use.

“If we don’t address that population, and we only target the general population, we’re going to have a continual source of transmission,” Dr. Gonzalez warned. “In that case, we would never be able to achieve elimination.”

Dr. Gonzalez disclosed that he is a member of the speakers bureau for AbbVie and Salix.

[email protected]

LAS VEGAS – Between 2010 and 2017, the proportion of newly diagnosed cases of acute hepatitis C virus infection rose threefold, driven largely by the concomitant opioid epidemic.

Doug Brunk/MDedge News

That makes efforts to screen, diagnose, and cure high-risk populations more important than ever, Stevan A. Gonzalez, MD, said at an annual psychopharmacology update held by the Nevada Psychiatric Association.

About 70% of HCV cases are related to injection drug use,” said Dr. Gonzalez, medical director of liver transplantation at the Baylor Simmons Transplant Institute at the Baylor Scott & White All Saints Medical Center in Fort Worth, Tex. “This is affecting whites as much as blacks and Hispanics, females as much as males, and in nonurban areas as much as in urban areas.”

Data from the Centers for Disease Control and Prevention and the Substance Abuse and Mental Health Services Administration indicate that during 2004-2014, the number of acute HCV cases among those aged 18-29 years increased 400%, and the use of injection opioids rose 600%.

At the same time, the number of HCV cases among those aged 30-39 years increased 325%, and the use of injection opioids rose 83%.

“We’re starting to see a pattern overlapping between HCV exposure and opioid injection,” Dr. Gonzalez said. Other high-risk populations include homeless and incarcerated individuals.

More than 70 million people worldwide have chronic HCV infection, Dr. Gonzalez noted, with possibly as many as 5 million cases in the United States. It remains the nation’s most common blood-borne infection.

Chronic disease develops in up to 85% of people who are exposed, infection is asymptomatic, and HCV remains one of the leading indications for liver transplantation and causes of liver cancer.

From a geographic standpoint, the prevalence of HCV in young adults is eclipsing that of Baby Boomers in several states in the Appalachian region and in Northeast, which have long been trouble spots for opioid use disorder (Gastroenterol. 2018 May;154[6]:1850-1).

Surprising exposure risk

The primary risk of transmission is through contaminated blood and the exposure through needles.

“It really doesn’t matter whether it’s a needle that has a small amount of dead space where a little bit of blood can remain or needles that have a larger amount of blood,” Dr. Gonzalez said.

“I’ve had patients who come to me and say, ‘I can’t believe I have HCV. It’s impossible. I always use my own needles. They’re always brand new; I’ve never shared with anybody,’” he continued.

“This is where education and awareness is so critical, because it’s not just the needles,” Dr. Gonzalez explained. “HCV can survive on inanimate objects. For example, on a tabletop surface or a water container, HCV can remain viable up to 3 weeks. In a syringe, 2 months. For that reason, HCV can also be transmitted through crack pipes and nasal drug use, where the prevalence can be up to 35%.”

The duration of a person’s HCV infection drives the transmission.

“That’s important to think about, because people who have chronic hepatitis C are infectious until they’re treated,” Dr. Gonzalez said. “If they don’t know that they have hepatitis C, they continue to transmit the virus to others.”

One study found that half of people living with HCV are unaware of their infection (PLoS One. 2014 Jul 2;9[7]:e101554). According to Dr. Gonzalez, forthcoming guidelines from the U.S. Preventive Services Task Force are expected to recommend a one-time screening for HCV infection in all adults aged 18-79 years, a Grade B recommendation. “That’s a big deal,” he said. (The draft recommendations are available here.)

HCV infection disproportionately affects individuals in correctional institutions. In fact, an estimated one in three inmates in the United States has chronic HCV.

“This is sort of a forgotten population with a lot of substance use and mental illness,” Dr. Gonzalez said. “Injection drug use in that setting is the most common risk factor: It’s about 60% in terms of the risk of transmission within correctional settings. HCV-associated liver disease has now surpassed HIV as a cause of death within correctional settings.”
 

Weighing treatment options

The most common oral regimens for chronic HCV include sofosbuvir/ledipasvir, sofosbuvir/velpatasvir, and glecaprevir/pibrentasvir. They achieve cure in 93%-100% of cases.

“HCV can be cured; it can be eradicated from the body long term,” Dr. Gonzalez said. “The choice of regimen, treatment duration, and use of ribavirin depends on the presence/absence of cirrhosis, prior treatment experience, and the genotype.”

All six forms of the HCV genotype can be treated with oral medication, he added, and methadone, bupropion, and naloxone are safe to use during therapy.

Reinfection following HCV treatment occurs infrequently. Dr. Gonzalez cited a randomized, controlled trial presented as an abstract at the 2018 annual meeting of the American Association for the Study of Liver Diseases. That study’s researchers found that – among 199 patients on opioid-replacement therapy who were receiving direct-acting antiviral therapy, in whom greater than 50% were actively using drugs – the rate of reinfection at 3 years was 1.8 reinfections/100 person-years.

“That’s lower than people expect,” Dr. Gonzalez said.
 

How to boost screening

Electronic health record systems can be used as an important tool to increase HCV screening in health care settings.

In 2017, researchers published an analysis of three randomized trials carried out at three separate primary care settings to improve screening for HCV: repeated mailings, an EHR best practice alert (BPA), and patient solicitation (Hepatology 2017 Jan;65[1]:44-53). They evaluated HCV antibody testing, diagnosis, and costs for each of the interventions, compared with standard-of-care testing.

The investigators found that the BPA intervention had the lowest incremental cost per completed test – $24 with fixed start-up costs, including technical design and development of the BPA system; $3 without fixed start-up costs. The BPA intervention also had the lowest incremental cost per new case identified.

Other efforts to expand access to screening and treatment are underway.

In 2019, Louisiana health officials negotiated a one-time fee for unlimited access for 5 years to sofosbuvir/velpatasvir (Epclusa) to treat the estimated 30,000 patients on Louisiana Medicaid and in that state’s department of corrections who have HCV.

“The goal is 90% cure; the burden is on the state health department to screen, diagnose, and dispense medication,” Dr. Gonzalez said.

Also in 2019, the state of Washington used an open bidding process to negotiate access to glecaprevir/pibrentasvir (Mavyret) for the state’s Medicaid population who have HCV.

“Those states are setting the pace,” Dr. Gonzalez said. “They are showing examples of how we can start implementing a process to treat these vulnerable populations.”

Meanwhile, the World Health Organization set a goal of eliminating viral hepatitis as a major public health threat by 2030.

“That sounds ambitious, but I think it’s possible,” Dr. Gonzalez said. “It’s important to address these high-risk populations: the incarcerated, people who use drugs, and the homeless, because those are the groups that have a high prevalence of HCV – mainly through injection drug use.

“If we don’t address that population, and we only target the general population, we’re going to have a continual source of transmission,” Dr. Gonzalez warned. “In that case, we would never be able to achieve elimination.”

Dr. Gonzalez disclosed that he is a member of the speakers bureau for AbbVie and Salix.

[email protected]

LAS VEGAS – Clinicians should spend 1 hour with patients who present with a chief complaint of insomnia, rather than rushing to a treatment after a 10- to 15-minute office visit, according to John W. Winkelman, MD, PhD.

Doug Brunk/MDedge News

“Why? Because sleep problems are usually multifactorial, involving psychiatric illness, sleep disorders, medical illness, medication, and poor sleep hygiene/stress,” he said at an annual psychopharmacology update held by the Nevada Psychiatric Association. “There are usually many contributing problems, and sleep quality is only as strong as the weakest link. Maybe you don’t have an hour [to meet with new patients], but you need to give adequate time, otherwise you’re not going to do justice to the problem.”

During that first visit, Dr. Winkelman recommends establishing and prioritizing goals with the patient. “Ask, ‘what is it that bothers you most about your insomnia? Is it the time awake at night, your total sleep time, or how you feel during the day?’ Because we’re going to use different approaches based on that chief complaint of the insomnia,” said Dr. Winkelman, chief of the Massachusetts General Sleep Disorders Clinical Research Program in the department of psychiatry at Harvard Medical School, Boston. “Cognitive-behavioral therapy for insomnia [CBT-I], for instance, is very good at reducing time awake at night. It won’t increase total sleep time, but it reduces time awake at night dramatically.”

According to the DSM-5, insomnia disorder is marked by dissatisfaction with sleep quality or quantity associated with at least one of the following: difficulty initiating sleep, difficulty maintaining sleep, and early morning awakening. “Just getting up to pee five times a night is not insomnia,” he said. “Just taking an hour and a half to fall asleep at the beginning of the night is not insomnia. There has to be distress or dysfunction related to the sleep disturbance, for a minimum of three times per week for 3 months.”

Most sleep problems are transient, but 25%-30% last more than 1 year. The differential diagnosis for chronic insomnia includes primary psychiatric disorders, medications, substances, restless legs syndrome, sleep schedule disorders, and obstructive sleep apnea.

“In general, we do not order sleep studies in people with insomnia unless we suspect sleep apnea; it’s just a waste of time,” said Dr. Winkelman, who is also a professor of psychiatry at Harvard Medical School. Indications for polysomnography include loud snoring plus one of the following: daytime sleepiness, witnessed apneas, or refractory hypertension. Other indications include abnormal behaviors or movements during sleep, unexplained excessive daytime sleepiness, and refractory sleep complaints, especially repetitive brief awakenings.

Many common cognitive and behavioral issues can produce or worsen insomnia, including inconsistent bedtimes and wake times. “That irregular schedule wreaks havoc with sleep,” he said. “It messes up the circadian rhythm. Also, homeostatic drive needs to build up: We need to be awake 16 or more hours in order to be sleepy. If people are sleeping until noon on Sundays and then trying to go to bed at their usual time, 10 or 11 at night, they’ve only been awake 10 or 11 hours. That’s why they’re going to have problems falling asleep. Also, a lot of people doze off after dinner in front of the TV. That doesn’t help.”

Spending excessive time in bed can also trigger or worsen insomnia. Dr. Winkelman recommends that people restrict their access to bed to the number of hours it is reasonable to sleep. “I see a lot of people in their 70s and 80s spending 10 hours in bed,” he said. “It doesn’t sound that crazy, but there is no way they’re going to get 10 hours of sleep. It’s physically impossible, so they spend 2 or 3 hours awake at night.” Clock-watching is another no-no. “In the middle of the night you wake up, look at the clock, and say to yourself: ‘Oh my god, I’ve been awake for 3 hours. I have 4 hours left. I need 7 hours. That means I need to go to sleep now!’ ”

An estimated 30%-40% of people with chronic insomnia have a psychiatric disorder. That means “you have to be thorough in your evaluation and act as if you’re doing a structured interview,” Dr. Winkelman said. “Ask about obsessive-compulsive disorder, generalized anxiety disorder, PTSD, et cetera, so that you understand the complete myriad of psychiatric illnesses, because psychiatric illnesses run in gangs. Comorbidity is generally the rule.”

The first-line treatment for chronic insomnia disorder is CBT-I, a multicomponent approach that includes time-in-bed restriction, stimulus control, cognitive therapy, relaxation therapy, and sleep hygiene. According to Dr. Winkelman, the cornerstone of CBT-I is time-in-bed restriction. “Many people with insomnia are spending 8.5 hours in bed to get 6.5 hours of sleep,” he said. “What you do is restrict access to bed to 6.5 hours; you initially sleep deprive them. Over the first few weeks, they hate you. After a few weeks when they start sleeping well, you start gradually increasing time in bed, but they rarely get back to the 8.5 hours in bed they were spending beforehand.”

Online CBT-I programs such as Sleepio can also be effective for improving sleep latency and wake after sleep onset, but not for total sleep time (JAMA Psychiatry. 2017;74[1]:68-75). “Not everybody responds to CBT; 50% don’t respond at a couple of months,” he said. “These are the people you need to think about medication for.”

Medications commonly used for chronic insomnia include benzodiazepine receptor agonists (BzRAs) – temazepam, eszopiclone, triazolam, zolpidem, and zaleplon are Food and Drug Administration approved – melatonin agonists, orexin antagonists, sedating antidepressants, anticonvulsants, and dopaminergic antagonists. “Each of the agents in these categories has somewhat similar mechanisms of action, and similar efficacy and contraindications,” Dr. Winkelman said. “The best way to divide the benzodiazepine receptor agonists is based on half-life. How long do you want drug on receptor in somebody with insomnia? Probably not much longer than 8 hours. Nevertheless, some psychiatrists love clonazepam, which has a 40-hour half-life. The circumstances under which clonazepam should be used for insomnia are small, such as in people with a daytime anxiety disorder.”

Consider trying triazolam, zolpidem, and zaleplon for patients who have problems falling asleep, he said, while oxazepam and eszopiclone are sensible options for people who have difficulty falling and staying asleep. Clinical response to BzRAs is common, yet only about half of people who have insomnia remit with one of these agents.

Dr. Winkelman said that patients and physicians often ask him whether BzRAs and other agents used as sleep aids are addictive. Abuse is identified when recurrent use causes clinically and functionally significant impairment, such as health problems; disability; and failure to meet major responsibilities at work, home, or school. “These are concerns with BzRAs. Misuse and abuse generally occur in younger people. Once you get to 35 years old, misuse rates get very low. In older people, rates of side effects go up.

“Tolerance, physiological and psychological dependence, and nonmedical diversion are also of concern,” he said. However, for the majority of people, BzRA hypnotics are effective and safe.

As for other agents, meta-analyses have demonstrated that melatonin 1-3 mg can help people fall asleep when it’s not being endogenously released. “That’s during the day,” he said. “That might be most relevant for jet lag and for people doing shift work.” Two orexin antagonists on the market for insomnia include suvorexant and lemborexant 10-20 mg. Advantages of these include little abuse liability and few side effects. “In one head-to-head polysomnography study in the elderly, lemborexant was superior to zolpidem 6.25 mg CR on both objective and subjective ability to fall asleep and stay asleep,” Dr. Winkelman said. (JAMA Netw Open. 2019;2[12]:e1918254).

Antidepressants are another treatment option, including mirtazapine 15-30 mg, trazodone 25-100 mg, and amitriptyline and doxepin (10-50 mg). Advantages include little abuse liability, while potential drawbacks include daytime sedation, weight gain, and anticholinergic side effects. Meanwhile, atypical antipsychotics such as quetiapine 25-100 mg have long been known to be helpful for sleep. “Advantages are that they’re anxiolytic, they’re mood stabilizing, and there is little abuse liability,” Dr. Winkelman said. “Drawbacks are that they’re probably less effective than BzRAs, they cause daytime sedation, weight gain, risks of extrapyramidal symptoms and glucose and lipid abnormalities.”

Dr. Winkelman said that he uses “a fair amount” of the anticonvulsant gabapentin as a second- or third-line hypnotic agent. “I usually start with 300 mg [at bedtime],” he added. “Drawbacks are that it’s probably less effective than BzRAs; it affects cognition; and can cause daytime sedation, dizziness, and weight gain. There are also concerns about abuse.”

Dr. Winkelman reported that he has received grant/research support from Merck, the RLS Foundation, and Luitpold Pharmaceuticals. He is also a consultant for Advance Medical, Avadel Pharmaceuticals, and UpToDate and is a member of the speakers’ bureau for Luitpold.

[email protected]

LAS VEGAS – Clinicians should spend 1 hour with patients who present with a chief complaint of insomnia, rather than rushing to a treatment after a 10- to 15-minute office visit, according to John W. Winkelman, MD, PhD.

Doug Brunk/MDedge News

“Why? Because sleep problems are usually multifactorial, involving psychiatric illness, sleep disorders, medical illness, medication, and poor sleep hygiene/stress,” he said at an annual psychopharmacology update held by the Nevada Psychiatric Association. “There are usually many contributing problems, and sleep quality is only as strong as the weakest link. Maybe you don’t have an hour [to meet with new patients], but you need to give adequate time, otherwise you’re not going to do justice to the problem.”

During that first visit, Dr. Winkelman recommends establishing and prioritizing goals with the patient. “Ask, ‘what is it that bothers you most about your insomnia? Is it the time awake at night, your total sleep time, or how you feel during the day?’ Because we’re going to use different approaches based on that chief complaint of the insomnia,” said Dr. Winkelman, chief of the Massachusetts General Sleep Disorders Clinical Research Program in the department of psychiatry at Harvard Medical School, Boston. “Cognitive-behavioral therapy for insomnia [CBT-I], for instance, is very good at reducing time awake at night. It won’t increase total sleep time, but it reduces time awake at night dramatically.”

According to the DSM-5, insomnia disorder is marked by dissatisfaction with sleep quality or quantity associated with at least one of the following: difficulty initiating sleep, difficulty maintaining sleep, and early morning awakening. “Just getting up to pee five times a night is not insomnia,” he said. “Just taking an hour and a half to fall asleep at the beginning of the night is not insomnia. There has to be distress or dysfunction related to the sleep disturbance, for a minimum of three times per week for 3 months.”

Most sleep problems are transient, but 25%-30% last more than 1 year. The differential diagnosis for chronic insomnia includes primary psychiatric disorders, medications, substances, restless legs syndrome, sleep schedule disorders, and obstructive sleep apnea.

“In general, we do not order sleep studies in people with insomnia unless we suspect sleep apnea; it’s just a waste of time,” said Dr. Winkelman, who is also a professor of psychiatry at Harvard Medical School. Indications for polysomnography include loud snoring plus one of the following: daytime sleepiness, witnessed apneas, or refractory hypertension. Other indications include abnormal behaviors or movements during sleep, unexplained excessive daytime sleepiness, and refractory sleep complaints, especially repetitive brief awakenings.

Many common cognitive and behavioral issues can produce or worsen insomnia, including inconsistent bedtimes and wake times. “That irregular schedule wreaks havoc with sleep,” he said. “It messes up the circadian rhythm. Also, homeostatic drive needs to build up: We need to be awake 16 or more hours in order to be sleepy. If people are sleeping until noon on Sundays and then trying to go to bed at their usual time, 10 or 11 at night, they’ve only been awake 10 or 11 hours. That’s why they’re going to have problems falling asleep. Also, a lot of people doze off after dinner in front of the TV. That doesn’t help.”

Spending excessive time in bed can also trigger or worsen insomnia. Dr. Winkelman recommends that people restrict their access to bed to the number of hours it is reasonable to sleep. “I see a lot of people in their 70s and 80s spending 10 hours in bed,” he said. “It doesn’t sound that crazy, but there is no way they’re going to get 10 hours of sleep. It’s physically impossible, so they spend 2 or 3 hours awake at night.” Clock-watching is another no-no. “In the middle of the night you wake up, look at the clock, and say to yourself: ‘Oh my god, I’ve been awake for 3 hours. I have 4 hours left. I need 7 hours. That means I need to go to sleep now!’ ”

An estimated 30%-40% of people with chronic insomnia have a psychiatric disorder. That means “you have to be thorough in your evaluation and act as if you’re doing a structured interview,” Dr. Winkelman said. “Ask about obsessive-compulsive disorder, generalized anxiety disorder, PTSD, et cetera, so that you understand the complete myriad of psychiatric illnesses, because psychiatric illnesses run in gangs. Comorbidity is generally the rule.”

The first-line treatment for chronic insomnia disorder is CBT-I, a multicomponent approach that includes time-in-bed restriction, stimulus control, cognitive therapy, relaxation therapy, and sleep hygiene. According to Dr. Winkelman, the cornerstone of CBT-I is time-in-bed restriction. “Many people with insomnia are spending 8.5 hours in bed to get 6.5 hours of sleep,” he said. “What you do is restrict access to bed to 6.5 hours; you initially sleep deprive them. Over the first few weeks, they hate you. After a few weeks when they start sleeping well, you start gradually increasing time in bed, but they rarely get back to the 8.5 hours in bed they were spending beforehand.”

Online CBT-I programs such as Sleepio can also be effective for improving sleep latency and wake after sleep onset, but not for total sleep time (JAMA Psychiatry. 2017;74[1]:68-75). “Not everybody responds to CBT; 50% don’t respond at a couple of months,” he said. “These are the people you need to think about medication for.”

Medications commonly used for chronic insomnia include benzodiazepine receptor agonists (BzRAs) – temazepam, eszopiclone, triazolam, zolpidem, and zaleplon are Food and Drug Administration approved – melatonin agonists, orexin antagonists, sedating antidepressants, anticonvulsants, and dopaminergic antagonists. “Each of the agents in these categories has somewhat similar mechanisms of action, and similar efficacy and contraindications,” Dr. Winkelman said. “The best way to divide the benzodiazepine receptor agonists is based on half-life. How long do you want drug on receptor in somebody with insomnia? Probably not much longer than 8 hours. Nevertheless, some psychiatrists love clonazepam, which has a 40-hour half-life. The circumstances under which clonazepam should be used for insomnia are small, such as in people with a daytime anxiety disorder.”

Consider trying triazolam, zolpidem, and zaleplon for patients who have problems falling asleep, he said, while oxazepam and eszopiclone are sensible options for people who have difficulty falling and staying asleep. Clinical response to BzRAs is common, yet only about half of people who have insomnia remit with one of these agents.

Dr. Winkelman said that patients and physicians often ask him whether BzRAs and other agents used as sleep aids are addictive. Abuse is identified when recurrent use causes clinically and functionally significant impairment, such as health problems; disability; and failure to meet major responsibilities at work, home, or school. “These are concerns with BzRAs. Misuse and abuse generally occur in younger people. Once you get to 35 years old, misuse rates get very low. In older people, rates of side effects go up.

“Tolerance, physiological and psychological dependence, and nonmedical diversion are also of concern,” he said. However, for the majority of people, BzRA hypnotics are effective and safe.

As for other agents, meta-analyses have demonstrated that melatonin 1-3 mg can help people fall asleep when it’s not being endogenously released. “That’s during the day,” he said. “That might be most relevant for jet lag and for people doing shift work.” Two orexin antagonists on the market for insomnia include suvorexant and lemborexant 10-20 mg. Advantages of these include little abuse liability and few side effects. “In one head-to-head polysomnography study in the elderly, lemborexant was superior to zolpidem 6.25 mg CR on both objective and subjective ability to fall asleep and stay asleep,” Dr. Winkelman said. (JAMA Netw Open. 2019;2[12]:e1918254).

Antidepressants are another treatment option, including mirtazapine 15-30 mg, trazodone 25-100 mg, and amitriptyline and doxepin (10-50 mg). Advantages include little abuse liability, while potential drawbacks include daytime sedation, weight gain, and anticholinergic side effects. Meanwhile, atypical antipsychotics such as quetiapine 25-100 mg have long been known to be helpful for sleep. “Advantages are that they’re anxiolytic, they’re mood stabilizing, and there is little abuse liability,” Dr. Winkelman said. “Drawbacks are that they’re probably less effective than BzRAs, they cause daytime sedation, weight gain, risks of extrapyramidal symptoms and glucose and lipid abnormalities.”

Dr. Winkelman said that he uses “a fair amount” of the anticonvulsant gabapentin as a second- or third-line hypnotic agent. “I usually start with 300 mg [at bedtime],” he added. “Drawbacks are that it’s probably less effective than BzRAs; it affects cognition; and can cause daytime sedation, dizziness, and weight gain. There are also concerns about abuse.”

Dr. Winkelman reported that he has received grant/research support from Merck, the RLS Foundation, and Luitpold Pharmaceuticals. He is also a consultant for Advance Medical, Avadel Pharmaceuticals, and UpToDate and is a member of the speakers’ bureau for Luitpold.

[email protected]

LAS VEGAS – Clinicians should spend 1 hour with patients who present with a chief complaint of insomnia, rather than rushing to a treatment after a 10- to 15-minute office visit, according to John W. Winkelman, MD, PhD.

Doug Brunk/MDedge News

“Why? Because sleep problems are usually multifactorial, involving psychiatric illness, sleep disorders, medical illness, medication, and poor sleep hygiene/stress,” he said at an annual psychopharmacology update held by the Nevada Psychiatric Association. “There are usually many contributing problems, and sleep quality is only as strong as the weakest link. Maybe you don’t have an hour [to meet with new patients], but you need to give adequate time, otherwise you’re not going to do justice to the problem.”

During that first visit, Dr. Winkelman recommends establishing and prioritizing goals with the patient. “Ask, ‘what is it that bothers you most about your insomnia? Is it the time awake at night, your total sleep time, or how you feel during the day?’ Because we’re going to use different approaches based on that chief complaint of the insomnia,” said Dr. Winkelman, chief of the Massachusetts General Sleep Disorders Clinical Research Program in the department of psychiatry at Harvard Medical School, Boston. “Cognitive-behavioral therapy for insomnia [CBT-I], for instance, is very good at reducing time awake at night. It won’t increase total sleep time, but it reduces time awake at night dramatically.”

According to the DSM-5, insomnia disorder is marked by dissatisfaction with sleep quality or quantity associated with at least one of the following: difficulty initiating sleep, difficulty maintaining sleep, and early morning awakening. “Just getting up to pee five times a night is not insomnia,” he said. “Just taking an hour and a half to fall asleep at the beginning of the night is not insomnia. There has to be distress or dysfunction related to the sleep disturbance, for a minimum of three times per week for 3 months.”

Most sleep problems are transient, but 25%-30% last more than 1 year. The differential diagnosis for chronic insomnia includes primary psychiatric disorders, medications, substances, restless legs syndrome, sleep schedule disorders, and obstructive sleep apnea.

“In general, we do not order sleep studies in people with insomnia unless we suspect sleep apnea; it’s just a waste of time,” said Dr. Winkelman, who is also a professor of psychiatry at Harvard Medical School. Indications for polysomnography include loud snoring plus one of the following: daytime sleepiness, witnessed apneas, or refractory hypertension. Other indications include abnormal behaviors or movements during sleep, unexplained excessive daytime sleepiness, and refractory sleep complaints, especially repetitive brief awakenings.

Many common cognitive and behavioral issues can produce or worsen insomnia, including inconsistent bedtimes and wake times. “That irregular schedule wreaks havoc with sleep,” he said. “It messes up the circadian rhythm. Also, homeostatic drive needs to build up: We need to be awake 16 or more hours in order to be sleepy. If people are sleeping until noon on Sundays and then trying to go to bed at their usual time, 10 or 11 at night, they’ve only been awake 10 or 11 hours. That’s why they’re going to have problems falling asleep. Also, a lot of people doze off after dinner in front of the TV. That doesn’t help.”

Spending excessive time in bed can also trigger or worsen insomnia. Dr. Winkelman recommends that people restrict their access to bed to the number of hours it is reasonable to sleep. “I see a lot of people in their 70s and 80s spending 10 hours in bed,” he said. “It doesn’t sound that crazy, but there is no way they’re going to get 10 hours of sleep. It’s physically impossible, so they spend 2 or 3 hours awake at night.” Clock-watching is another no-no. “In the middle of the night you wake up, look at the clock, and say to yourself: ‘Oh my god, I’ve been awake for 3 hours. I have 4 hours left. I need 7 hours. That means I need to go to sleep now!’ ”

An estimated 30%-40% of people with chronic insomnia have a psychiatric disorder. That means “you have to be thorough in your evaluation and act as if you’re doing a structured interview,” Dr. Winkelman said. “Ask about obsessive-compulsive disorder, generalized anxiety disorder, PTSD, et cetera, so that you understand the complete myriad of psychiatric illnesses, because psychiatric illnesses run in gangs. Comorbidity is generally the rule.”

The first-line treatment for chronic insomnia disorder is CBT-I, a multicomponent approach that includes time-in-bed restriction, stimulus control, cognitive therapy, relaxation therapy, and sleep hygiene. According to Dr. Winkelman, the cornerstone of CBT-I is time-in-bed restriction. “Many people with insomnia are spending 8.5 hours in bed to get 6.5 hours of sleep,” he said. “What you do is restrict access to bed to 6.5 hours; you initially sleep deprive them. Over the first few weeks, they hate you. After a few weeks when they start sleeping well, you start gradually increasing time in bed, but they rarely get back to the 8.5 hours in bed they were spending beforehand.”

Online CBT-I programs such as Sleepio can also be effective for improving sleep latency and wake after sleep onset, but not for total sleep time (JAMA Psychiatry. 2017;74[1]:68-75). “Not everybody responds to CBT; 50% don’t respond at a couple of months,” he said. “These are the people you need to think about medication for.”

Medications commonly used for chronic insomnia include benzodiazepine receptor agonists (BzRAs) – temazepam, eszopiclone, triazolam, zolpidem, and zaleplon are Food and Drug Administration approved – melatonin agonists, orexin antagonists, sedating antidepressants, anticonvulsants, and dopaminergic antagonists. “Each of the agents in these categories has somewhat similar mechanisms of action, and similar efficacy and contraindications,” Dr. Winkelman said. “The best way to divide the benzodiazepine receptor agonists is based on half-life. How long do you want drug on receptor in somebody with insomnia? Probably not much longer than 8 hours. Nevertheless, some psychiatrists love clonazepam, which has a 40-hour half-life. The circumstances under which clonazepam should be used for insomnia are small, such as in people with a daytime anxiety disorder.”

Consider trying triazolam, zolpidem, and zaleplon for patients who have problems falling asleep, he said, while oxazepam and eszopiclone are sensible options for people who have difficulty falling and staying asleep. Clinical response to BzRAs is common, yet only about half of people who have insomnia remit with one of these agents.

Dr. Winkelman said that patients and physicians often ask him whether BzRAs and other agents used as sleep aids are addictive. Abuse is identified when recurrent use causes clinically and functionally significant impairment, such as health problems; disability; and failure to meet major responsibilities at work, home, or school. “These are concerns with BzRAs. Misuse and abuse generally occur in younger people. Once you get to 35 years old, misuse rates get very low. In older people, rates of side effects go up.

“Tolerance, physiological and psychological dependence, and nonmedical diversion are also of concern,” he said. However, for the majority of people, BzRA hypnotics are effective and safe.

As for other agents, meta-analyses have demonstrated that melatonin 1-3 mg can help people fall asleep when it’s not being endogenously released. “That’s during the day,” he said. “That might be most relevant for jet lag and for people doing shift work.” Two orexin antagonists on the market for insomnia include suvorexant and lemborexant 10-20 mg. Advantages of these include little abuse liability and few side effects. “In one head-to-head polysomnography study in the elderly, lemborexant was superior to zolpidem 6.25 mg CR on both objective and subjective ability to fall asleep and stay asleep,” Dr. Winkelman said. (JAMA Netw Open. 2019;2[12]:e1918254).

Antidepressants are another treatment option, including mirtazapine 15-30 mg, trazodone 25-100 mg, and amitriptyline and doxepin (10-50 mg). Advantages include little abuse liability, while potential drawbacks include daytime sedation, weight gain, and anticholinergic side effects. Meanwhile, atypical antipsychotics such as quetiapine 25-100 mg have long been known to be helpful for sleep. “Advantages are that they’re anxiolytic, they’re mood stabilizing, and there is little abuse liability,” Dr. Winkelman said. “Drawbacks are that they’re probably less effective than BzRAs, they cause daytime sedation, weight gain, risks of extrapyramidal symptoms and glucose and lipid abnormalities.”

Dr. Winkelman said that he uses “a fair amount” of the anticonvulsant gabapentin as a second- or third-line hypnotic agent. “I usually start with 300 mg [at bedtime],” he added. “Drawbacks are that it’s probably less effective than BzRAs; it affects cognition; and can cause daytime sedation, dizziness, and weight gain. There are also concerns about abuse.”

Dr. Winkelman reported that he has received grant/research support from Merck, the RLS Foundation, and Luitpold Pharmaceuticals. He is also a consultant for Advance Medical, Avadel Pharmaceuticals, and UpToDate and is a member of the speakers’ bureau for Luitpold.

[email protected]

As many as 24% of individuals with schizophrenia spectrum disorder who underwent a comprehensive neurocognitive battery performed above the mean healthy score for some neurocognitive domains, compared with a group of controls, results from a novel study show.

“Based on these findings, we recommend that neurocognitive assessment should be performed as early as possible after illness onset,” researchers led by Lars Helldin, MD, PhD, of the department of psychiatry at NU Health-Care Hospital, Region Västra Götaland, Sweden, wrote in a study published in Schizophrenia Research: Cognition (2020 Jun doi: 10.1016/j.scog.2020.100172). “Early identification of cognitive risk factors for poor real-life functional outcome is necessary in order to alert the clinical and rehabilitation services about patients in need of extra care.”

For the study, 291 men and women suffering from schizophrenia spectrum disorder (SSD) and 302 controls underwent assessment with a series of comprehensive neurocognitive tests, including the Global Assessment of Functioning (GAF), the Positive and Negative Syndrome Scale (PANSS), the Specific Level of Functioning Scale (SLOF), the Rey Auditory Verbal Learning Test (RAVLT), and the Wisconsin Card Sorting Test (WCST). The researchers found that the neurocognitive function of the SSD patients was significantly lower than that of the healthy controls on all assessments, with very large effect sizes. “There was considerable diversity within each group, as subgroups of patients scored higher than the control mean and subgroups of controls scored lower than the patient mean, particularly on tests of working memory, verbal learning and memory, and executive function,” wrote Dr. Helldin and associates.

As for the WSCT score, the cognitively intact group had a significantly lower PANSS negative symptom level (P less than .01), a lower PANSS general pathology level (P less than .05), and a lower PANSS total symptom level (P less than .01). As for the WAIS Vocabulary score, the patient group with a higher score than the controls had a significantly lower PANSS negative symptom level (P less than .05).

“Here, we have linked neurocognitive heterogeneity to functional outcome differences, and suggest that personalized treatment with emphasis on practical daily skills may be of great significance especially for those with large baseline cognitive deficits,” the researchers concluded. “Such efforts are imperative not only in order to reduce personal suffering and increase quality of life for the patients, but also to reduce the enormous society level economic costs of functional deficits.”

The study was funded by the Regional Health Authority, VG Region, Sweden. The authors reported having no financial disclosures.

[email protected]

As many as 24% of individuals with schizophrenia spectrum disorder who underwent a comprehensive neurocognitive battery performed above the mean healthy score for some neurocognitive domains, compared with a group of controls, results from a novel study show.

“Based on these findings, we recommend that neurocognitive assessment should be performed as early as possible after illness onset,” researchers led by Lars Helldin, MD, PhD, of the department of psychiatry at NU Health-Care Hospital, Region Västra Götaland, Sweden, wrote in a study published in Schizophrenia Research: Cognition (2020 Jun doi: 10.1016/j.scog.2020.100172). “Early identification of cognitive risk factors for poor real-life functional outcome is necessary in order to alert the clinical and rehabilitation services about patients in need of extra care.”

For the study, 291 men and women suffering from schizophrenia spectrum disorder (SSD) and 302 controls underwent assessment with a series of comprehensive neurocognitive tests, including the Global Assessment of Functioning (GAF), the Positive and Negative Syndrome Scale (PANSS), the Specific Level of Functioning Scale (SLOF), the Rey Auditory Verbal Learning Test (RAVLT), and the Wisconsin Card Sorting Test (WCST). The researchers found that the neurocognitive function of the SSD patients was significantly lower than that of the healthy controls on all assessments, with very large effect sizes. “There was considerable diversity within each group, as subgroups of patients scored higher than the control mean and subgroups of controls scored lower than the patient mean, particularly on tests of working memory, verbal learning and memory, and executive function,” wrote Dr. Helldin and associates.

As for the WSCT score, the cognitively intact group had a significantly lower PANSS negative symptom level (P less than .01), a lower PANSS general pathology level (P less than .05), and a lower PANSS total symptom level (P less than .01). As for the WAIS Vocabulary score, the patient group with a higher score than the controls had a significantly lower PANSS negative symptom level (P less than .05).

“Here, we have linked neurocognitive heterogeneity to functional outcome differences, and suggest that personalized treatment with emphasis on practical daily skills may be of great significance especially for those with large baseline cognitive deficits,” the researchers concluded. “Such efforts are imperative not only in order to reduce personal suffering and increase quality of life for the patients, but also to reduce the enormous society level economic costs of functional deficits.”

The study was funded by the Regional Health Authority, VG Region, Sweden. The authors reported having no financial disclosures.

[email protected]

As many as 24% of individuals with schizophrenia spectrum disorder who underwent a comprehensive neurocognitive battery performed above the mean healthy score for some neurocognitive domains, compared with a group of controls, results from a novel study show.

“Based on these findings, we recommend that neurocognitive assessment should be performed as early as possible after illness onset,” researchers led by Lars Helldin, MD, PhD, of the department of psychiatry at NU Health-Care Hospital, Region Västra Götaland, Sweden, wrote in a study published in Schizophrenia Research: Cognition (2020 Jun doi: 10.1016/j.scog.2020.100172). “Early identification of cognitive risk factors for poor real-life functional outcome is necessary in order to alert the clinical and rehabilitation services about patients in need of extra care.”

For the study, 291 men and women suffering from schizophrenia spectrum disorder (SSD) and 302 controls underwent assessment with a series of comprehensive neurocognitive tests, including the Global Assessment of Functioning (GAF), the Positive and Negative Syndrome Scale (PANSS), the Specific Level of Functioning Scale (SLOF), the Rey Auditory Verbal Learning Test (RAVLT), and the Wisconsin Card Sorting Test (WCST). The researchers found that the neurocognitive function of the SSD patients was significantly lower than that of the healthy controls on all assessments, with very large effect sizes. “There was considerable diversity within each group, as subgroups of patients scored higher than the control mean and subgroups of controls scored lower than the patient mean, particularly on tests of working memory, verbal learning and memory, and executive function,” wrote Dr. Helldin and associates.

As for the WSCT score, the cognitively intact group had a significantly lower PANSS negative symptom level (P less than .01), a lower PANSS general pathology level (P less than .05), and a lower PANSS total symptom level (P less than .01). As for the WAIS Vocabulary score, the patient group with a higher score than the controls had a significantly lower PANSS negative symptom level (P less than .05).

“Here, we have linked neurocognitive heterogeneity to functional outcome differences, and suggest that personalized treatment with emphasis on practical daily skills may be of great significance especially for those with large baseline cognitive deficits,” the researchers concluded. “Such efforts are imperative not only in order to reduce personal suffering and increase quality of life for the patients, but also to reduce the enormous society level economic costs of functional deficits.”

The study was funded by the Regional Health Authority, VG Region, Sweden. The authors reported having no financial disclosures.

[email protected]

LAS VEGAS – For Karen J. Hartwell, MD, few things in her clinical work bring more reward than providing medication-assisted treatment (MAT) to patients with opioid use disorder.

Doug Brunk/MDedge News

“Seeing people get into recovery on buprenorphine is as exciting as seeing your first person respond to clozapine, or to see a depression remit on your selection of an antidepressant,” she said at an annual psychopharmacology update held by the Nevada Psychiatric Association. “We know that medication-assisted treatment is underused and, sadly, relapse rates remain high.”

According to the Centers for Disease Control and Prevention, there were 70,237 drug-related overdose deaths in 2017 – 47,600 from prescription and illicit opioids. “This is being driven predominately by fentanyl and other high-potency synthetic opioids, followed by prescription opioids and heroin,” said Dr. Hartwell, an associate professor in the addiction sciences division in the department of psychiatry and behavioral sciences at the Medical University of South Carolina, Charleston.

There were an estimated 2 million Americans with an opioid use disorder (OUD) in 2018, she said, and more than 10 million misused prescription opioids. At the same time, prescriptions for opioids have dropped to lowest level in 10 years from a peak in 2012 of 81.3 prescriptions per 100 persons to 58.7 prescriptions per 100 persons in 2017 – total of more than 191 million scripts. “There is a decline in the number of opioid prescriptions, but there is still a lot of diversion, and there are some prescription ‘hot spots’ in the Southeast,” Dr. Hartwell said. “Heroin is a very low cost, and we’re wrestling with the issue of fentanyl.”

To complicate matters, most Americans with opioid use disorder are not in treatment. “In many people, the disorder is never diagnosed, and even fewer engage in care,” she said. “There are challenges with treatment retention, and even fewer achieve remission. There’s a lot of work to be done. One of which is the availability of medication-assisted treatment.”

Dr. Hartwell said that she knows of physician colleagues who have obtained a waiver to prescribe buprenorphine but have yet to prescribe it. “Some people may prefer to avoid the dance [of buprenorphine prescribing],” she said. “I’m here to advise you to dance.” Clinicians can learn about MAT waiver training opportunities by visiting the website of the Providers Clinical Support System, a program funded by the Substance Abuse and Mental Health Services Administration (SAMHSA).

Another option is to join a telementoring session on the topic facilitated by Project ECHO, or Extension for Community Healthcare Outcomes, which is being used by the University of New Mexico, Albuquerque. The goal of this model is to break down the walls between specialty and primary care by linking experts at an academic “hub” with primary care doctors and nurses in nearby communities.

“Our Project ECHO at the Medical University of South Carolina is twice a month on Fridays,” Dr. Hartwell said. “The first half is a case. The second half is a didactic [session], and you get a free hour of CME.”

The most common drugs used for medication-assisted treatment of opioid disorder are buprenorphine (a partial agonist), naltrexone (an antagonist), and methadone (a full agonist). Methadone retention generally is better than buprenorphine or naltrexone. The recommended treatment duration is 6-12 months, yet many studies demonstrate that many only stay on treatment for 30-60 days.

“You want to keep patients on treatment as long as they benefit from the medication,” Dr. Hartwell said. One large study of Medicaid claims data found that the risk of acute care service use and overdose were high following buprenorphine discontinuation, regardless of treatment duration. Superior outcomes became significant with treatment duration beyond 15 months, although rates of the primary adverse outcomes remained high (Am J Psychiatry. 2020 Feb 1;177[2]:117-24). About 5% of patients across all cohorts experienced one or more medically treated overdoses.

“One thing I don’t want is for people to drop out of treatment and not come back to see me,” Dr. Hartwell said. “This is a time for us to use our shared decision-making skills. I like to use the Tapering Readiness Inventory, a list of 16 questions. It asks such things as ‘Are you able to cope with difficult situations without using?’ and ‘Do you have all of the [drug] paraphernalia out of the house?’ We then have a discussion. If the patient decides to go ahead and do a taper, I always leave the door open. So, as that taper persists and someone says, ‘I’m starting to think about using, Doctor,’ I’ll put them back on [buprenorphine]. Or, if they come off the drug and they find themselves at risk of relapsing, they come back in and see me.”

There’s also some evidence that contingency management might be helpful, both in terms of opioid negative urines, and retention and treatment. Meanwhile, extended-release forms of buprenorphine are emerging.

In 2017, the Food and Drug Administration approved Sublocade, the first once-monthly injectable buprenorphine product for the treatment of moderate-to-severe OUD in adult patients who have initiated treatment with a transmucosal buprenorphine-containing product. “The recommendations are that you have about a 7-day lead-in of sublingual buprenorphine, and then 2 months of a 300-mg IV injection,” Dr. Hartwell said. “This is followed by either 100-mg injections monthly or 300-mg maintenance in select cases. There is some pain at the injection site. Some clinicians are getting around this by using a little bit of lidocaine prior to giving the injection.”

Another product, Brixadi, is an extended-release weekly (8 mg, 16 mg, 24 mg, 32 mg) and monthly (64 mg, 96 mg, 128 mg) buprenorphine injection used for the treatment of moderate to severe OUD. It is expected to be available in December 2020.

In 2016, the FDA approved Probuphine, the first buprenorphine implant for the maintenance treatment of opioid dependence. Probuphine is designed to provide a constant, low-level dose of buprenorphine for 6 months in patients who are already stable on low to moderate doses of other forms of buprenorphine, as part of a complete treatment program. “The 6-month duration kind of takes the issue of adherence off the table,” Dr. Hartwell said. “The caveat with this is that you have to be stable on 8 mg of buprenorphine per day or less. The majority of my patients require much higher doses.”

Dr. Hartwell reported having no relevant disclosures.

[email protected]

LAS VEGAS – For Karen J. Hartwell, MD, few things in her clinical work bring more reward than providing medication-assisted treatment (MAT) to patients with opioid use disorder.

Doug Brunk/MDedge News

“Seeing people get into recovery on buprenorphine is as exciting as seeing your first person respond to clozapine, or to see a depression remit on your selection of an antidepressant,” she said at an annual psychopharmacology update held by the Nevada Psychiatric Association. “We know that medication-assisted treatment is underused and, sadly, relapse rates remain high.”

According to the Centers for Disease Control and Prevention, there were 70,237 drug-related overdose deaths in 2017 – 47,600 from prescription and illicit opioids. “This is being driven predominately by fentanyl and other high-potency synthetic opioids, followed by prescription opioids and heroin,” said Dr. Hartwell, an associate professor in the addiction sciences division in the department of psychiatry and behavioral sciences at the Medical University of South Carolina, Charleston.

There were an estimated 2 million Americans with an opioid use disorder (OUD) in 2018, she said, and more than 10 million misused prescription opioids. At the same time, prescriptions for opioids have dropped to lowest level in 10 years from a peak in 2012 of 81.3 prescriptions per 100 persons to 58.7 prescriptions per 100 persons in 2017 – total of more than 191 million scripts. “There is a decline in the number of opioid prescriptions, but there is still a lot of diversion, and there are some prescription ‘hot spots’ in the Southeast,” Dr. Hartwell said. “Heroin is a very low cost, and we’re wrestling with the issue of fentanyl.”

To complicate matters, most Americans with opioid use disorder are not in treatment. “In many people, the disorder is never diagnosed, and even fewer engage in care,” she said. “There are challenges with treatment retention, and even fewer achieve remission. There’s a lot of work to be done. One of which is the availability of medication-assisted treatment.”

Dr. Hartwell said that she knows of physician colleagues who have obtained a waiver to prescribe buprenorphine but have yet to prescribe it. “Some people may prefer to avoid the dance [of buprenorphine prescribing],” she said. “I’m here to advise you to dance.” Clinicians can learn about MAT waiver training opportunities by visiting the website of the Providers Clinical Support System, a program funded by the Substance Abuse and Mental Health Services Administration (SAMHSA).

Another option is to join a telementoring session on the topic facilitated by Project ECHO, or Extension for Community Healthcare Outcomes, which is being used by the University of New Mexico, Albuquerque. The goal of this model is to break down the walls between specialty and primary care by linking experts at an academic “hub” with primary care doctors and nurses in nearby communities.

“Our Project ECHO at the Medical University of South Carolina is twice a month on Fridays,” Dr. Hartwell said. “The first half is a case. The second half is a didactic [session], and you get a free hour of CME.”

The most common drugs used for medication-assisted treatment of opioid disorder are buprenorphine (a partial agonist), naltrexone (an antagonist), and methadone (a full agonist). Methadone retention generally is better than buprenorphine or naltrexone. The recommended treatment duration is 6-12 months, yet many studies demonstrate that many only stay on treatment for 30-60 days.

“You want to keep patients on treatment as long as they benefit from the medication,” Dr. Hartwell said. One large study of Medicaid claims data found that the risk of acute care service use and overdose were high following buprenorphine discontinuation, regardless of treatment duration. Superior outcomes became significant with treatment duration beyond 15 months, although rates of the primary adverse outcomes remained high (Am J Psychiatry. 2020 Feb 1;177[2]:117-24). About 5% of patients across all cohorts experienced one or more medically treated overdoses.

“One thing I don’t want is for people to drop out of treatment and not come back to see me,” Dr. Hartwell said. “This is a time for us to use our shared decision-making skills. I like to use the Tapering Readiness Inventory, a list of 16 questions. It asks such things as ‘Are you able to cope with difficult situations without using?’ and ‘Do you have all of the [drug] paraphernalia out of the house?’ We then have a discussion. If the patient decides to go ahead and do a taper, I always leave the door open. So, as that taper persists and someone says, ‘I’m starting to think about using, Doctor,’ I’ll put them back on [buprenorphine]. Or, if they come off the drug and they find themselves at risk of relapsing, they come back in and see me.”

There’s also some evidence that contingency management might be helpful, both in terms of opioid negative urines, and retention and treatment. Meanwhile, extended-release forms of buprenorphine are emerging.

In 2017, the Food and Drug Administration approved Sublocade, the first once-monthly injectable buprenorphine product for the treatment of moderate-to-severe OUD in adult patients who have initiated treatment with a transmucosal buprenorphine-containing product. “The recommendations are that you have about a 7-day lead-in of sublingual buprenorphine, and then 2 months of a 300-mg IV injection,” Dr. Hartwell said. “This is followed by either 100-mg injections monthly or 300-mg maintenance in select cases. There is some pain at the injection site. Some clinicians are getting around this by using a little bit of lidocaine prior to giving the injection.”

Another product, Brixadi, is an extended-release weekly (8 mg, 16 mg, 24 mg, 32 mg) and monthly (64 mg, 96 mg, 128 mg) buprenorphine injection used for the treatment of moderate to severe OUD. It is expected to be available in December 2020.

In 2016, the FDA approved Probuphine, the first buprenorphine implant for the maintenance treatment of opioid dependence. Probuphine is designed to provide a constant, low-level dose of buprenorphine for 6 months in patients who are already stable on low to moderate doses of other forms of buprenorphine, as part of a complete treatment program. “The 6-month duration kind of takes the issue of adherence off the table,” Dr. Hartwell said. “The caveat with this is that you have to be stable on 8 mg of buprenorphine per day or less. The majority of my patients require much higher doses.”

Dr. Hartwell reported having no relevant disclosures.

[email protected]

LAS VEGAS – For Karen J. Hartwell, MD, few things in her clinical work bring more reward than providing medication-assisted treatment (MAT) to patients with opioid use disorder.

Doug Brunk/MDedge News

“Seeing people get into recovery on buprenorphine is as exciting as seeing your first person respond to clozapine, or to see a depression remit on your selection of an antidepressant,” she said at an annual psychopharmacology update held by the Nevada Psychiatric Association. “We know that medication-assisted treatment is underused and, sadly, relapse rates remain high.”

According to the Centers for Disease Control and Prevention, there were 70,237 drug-related overdose deaths in 2017 – 47,600 from prescription and illicit opioids. “This is being driven predominately by fentanyl and other high-potency synthetic opioids, followed by prescription opioids and heroin,” said Dr. Hartwell, an associate professor in the addiction sciences division in the department of psychiatry and behavioral sciences at the Medical University of South Carolina, Charleston.

There were an estimated 2 million Americans with an opioid use disorder (OUD) in 2018, she said, and more than 10 million misused prescription opioids. At the same time, prescriptions for opioids have dropped to lowest level in 10 years from a peak in 2012 of 81.3 prescriptions per 100 persons to 58.7 prescriptions per 100 persons in 2017 – total of more than 191 million scripts. “There is a decline in the number of opioid prescriptions, but there is still a lot of diversion, and there are some prescription ‘hot spots’ in the Southeast,” Dr. Hartwell said. “Heroin is a very low cost, and we’re wrestling with the issue of fentanyl.”

To complicate matters, most Americans with opioid use disorder are not in treatment. “In many people, the disorder is never diagnosed, and even fewer engage in care,” she said. “There are challenges with treatment retention, and even fewer achieve remission. There’s a lot of work to be done. One of which is the availability of medication-assisted treatment.”

Dr. Hartwell said that she knows of physician colleagues who have obtained a waiver to prescribe buprenorphine but have yet to prescribe it. “Some people may prefer to avoid the dance [of buprenorphine prescribing],” she said. “I’m here to advise you to dance.” Clinicians can learn about MAT waiver training opportunities by visiting the website of the Providers Clinical Support System, a program funded by the Substance Abuse and Mental Health Services Administration (SAMHSA).

Another option is to join a telementoring session on the topic facilitated by Project ECHO, or Extension for Community Healthcare Outcomes, which is being used by the University of New Mexico, Albuquerque. The goal of this model is to break down the walls between specialty and primary care by linking experts at an academic “hub” with primary care doctors and nurses in nearby communities.

“Our Project ECHO at the Medical University of South Carolina is twice a month on Fridays,” Dr. Hartwell said. “The first half is a case. The second half is a didactic [session], and you get a free hour of CME.”

The most common drugs used for medication-assisted treatment of opioid disorder are buprenorphine (a partial agonist), naltrexone (an antagonist), and methadone (a full agonist). Methadone retention generally is better than buprenorphine or naltrexone. The recommended treatment duration is 6-12 months, yet many studies demonstrate that many only stay on treatment for 30-60 days.

“You want to keep patients on treatment as long as they benefit from the medication,” Dr. Hartwell said. One large study of Medicaid claims data found that the risk of acute care service use and overdose were high following buprenorphine discontinuation, regardless of treatment duration. Superior outcomes became significant with treatment duration beyond 15 months, although rates of the primary adverse outcomes remained high (Am J Psychiatry. 2020 Feb 1;177[2]:117-24). About 5% of patients across all cohorts experienced one or more medically treated overdoses.

“One thing I don’t want is for people to drop out of treatment and not come back to see me,” Dr. Hartwell said. “This is a time for us to use our shared decision-making skills. I like to use the Tapering Readiness Inventory, a list of 16 questions. It asks such things as ‘Are you able to cope with difficult situations without using?’ and ‘Do you have all of the [drug] paraphernalia out of the house?’ We then have a discussion. If the patient decides to go ahead and do a taper, I always leave the door open. So, as that taper persists and someone says, ‘I’m starting to think about using, Doctor,’ I’ll put them back on [buprenorphine]. Or, if they come off the drug and they find themselves at risk of relapsing, they come back in and see me.”

There’s also some evidence that contingency management might be helpful, both in terms of opioid negative urines, and retention and treatment. Meanwhile, extended-release forms of buprenorphine are emerging.

In 2017, the Food and Drug Administration approved Sublocade, the first once-monthly injectable buprenorphine product for the treatment of moderate-to-severe OUD in adult patients who have initiated treatment with a transmucosal buprenorphine-containing product. “The recommendations are that you have about a 7-day lead-in of sublingual buprenorphine, and then 2 months of a 300-mg IV injection,” Dr. Hartwell said. “This is followed by either 100-mg injections monthly or 300-mg maintenance in select cases. There is some pain at the injection site. Some clinicians are getting around this by using a little bit of lidocaine prior to giving the injection.”

Another product, Brixadi, is an extended-release weekly (8 mg, 16 mg, 24 mg, 32 mg) and monthly (64 mg, 96 mg, 128 mg) buprenorphine injection used for the treatment of moderate to severe OUD. It is expected to be available in December 2020.

In 2016, the FDA approved Probuphine, the first buprenorphine implant for the maintenance treatment of opioid dependence. Probuphine is designed to provide a constant, low-level dose of buprenorphine for 6 months in patients who are already stable on low to moderate doses of other forms of buprenorphine, as part of a complete treatment program. “The 6-month duration kind of takes the issue of adherence off the table,” Dr. Hartwell said. “The caveat with this is that you have to be stable on 8 mg of buprenorphine per day or less. The majority of my patients require much higher doses.”

Dr. Hartwell reported having no relevant disclosures.

[email protected]

LAS VEGAS – The risk-benefit ratio of new and emerging drugs for depression is going to be under the spotlight more than ever before, according to an expert in mood disorders.

Doug Brunk/MDedge News

“We’ve seen a shift in the landscape,” Alan F. Schatzberg, MD, said at an annual psychopharmacology update held by the Nevada Psychiatric Association. “We’ve gone from the development of ‘me too’ agents such as venlafaxine and fluoxetine to developing drugs that may have more dramatic effects, but they also may have more baggage in terms of risks. The risk-benefit ratio is going to become increasingly more of a focus in drug development, in terms of increasing risk.”

The development of the SSRIs, he continued, led to the introduction of agents that were generally effective and well tolerated.

“Particularly, they were well tolerated in terms of their wide safety margin,” said Dr. Schatzberg, who directs the Mood Disorders Center at Stanford (Calif.) University. “It’s difficult to [die by suicide] on an SSRI. Because of that, we had greater numbers of individuals treated than we did with the tricyclics.” The introduction of SSRIs led to “widening of the net in terms of the numbers of depressed patients,” he said. “Combine that with DSM-III, and DSM-IV having relatively easy criteria to obtain a diagnosis [of depression, and] you see a large group of subjects who are exposed to treatment. But a lot of those people may not respond to a particular agent. As new treatments are promulgated and tried, what you find is [that] a reasonable number of subjects are, in fact, truly resistant. That becomes a tough nut to crack for all of us who treat depression.”

Drugs for depression that clinicians commonly have in their armamentarium commonly revolve around monoaminergic function. New and emerging agents include hallucinatory serotonin 2a agonists, glutamatergic drugs such as ketamine, GABAergic neurosteroids, opioid modulators, and onabotulinumtoxinA.

In 2013, the Food and Drug Administration approved the multimodal agent vortioxetine for the treatment of major depressive disorder. The recommended dosing is 20 mg/day, and the drug appears to have a positive effect on cognition. A meta-analysis of vortioxetine, duloxetine, and placebo comparison trials evaluated the effect of each treatment on the Digit Symbol Substitution Test (Int J Neuropsychopharmacol. 2016 Jun 15;19[10]). Vortioxetine was superior to placebo in all three trials and was superior to duloxetine in two trials. Duloxetine was not superior to placebo in two trials.

In two double-blind studies, researchers evaluated the effects of psilocybin in cancer patients with comorbid depression and anxiety. Full doses of psilocybin were 0.3 mg/kg or 22-30 mg per 70 kg. Both studies demonstrated sustained responses at full doses (J Psychopharmacol. 2016 Nov 30;30[12]:1181-97 and J Psychopharmacol. 2016 Nov 30;30[12]:1165-80).

In an open label study of psilocybin in refractory major depression, 12 patients received 10 mg on day 1 and 25 mg on day 8. Eight of 12 patients responded at 1 week, and 7 of the 12 maintained response at 3 months (Lancet Psychiatry. 2016 Jul;3[7]:619-27). According to Dr. Schatzberg, this trial became the basis for a blinded study that Compass is conducting in the United States and in the United Kingdom in which refractory patients are going to be randomized to 1 mg, 10 mg, or 25 mg psilocybin using an independent rater. “These patients are accompanied during this experience by two therapists for up to 8 hours. It’s not quite a guided therapy; it’s kind of a safety net therapy if the patient needs [help]. We’ll see what happens.”

Another agent being studied is ketamine, which works on the glutamate system, an excitatory neurotransmitter. “Glutamate is the juice that keeps us going,” said Dr. Schatzberg, who is also the Kenneth T. Norris Jr. professor of psychiatry and behavioral sciences at the university. “We can’t live without glutamate.” An anesthetic agent that has been used for 50 years, ketamine is a N-methyl-d-aspartate antagonist that has mu opioid agonist effects and stimulant properties. “It causes a psychotomimetic dissociative kind of reaction,” he said. “The doses used in depression are subanesthetic. They may put the patient asleep, but they usually don’t. The problem with the antidepressant effect is that 70% of people who initially respond don’t continue to respond beyond 1 week.”

In a randomized, placebo-controlled, double-blind crossover study of patients with treatment-resistant depression, subjects who received ketamine showed significant improvement in depression, compared with subjects who received placebo within 110 minutes after injection, which remained significant throughout the following week (Arch Gen Psychiatry. 2006;63:856-64). Specifically, of the 17 subjects treated with ketamine, 71% met response and 29% met remission criteria the day following ketamine infusion. Thirty-five percent of subjects maintained response for at least 1 week.

In an effort to further evaluate the antidepressive effects of ketamine, researchers conducted a two-site, parallel-arm, randomized, controlled trial of a single infusion of ketamine, compared with an active placebo control condition, the anesthetic midazolam (Am J Psychiatry. 2013 Oct;170[10]:1134-42). After adjustment for baseline scores and site, the Montgomery-Åsberg Depression Rating Scale score was lower in the ketamine group than in the midazolam group by 7.95 points. The likelihood of response at 24 hours was greater with ketamine than with midazolam (odds ratio, 2.18), with response rates of 64% and 28%, respectively.

In 2019, the FDA approved esketamine nasal spray, in conjunction with an oral antidepressant, for the treatment of depression in adults with treatment-resistant depression. In three phase 3 double-blind studies of esketamine in treatment-refractory depression, one was positive, two were nearly positive, and the effect sizes were mild. One maintenance discontinuation trial was positive. Based on this data, Dr. Schatzberg said, there “is not much evidence” that patients get further gain beyond an antidepressant alone in the first 24-48 hours following ketamine administration. “It makes me wonder: Should we be continuing to give this drug intranasally beyond 48 hours?” he asked. “The reason I have concern is that in certain cultures, ketamine is a highly abusable drug.”

He and Gerard Sanacora, PhD, MD, addressed the topic in a 2015 opinion piece entitled, “Ketamine: Promising path or false prophecy in the development of novel therapeutics for mood disorders?”

“If we step back for a moment and look at where we are – an intravenously administered agent that is a street drug of abuse, works rapidly, and whose enantiomers are being studied by industry for intranasal use – we should be anxious, “ they wrote (Neuropsychopharmacology. 2015 Jan;40[2]:259-67). “We need to be as careful and conservative as possible and understand how it is acting and rule out the possibility of whether it acts as an opioid.”

Dr. Schatzberg disclosed that he has served a consultant to Alkermes, Avanir, Bracket, Compass, Delpor, Epiodyne, Janssen, Jazz, Lundbeck, McKinsey, Merck, Myriad Genetics, Owl, Neuronetics, Pfizer, Sage, and Sunovion. He has received research funding from Janssen and also holds an ownership interest in Corcept, Dermira, Delpor, Epiodyne, Incyte Genetics, Madrigal, Maerck, Owl Analytics, Seattle Genetics, Titan, and Xhale.

[email protected]

LAS VEGAS – The risk-benefit ratio of new and emerging drugs for depression is going to be under the spotlight more than ever before, according to an expert in mood disorders.

Doug Brunk/MDedge News

“We’ve seen a shift in the landscape,” Alan F. Schatzberg, MD, said at an annual psychopharmacology update held by the Nevada Psychiatric Association. “We’ve gone from the development of ‘me too’ agents such as venlafaxine and fluoxetine to developing drugs that may have more dramatic effects, but they also may have more baggage in terms of risks. The risk-benefit ratio is going to become increasingly more of a focus in drug development, in terms of increasing risk.”

The development of the SSRIs, he continued, led to the introduction of agents that were generally effective and well tolerated.

“Particularly, they were well tolerated in terms of their wide safety margin,” said Dr. Schatzberg, who directs the Mood Disorders Center at Stanford (Calif.) University. “It’s difficult to [die by suicide] on an SSRI. Because of that, we had greater numbers of individuals treated than we did with the tricyclics.” The introduction of SSRIs led to “widening of the net in terms of the numbers of depressed patients,” he said. “Combine that with DSM-III, and DSM-IV having relatively easy criteria to obtain a diagnosis [of depression, and] you see a large group of subjects who are exposed to treatment. But a lot of those people may not respond to a particular agent. As new treatments are promulgated and tried, what you find is [that] a reasonable number of subjects are, in fact, truly resistant. That becomes a tough nut to crack for all of us who treat depression.”

Drugs for depression that clinicians commonly have in their armamentarium commonly revolve around monoaminergic function. New and emerging agents include hallucinatory serotonin 2a agonists, glutamatergic drugs such as ketamine, GABAergic neurosteroids, opioid modulators, and onabotulinumtoxinA.

In 2013, the Food and Drug Administration approved the multimodal agent vortioxetine for the treatment of major depressive disorder. The recommended dosing is 20 mg/day, and the drug appears to have a positive effect on cognition. A meta-analysis of vortioxetine, duloxetine, and placebo comparison trials evaluated the effect of each treatment on the Digit Symbol Substitution Test (Int J Neuropsychopharmacol. 2016 Jun 15;19[10]). Vortioxetine was superior to placebo in all three trials and was superior to duloxetine in two trials. Duloxetine was not superior to placebo in two trials.

In two double-blind studies, researchers evaluated the effects of psilocybin in cancer patients with comorbid depression and anxiety. Full doses of psilocybin were 0.3 mg/kg or 22-30 mg per 70 kg. Both studies demonstrated sustained responses at full doses (J Psychopharmacol. 2016 Nov 30;30[12]:1181-97 and J Psychopharmacol. 2016 Nov 30;30[12]:1165-80).

In an open label study of psilocybin in refractory major depression, 12 patients received 10 mg on day 1 and 25 mg on day 8. Eight of 12 patients responded at 1 week, and 7 of the 12 maintained response at 3 months (Lancet Psychiatry. 2016 Jul;3[7]:619-27). According to Dr. Schatzberg, this trial became the basis for a blinded study that Compass is conducting in the United States and in the United Kingdom in which refractory patients are going to be randomized to 1 mg, 10 mg, or 25 mg psilocybin using an independent rater. “These patients are accompanied during this experience by two therapists for up to 8 hours. It’s not quite a guided therapy; it’s kind of a safety net therapy if the patient needs [help]. We’ll see what happens.”

Another agent being studied is ketamine, which works on the glutamate system, an excitatory neurotransmitter. “Glutamate is the juice that keeps us going,” said Dr. Schatzberg, who is also the Kenneth T. Norris Jr. professor of psychiatry and behavioral sciences at the university. “We can’t live without glutamate.” An anesthetic agent that has been used for 50 years, ketamine is a N-methyl-d-aspartate antagonist that has mu opioid agonist effects and stimulant properties. “It causes a psychotomimetic dissociative kind of reaction,” he said. “The doses used in depression are subanesthetic. They may put the patient asleep, but they usually don’t. The problem with the antidepressant effect is that 70% of people who initially respond don’t continue to respond beyond 1 week.”

In a randomized, placebo-controlled, double-blind crossover study of patients with treatment-resistant depression, subjects who received ketamine showed significant improvement in depression, compared with subjects who received placebo within 110 minutes after injection, which remained significant throughout the following week (Arch Gen Psychiatry. 2006;63:856-64). Specifically, of the 17 subjects treated with ketamine, 71% met response and 29% met remission criteria the day following ketamine infusion. Thirty-five percent of subjects maintained response for at least 1 week.

In an effort to further evaluate the antidepressive effects of ketamine, researchers conducted a two-site, parallel-arm, randomized, controlled trial of a single infusion of ketamine, compared with an active placebo control condition, the anesthetic midazolam (Am J Psychiatry. 2013 Oct;170[10]:1134-42). After adjustment for baseline scores and site, the Montgomery-Åsberg Depression Rating Scale score was lower in the ketamine group than in the midazolam group by 7.95 points. The likelihood of response at 24 hours was greater with ketamine than with midazolam (odds ratio, 2.18), with response rates of 64% and 28%, respectively.

In 2019, the FDA approved esketamine nasal spray, in conjunction with an oral antidepressant, for the treatment of depression in adults with treatment-resistant depression. In three phase 3 double-blind studies of esketamine in treatment-refractory depression, one was positive, two were nearly positive, and the effect sizes were mild. One maintenance discontinuation trial was positive. Based on this data, Dr. Schatzberg said, there “is not much evidence” that patients get further gain beyond an antidepressant alone in the first 24-48 hours following ketamine administration. “It makes me wonder: Should we be continuing to give this drug intranasally beyond 48 hours?” he asked. “The reason I have concern is that in certain cultures, ketamine is a highly abusable drug.”

He and Gerard Sanacora, PhD, MD, addressed the topic in a 2015 opinion piece entitled, “Ketamine: Promising path or false prophecy in the development of novel therapeutics for mood disorders?”

“If we step back for a moment and look at where we are – an intravenously administered agent that is a street drug of abuse, works rapidly, and whose enantiomers are being studied by industry for intranasal use – we should be anxious, “ they wrote (Neuropsychopharmacology. 2015 Jan;40[2]:259-67). “We need to be as careful and conservative as possible and understand how it is acting and rule out the possibility of whether it acts as an opioid.”

Dr. Schatzberg disclosed that he has served a consultant to Alkermes, Avanir, Bracket, Compass, Delpor, Epiodyne, Janssen, Jazz, Lundbeck, McKinsey, Merck, Myriad Genetics, Owl, Neuronetics, Pfizer, Sage, and Sunovion. He has received research funding from Janssen and also holds an ownership interest in Corcept, Dermira, Delpor, Epiodyne, Incyte Genetics, Madrigal, Maerck, Owl Analytics, Seattle Genetics, Titan, and Xhale.

[email protected]

LAS VEGAS – The risk-benefit ratio of new and emerging drugs for depression is going to be under the spotlight more than ever before, according to an expert in mood disorders.

Doug Brunk/MDedge News

“We’ve seen a shift in the landscape,” Alan F. Schatzberg, MD, said at an annual psychopharmacology update held by the Nevada Psychiatric Association. “We’ve gone from the development of ‘me too’ agents such as venlafaxine and fluoxetine to developing drugs that may have more dramatic effects, but they also may have more baggage in terms of risks. The risk-benefit ratio is going to become increasingly more of a focus in drug development, in terms of increasing risk.”

The development of the SSRIs, he continued, led to the introduction of agents that were generally effective and well tolerated.

“Particularly, they were well tolerated in terms of their wide safety margin,” said Dr. Schatzberg, who directs the Mood Disorders Center at Stanford (Calif.) University. “It’s difficult to [die by suicide] on an SSRI. Because of that, we had greater numbers of individuals treated than we did with the tricyclics.” The introduction of SSRIs led to “widening of the net in terms of the numbers of depressed patients,” he said. “Combine that with DSM-III, and DSM-IV having relatively easy criteria to obtain a diagnosis [of depression, and] you see a large group of subjects who are exposed to treatment. But a lot of those people may not respond to a particular agent. As new treatments are promulgated and tried, what you find is [that] a reasonable number of subjects are, in fact, truly resistant. That becomes a tough nut to crack for all of us who treat depression.”

Drugs for depression that clinicians commonly have in their armamentarium commonly revolve around monoaminergic function. New and emerging agents include hallucinatory serotonin 2a agonists, glutamatergic drugs such as ketamine, GABAergic neurosteroids, opioid modulators, and onabotulinumtoxinA.

In 2013, the Food and Drug Administration approved the multimodal agent vortioxetine for the treatment of major depressive disorder. The recommended dosing is 20 mg/day, and the drug appears to have a positive effect on cognition. A meta-analysis of vortioxetine, duloxetine, and placebo comparison trials evaluated the effect of each treatment on the Digit Symbol Substitution Test (Int J Neuropsychopharmacol. 2016 Jun 15;19[10]). Vortioxetine was superior to placebo in all three trials and was superior to duloxetine in two trials. Duloxetine was not superior to placebo in two trials.

In two double-blind studies, researchers evaluated the effects of psilocybin in cancer patients with comorbid depression and anxiety. Full doses of psilocybin were 0.3 mg/kg or 22-30 mg per 70 kg. Both studies demonstrated sustained responses at full doses (J Psychopharmacol. 2016 Nov 30;30[12]:1181-97 and J Psychopharmacol. 2016 Nov 30;30[12]:1165-80).

In an open label study of psilocybin in refractory major depression, 12 patients received 10 mg on day 1 and 25 mg on day 8. Eight of 12 patients responded at 1 week, and 7 of the 12 maintained response at 3 months (Lancet Psychiatry. 2016 Jul;3[7]:619-27). According to Dr. Schatzberg, this trial became the basis for a blinded study that Compass is conducting in the United States and in the United Kingdom in which refractory patients are going to be randomized to 1 mg, 10 mg, or 25 mg psilocybin using an independent rater. “These patients are accompanied during this experience by two therapists for up to 8 hours. It’s not quite a guided therapy; it’s kind of a safety net therapy if the patient needs [help]. We’ll see what happens.”

Another agent being studied is ketamine, which works on the glutamate system, an excitatory neurotransmitter. “Glutamate is the juice that keeps us going,” said Dr. Schatzberg, who is also the Kenneth T. Norris Jr. professor of psychiatry and behavioral sciences at the university. “We can’t live without glutamate.” An anesthetic agent that has been used for 50 years, ketamine is a N-methyl-d-aspartate antagonist that has mu opioid agonist effects and stimulant properties. “It causes a psychotomimetic dissociative kind of reaction,” he said. “The doses used in depression are subanesthetic. They may put the patient asleep, but they usually don’t. The problem with the antidepressant effect is that 70% of people who initially respond don’t continue to respond beyond 1 week.”

In a randomized, placebo-controlled, double-blind crossover study of patients with treatment-resistant depression, subjects who received ketamine showed significant improvement in depression, compared with subjects who received placebo within 110 minutes after injection, which remained significant throughout the following week (Arch Gen Psychiatry. 2006;63:856-64). Specifically, of the 17 subjects treated with ketamine, 71% met response and 29% met remission criteria the day following ketamine infusion. Thirty-five percent of subjects maintained response for at least 1 week.

In an effort to further evaluate the antidepressive effects of ketamine, researchers conducted a two-site, parallel-arm, randomized, controlled trial of a single infusion of ketamine, compared with an active placebo control condition, the anesthetic midazolam (Am J Psychiatry. 2013 Oct;170[10]:1134-42). After adjustment for baseline scores and site, the Montgomery-Åsberg Depression Rating Scale score was lower in the ketamine group than in the midazolam group by 7.95 points. The likelihood of response at 24 hours was greater with ketamine than with midazolam (odds ratio, 2.18), with response rates of 64% and 28%, respectively.

In 2019, the FDA approved esketamine nasal spray, in conjunction with an oral antidepressant, for the treatment of depression in adults with treatment-resistant depression. In three phase 3 double-blind studies of esketamine in treatment-refractory depression, one was positive, two were nearly positive, and the effect sizes were mild. One maintenance discontinuation trial was positive. Based on this data, Dr. Schatzberg said, there “is not much evidence” that patients get further gain beyond an antidepressant alone in the first 24-48 hours following ketamine administration. “It makes me wonder: Should we be continuing to give this drug intranasally beyond 48 hours?” he asked. “The reason I have concern is that in certain cultures, ketamine is a highly abusable drug.”

He and Gerard Sanacora, PhD, MD, addressed the topic in a 2015 opinion piece entitled, “Ketamine: Promising path or false prophecy in the development of novel therapeutics for mood disorders?”

“If we step back for a moment and look at where we are – an intravenously administered agent that is a street drug of abuse, works rapidly, and whose enantiomers are being studied by industry for intranasal use – we should be anxious, “ they wrote (Neuropsychopharmacology. 2015 Jan;40[2]:259-67). “We need to be as careful and conservative as possible and understand how it is acting and rule out the possibility of whether it acts as an opioid.”

Dr. Schatzberg disclosed that he has served a consultant to Alkermes, Avanir, Bracket, Compass, Delpor, Epiodyne, Janssen, Jazz, Lundbeck, McKinsey, Merck, Myriad Genetics, Owl, Neuronetics, Pfizer, Sage, and Sunovion. He has received research funding from Janssen and also holds an ownership interest in Corcept, Dermira, Delpor, Epiodyne, Incyte Genetics, Madrigal, Maerck, Owl Analytics, Seattle Genetics, Titan, and Xhale.

[email protected]

LAS VEGAS – No evidence-based medications are approved for the treatment of avoidant/restrictive food intake disorder, but olanzapine is a sensible option to consider, according to Timothy D. Brewerton, MD.

Doug Brunk/MDedge News

A newly classified disorder in the DSM-5, avoidant/restrictive food intake disorder (ARFID) is an eating/feeding disturbance manifested by the persistent failure to meet appropriate nutritional energy needs associated with one or more of the following factors: significant weight loss or failure to achieve expected growth, significant nutritional deficiency, dependence on enteral feeding or oral nutritional supplements to survive, and marked interference with psychosocial functioning. ARFID “is not better explained by lack of available food or by culturally sanctioned practices,” Dr. Brewerton, an affiliate professor of psychiatry and behavioral sciences at the Medical University of South Carolina, Charleston, said at an annual psychopharmacology update held by the Nevada Psychiatric Association. “It does not occur during the course of anorexia nervosa or bulimia nervosa, and there is no evidence of a disturbance in the way in which one’s body weight or shape is experienced. That’s what distinguishes it from anorexia nervosa.”

He added that, although many cases of ARFID have autism spectrum disorder traits, ARFID “is not attributable to a concurrent medical condition or to mental disorder.” When it does occur, the severity of the feeding disorder far outweighs that of the medical condition.”

Several ARFID case reports have been published in the medical literature, yet no randomized controlled trials exist to date. “Treatment is multidisciplinary and involves cognitive-behavioral therapy, sometimes occupational therapy,” said Dr. Brewerton, who is a founding fellow and former board member of the Academy for Eating Disorders.

He and his colleagues published a report on nine ARFID cases treated in an eating disorders program (J Child Adolesc Psychopharmacol. 2017;27[10]:920-2). The patients were treated with adjunctive olanzapine at a starting dose of 0.9 mg/day and discharge dose 2.8 mg/day. For the starting dose, “you have to break the [olanzapine pills] in pieces,” he said. “You have to have a pill cutter. What you don’t want to do is overwhelm the patient or their family members with oversedation. Too often, people start them with 2.5 mg or 5 mg [of olanzapine] right off the bat.”

The researchers found a significant increase in weight gain pre- versus post-olanzapine treatment (a mean of 3.3 pounds vs. 13.1 pounds, respectively; P less than .04) and BMI-for-weight percentiles (P less than .009). “Patients also had improvements in their Clinical Global Impressions Scale scores and a reduction in their associated anxious, depressive, and cognitive symptoms,” Dr. Brewerton said.

Similar findings were observed in a subsequent Canadian study of six ARFID cases (J Eat Disord. 2018;6:20). Five females and one male were treated with a combination of medical monitoring, family therapy, medication (including olanzapine, fluoxetine and in two cases, cyproheptadine), and CBT. At treatment termination, all six patients had achieved their goal weight.

At the University of California, San Diego, researchers led by Emily Gray, MD, conducted a retrospective chart review of six females and eight males with ARFID who ranged in age from 7 to 23 years. All but one of the 14 patients had a co-occurring diagnosis, including general anxiety disorder, social anxiety, unspecified anxiety, ADHD, major depressive disorder, and autism spectrum disorder (J Am Acad Child Adoles Psychiatry. 2018;57[4]:288-9). They were treated with mirtazapine at a dosing range of 7.5-45 mg per day. The average change in BMI per week rose from 0.10 BMI points per week pretreatment to 0.23 BMI points per week post-treatment (P less than .05).

“These cases illustrate that the judicious use of low-dose olanzapine, when used as an adjunct to other treatment modalities, may facilitate eating, weight gain, and the reduction of anxious, depressive, and cognitive symptoms,” said Dr. Brewerton, who also has a private practice in Charleston.

Dr. Brewerton disclosed that he is a consultant to Monte Nido & Affiliates and Sunovion. He receives royalties from Taylor & Francis and Springer-Verlag, and holds ownership interest in Monte Nido & Affiliates.

[email protected]

LAS VEGAS – No evidence-based medications are approved for the treatment of avoidant/restrictive food intake disorder, but olanzapine is a sensible option to consider, according to Timothy D. Brewerton, MD.

Doug Brunk/MDedge News

A newly classified disorder in the DSM-5, avoidant/restrictive food intake disorder (ARFID) is an eating/feeding disturbance manifested by the persistent failure to meet appropriate nutritional energy needs associated with one or more of the following factors: significant weight loss or failure to achieve expected growth, significant nutritional deficiency, dependence on enteral feeding or oral nutritional supplements to survive, and marked interference with psychosocial functioning. ARFID “is not better explained by lack of available food or by culturally sanctioned practices,” Dr. Brewerton, an affiliate professor of psychiatry and behavioral sciences at the Medical University of South Carolina, Charleston, said at an annual psychopharmacology update held by the Nevada Psychiatric Association. “It does not occur during the course of anorexia nervosa or bulimia nervosa, and there is no evidence of a disturbance in the way in which one’s body weight or shape is experienced. That’s what distinguishes it from anorexia nervosa.”

He added that, although many cases of ARFID have autism spectrum disorder traits, ARFID “is not attributable to a concurrent medical condition or to mental disorder.” When it does occur, the severity of the feeding disorder far outweighs that of the medical condition.”

Several ARFID case reports have been published in the medical literature, yet no randomized controlled trials exist to date. “Treatment is multidisciplinary and involves cognitive-behavioral therapy, sometimes occupational therapy,” said Dr. Brewerton, who is a founding fellow and former board member of the Academy for Eating Disorders.

He and his colleagues published a report on nine ARFID cases treated in an eating disorders program (J Child Adolesc Psychopharmacol. 2017;27[10]:920-2). The patients were treated with adjunctive olanzapine at a starting dose of 0.9 mg/day and discharge dose 2.8 mg/day. For the starting dose, “you have to break the [olanzapine pills] in pieces,” he said. “You have to have a pill cutter. What you don’t want to do is overwhelm the patient or their family members with oversedation. Too often, people start them with 2.5 mg or 5 mg [of olanzapine] right off the bat.”

The researchers found a significant increase in weight gain pre- versus post-olanzapine treatment (a mean of 3.3 pounds vs. 13.1 pounds, respectively; P less than .04) and BMI-for-weight percentiles (P less than .009). “Patients also had improvements in their Clinical Global Impressions Scale scores and a reduction in their associated anxious, depressive, and cognitive symptoms,” Dr. Brewerton said.

Similar findings were observed in a subsequent Canadian study of six ARFID cases (J Eat Disord. 2018;6:20). Five females and one male were treated with a combination of medical monitoring, family therapy, medication (including olanzapine, fluoxetine and in two cases, cyproheptadine), and CBT. At treatment termination, all six patients had achieved their goal weight.

At the University of California, San Diego, researchers led by Emily Gray, MD, conducted a retrospective chart review of six females and eight males with ARFID who ranged in age from 7 to 23 years. All but one of the 14 patients had a co-occurring diagnosis, including general anxiety disorder, social anxiety, unspecified anxiety, ADHD, major depressive disorder, and autism spectrum disorder (J Am Acad Child Adoles Psychiatry. 2018;57[4]:288-9). They were treated with mirtazapine at a dosing range of 7.5-45 mg per day. The average change in BMI per week rose from 0.10 BMI points per week pretreatment to 0.23 BMI points per week post-treatment (P less than .05).

“These cases illustrate that the judicious use of low-dose olanzapine, when used as an adjunct to other treatment modalities, may facilitate eating, weight gain, and the reduction of anxious, depressive, and cognitive symptoms,” said Dr. Brewerton, who also has a private practice in Charleston.

Dr. Brewerton disclosed that he is a consultant to Monte Nido & Affiliates and Sunovion. He receives royalties from Taylor & Francis and Springer-Verlag, and holds ownership interest in Monte Nido & Affiliates.

[email protected]

LAS VEGAS – No evidence-based medications are approved for the treatment of avoidant/restrictive food intake disorder, but olanzapine is a sensible option to consider, according to Timothy D. Brewerton, MD.

Doug Brunk/MDedge News

A newly classified disorder in the DSM-5, avoidant/restrictive food intake disorder (ARFID) is an eating/feeding disturbance manifested by the persistent failure to meet appropriate nutritional energy needs associated with one or more of the following factors: significant weight loss or failure to achieve expected growth, significant nutritional deficiency, dependence on enteral feeding or oral nutritional supplements to survive, and marked interference with psychosocial functioning. ARFID “is not better explained by lack of available food or by culturally sanctioned practices,” Dr. Brewerton, an affiliate professor of psychiatry and behavioral sciences at the Medical University of South Carolina, Charleston, said at an annual psychopharmacology update held by the Nevada Psychiatric Association. “It does not occur during the course of anorexia nervosa or bulimia nervosa, and there is no evidence of a disturbance in the way in which one’s body weight or shape is experienced. That’s what distinguishes it from anorexia nervosa.”

He added that, although many cases of ARFID have autism spectrum disorder traits, ARFID “is not attributable to a concurrent medical condition or to mental disorder.” When it does occur, the severity of the feeding disorder far outweighs that of the medical condition.”

Several ARFID case reports have been published in the medical literature, yet no randomized controlled trials exist to date. “Treatment is multidisciplinary and involves cognitive-behavioral therapy, sometimes occupational therapy,” said Dr. Brewerton, who is a founding fellow and former board member of the Academy for Eating Disorders.

He and his colleagues published a report on nine ARFID cases treated in an eating disorders program (J Child Adolesc Psychopharmacol. 2017;27[10]:920-2). The patients were treated with adjunctive olanzapine at a starting dose of 0.9 mg/day and discharge dose 2.8 mg/day. For the starting dose, “you have to break the [olanzapine pills] in pieces,” he said. “You have to have a pill cutter. What you don’t want to do is overwhelm the patient or their family members with oversedation. Too often, people start them with 2.5 mg or 5 mg [of olanzapine] right off the bat.”

The researchers found a significant increase in weight gain pre- versus post-olanzapine treatment (a mean of 3.3 pounds vs. 13.1 pounds, respectively; P less than .04) and BMI-for-weight percentiles (P less than .009). “Patients also had improvements in their Clinical Global Impressions Scale scores and a reduction in their associated anxious, depressive, and cognitive symptoms,” Dr. Brewerton said.

Similar findings were observed in a subsequent Canadian study of six ARFID cases (J Eat Disord. 2018;6:20). Five females and one male were treated with a combination of medical monitoring, family therapy, medication (including olanzapine, fluoxetine and in two cases, cyproheptadine), and CBT. At treatment termination, all six patients had achieved their goal weight.

At the University of California, San Diego, researchers led by Emily Gray, MD, conducted a retrospective chart review of six females and eight males with ARFID who ranged in age from 7 to 23 years. All but one of the 14 patients had a co-occurring diagnosis, including general anxiety disorder, social anxiety, unspecified anxiety, ADHD, major depressive disorder, and autism spectrum disorder (J Am Acad Child Adoles Psychiatry. 2018;57[4]:288-9). They were treated with mirtazapine at a dosing range of 7.5-45 mg per day. The average change in BMI per week rose from 0.10 BMI points per week pretreatment to 0.23 BMI points per week post-treatment (P less than .05).

“These cases illustrate that the judicious use of low-dose olanzapine, when used as an adjunct to other treatment modalities, may facilitate eating, weight gain, and the reduction of anxious, depressive, and cognitive symptoms,” said Dr. Brewerton, who also has a private practice in Charleston.

Dr. Brewerton disclosed that he is a consultant to Monte Nido & Affiliates and Sunovion. He receives royalties from Taylor & Francis and Springer-Verlag, and holds ownership interest in Monte Nido & Affiliates.

[email protected]

An analysis of four commonly performed surgical procedures for stress urinary incontinence found that they all improved sexual dysfunction to a similar degree over the course of 24 months.

Juanmonino/E+/Getty Images

“There is a growing body of literature concerning female sexual function after treatment for urinary incontinence,” Stephanie M. Glass Clark, MD, of the University of Pittsburgh, and colleagues wrote in a study published in Obstetrics & Gynecology. “Pelvic floor muscle therapy has been shown to improve sexual function as well as urinary incontinence symptoms. Surgical treatment, on the other hand, has had unclear effects on sexual function.”

Dr. Glass Clark and colleagues conducted a combined secondary analysis of the SISTEr (Stress Incontinence Surgical Treatment Efficacy Trial) and TOMUS (Trial of Mid-Urethral Slings) studies. Women in the original trials were randomized to receive surgical treatment for stress urinary incontinence with an autologous fascial sling or Burch colposuspension (SISTEr), or a retropubic or transobturator midurethral sling (TOMUS). Sexual function as assessed by the short version of the Pelvic Organ Prolapse/ Urinary Incontinence Sexual Questionnaire (PISQ-12) was compared between groups at baseline, 12 months, and 24 months.

Of the 924 women included, 249 (27%) had an autologous fascial sling, 239 (26%) underwent Burch colposuspension, 216 (23%) had a retropubic midurethral sling placed, and 220 (24%) had a transobturator midurethral sling placed. The researchers observed no significant differences in mean PISQ-12 scores between the four treatment groups at the time of baseline (P = .07) or at the 12- and 24-month visits (P = .42 and P = .50, respectively). Patients in the two studies showed an overall improvement in sexual function over the 24-month study period.

Specifically, PISQ-12 scores at baseline were 32.6 in the transobturator sling group, 33.1 in the retropubic sling group, 31.9 in the Burch procedure group, and 31.4 in the fascial sling group. At 12 months, the PISQ-12 scores rose to 37.7 in the transobturator sling group, 37.8 in the retropubic sling group, 36.9 in the Burch procedure group, and 37.1 in the fascial sling group. These scores were generally maintained at 24 months (37.7 in the transobturator sling group, 37.1 in the retropubic sling group, 36.7 in the Burch procedure group, and 37.4 in the fascial sling group), and were not statistically different than the scores tabulated at the 12-month follow-up visit (P = .97).

“This study and others demonstrate that sexual function improves with surgical improvement of stress incontinence which may suggest a possible association of urinary incontinence and sexual dysfunction,” Dr. Glass Clark and colleagues concluded. “As we continue to explore the complex and multifaceted problem of sexual dysfunction, further evaluation of the effect of pelvic floor disorders – and their treatments – will be important and necessary research.”

The researchers acknowledged certain limitations of the study, including the fact that there was a low degree of diversity among women in the studied trials, which limits the generalizability of the findings. They also pointed out that the PISQ-12 does not address sexual stimulation or nonpenetrative vaginal intercourse. “Additionally, it limits partner-related problems to erectile dysfunction and premature ejaculation; some eligible participants may be excluded secondary to sexual preferences given the assumptions inherent to the questionnaire that the partner is male,” they wrote.

This secondary analysis had no outside sources of funding. Dr. Glass Clark reported that she received a travel stipend from the Society of Gynecologic Surgeons, sponsored by OB-STATS. Her coauthors reported having no financial conflicts.

[email protected]

SOURCE: Glass Clark SM et al. Obstet Gynecol 2020;135(2):352-60.

An analysis of four commonly performed surgical procedures for stress urinary incontinence found that they all improved sexual dysfunction to a similar degree over the course of 24 months.

Juanmonino/E+/Getty Images

“There is a growing body of literature concerning female sexual function after treatment for urinary incontinence,” Stephanie M. Glass Clark, MD, of the University of Pittsburgh, and colleagues wrote in a study published in Obstetrics & Gynecology. “Pelvic floor muscle therapy has been shown to improve sexual function as well as urinary incontinence symptoms. Surgical treatment, on the other hand, has had unclear effects on sexual function.”

Dr. Glass Clark and colleagues conducted a combined secondary analysis of the SISTEr (Stress Incontinence Surgical Treatment Efficacy Trial) and TOMUS (Trial of Mid-Urethral Slings) studies. Women in the original trials were randomized to receive surgical treatment for stress urinary incontinence with an autologous fascial sling or Burch colposuspension (SISTEr), or a retropubic or transobturator midurethral sling (TOMUS). Sexual function as assessed by the short version of the Pelvic Organ Prolapse/ Urinary Incontinence Sexual Questionnaire (PISQ-12) was compared between groups at baseline, 12 months, and 24 months.

Of the 924 women included, 249 (27%) had an autologous fascial sling, 239 (26%) underwent Burch colposuspension, 216 (23%) had a retropubic midurethral sling placed, and 220 (24%) had a transobturator midurethral sling placed. The researchers observed no significant differences in mean PISQ-12 scores between the four treatment groups at the time of baseline (P = .07) or at the 12- and 24-month visits (P = .42 and P = .50, respectively). Patients in the two studies showed an overall improvement in sexual function over the 24-month study period.

Specifically, PISQ-12 scores at baseline were 32.6 in the transobturator sling group, 33.1 in the retropubic sling group, 31.9 in the Burch procedure group, and 31.4 in the fascial sling group. At 12 months, the PISQ-12 scores rose to 37.7 in the transobturator sling group, 37.8 in the retropubic sling group, 36.9 in the Burch procedure group, and 37.1 in the fascial sling group. These scores were generally maintained at 24 months (37.7 in the transobturator sling group, 37.1 in the retropubic sling group, 36.7 in the Burch procedure group, and 37.4 in the fascial sling group), and were not statistically different than the scores tabulated at the 12-month follow-up visit (P = .97).

“This study and others demonstrate that sexual function improves with surgical improvement of stress incontinence which may suggest a possible association of urinary incontinence and sexual dysfunction,” Dr. Glass Clark and colleagues concluded. “As we continue to explore the complex and multifaceted problem of sexual dysfunction, further evaluation of the effect of pelvic floor disorders – and their treatments – will be important and necessary research.”

The researchers acknowledged certain limitations of the study, including the fact that there was a low degree of diversity among women in the studied trials, which limits the generalizability of the findings. They also pointed out that the PISQ-12 does not address sexual stimulation or nonpenetrative vaginal intercourse. “Additionally, it limits partner-related problems to erectile dysfunction and premature ejaculation; some eligible participants may be excluded secondary to sexual preferences given the assumptions inherent to the questionnaire that the partner is male,” they wrote.

This secondary analysis had no outside sources of funding. Dr. Glass Clark reported that she received a travel stipend from the Society of Gynecologic Surgeons, sponsored by OB-STATS. Her coauthors reported having no financial conflicts.

[email protected]

SOURCE: Glass Clark SM et al. Obstet Gynecol 2020;135(2):352-60.

An analysis of four commonly performed surgical procedures for stress urinary incontinence found that they all improved sexual dysfunction to a similar degree over the course of 24 months.

Juanmonino/E+/Getty Images

“There is a growing body of literature concerning female sexual function after treatment for urinary incontinence,” Stephanie M. Glass Clark, MD, of the University of Pittsburgh, and colleagues wrote in a study published in Obstetrics & Gynecology. “Pelvic floor muscle therapy has been shown to improve sexual function as well as urinary incontinence symptoms. Surgical treatment, on the other hand, has had unclear effects on sexual function.”

Dr. Glass Clark and colleagues conducted a combined secondary analysis of the SISTEr (Stress Incontinence Surgical Treatment Efficacy Trial) and TOMUS (Trial of Mid-Urethral Slings) studies. Women in the original trials were randomized to receive surgical treatment for stress urinary incontinence with an autologous fascial sling or Burch colposuspension (SISTEr), or a retropubic or transobturator midurethral sling (TOMUS). Sexual function as assessed by the short version of the Pelvic Organ Prolapse/ Urinary Incontinence Sexual Questionnaire (PISQ-12) was compared between groups at baseline, 12 months, and 24 months.

Of the 924 women included, 249 (27%) had an autologous fascial sling, 239 (26%) underwent Burch colposuspension, 216 (23%) had a retropubic midurethral sling placed, and 220 (24%) had a transobturator midurethral sling placed. The researchers observed no significant differences in mean PISQ-12 scores between the four treatment groups at the time of baseline (P = .07) or at the 12- and 24-month visits (P = .42 and P = .50, respectively). Patients in the two studies showed an overall improvement in sexual function over the 24-month study period.

Specifically, PISQ-12 scores at baseline were 32.6 in the transobturator sling group, 33.1 in the retropubic sling group, 31.9 in the Burch procedure group, and 31.4 in the fascial sling group. At 12 months, the PISQ-12 scores rose to 37.7 in the transobturator sling group, 37.8 in the retropubic sling group, 36.9 in the Burch procedure group, and 37.1 in the fascial sling group. These scores were generally maintained at 24 months (37.7 in the transobturator sling group, 37.1 in the retropubic sling group, 36.7 in the Burch procedure group, and 37.4 in the fascial sling group), and were not statistically different than the scores tabulated at the 12-month follow-up visit (P = .97).

“This study and others demonstrate that sexual function improves with surgical improvement of stress incontinence which may suggest a possible association of urinary incontinence and sexual dysfunction,” Dr. Glass Clark and colleagues concluded. “As we continue to explore the complex and multifaceted problem of sexual dysfunction, further evaluation of the effect of pelvic floor disorders – and their treatments – will be important and necessary research.”

The researchers acknowledged certain limitations of the study, including the fact that there was a low degree of diversity among women in the studied trials, which limits the generalizability of the findings. They also pointed out that the PISQ-12 does not address sexual stimulation or nonpenetrative vaginal intercourse. “Additionally, it limits partner-related problems to erectile dysfunction and premature ejaculation; some eligible participants may be excluded secondary to sexual preferences given the assumptions inherent to the questionnaire that the partner is male,” they wrote.

This secondary analysis had no outside sources of funding. Dr. Glass Clark reported that she received a travel stipend from the Society of Gynecologic Surgeons, sponsored by OB-STATS. Her coauthors reported having no financial conflicts.

[email protected]

SOURCE: Glass Clark SM et al. Obstet Gynecol 2020;135(2):352-60.

In its first year of operation, a mobile stroke unit in Melbourne demonstrated substantial savings in time to commencement of both thrombolysis and endovascular thrombectomy (EVT), results from a prospective study showed.

“While previously published data from MSU [mobile stroke unit] services in Europe and North America show substantial reductions in time to thrombolysis of approximately 30-45 minutes, little is known about the clinical impact on EVT,” first author Henry Zhao, MBBS, and colleagues wrote in a study published in Stroke.

Launched in November 2017, the Melbourne MSU is based at a large comprehensive stroke center and operates with a 20-km radius, servicing about 1.7 million people within the city of Melbourne. It is staffed with an onboard neurologist or senior stroke fellow who provides primary assessment and treatment decisions, a stroke advanced practice nurse who provides clinical support and treatment administration, a clinician who provides CT imaging, and advanced life support and mobile intensive care paramedics who provide transport logistics and paramedicine support. For the current analysis, MSU patients who received reperfusion therapy were compared with control patients presenting to metropolitan Melbourne stroke units via standard ambulance within MSU operating hours. The primary outcome was median time difference in first ambulance dispatch to treatment, which the researchers used quantile regression analysis to determine. Time savings were subsequently converted to disability-adjusted life years (DALY) avoiding using published estimates.

Dr. Zhao of the Melbourne Brain Centre and department of neurology at Royal Melbourne Hospital and his colleagues reported that, in its first year of operation, the Melbourne MSU administered prehospital thrombolysis to 100 patients with a mean age of nearly 74 years. More than half of the patients (62%) were male. Compared with controls, the median time savings per MSU patient was 26 minutes for dispatch to hospital arrival and 15 minutes for hospital arrival to thrombolysis (P less than .0010 for both associations). The calculated overall time saving from dispatch to thrombolysis was 42.5 minutes.

Over the same time period, 41 MSU patients with a mean age of 76 years received EVT dispatch-to-treatment time saving of 51 minutes (P less than 0.001). This included a median time saving of 17 minutes for EVT hospital arrival to arterial puncture for MSU patients (P = .001). Overall estimated median DALYs saved through earlier provision of reperfusion therapies were 20.9 for thrombolysis and 24.6 for EVT.

“The benefit in EVT patients was primarily driven by prehospital MSU diagnosis of large vessel occlusion, which enabled bypass of a local non-EVT center directly to a comprehensive stroke center in almost 50% of patients with large vessel occlusion,” the researchers wrote. “Even when patients were located close to an EVT center, MSU pre-notification and facilitated workflows achieved a reduction in hospital arrival to arterial puncture by one-third. Furthermore, the time saving was seen despite the majority of EVT patients receiving repeat imaging in hospital to visualize the extracranial circulation.”

The study is scheduled to be presented at the International Stroke Conference on Feb. 20.

The Melbourne MSU received funding from the Australian Commonwealth Government, Victorian State Government, Royal Melbourne Hospital Neurosciences Foundation, Stroke Foundation, the Florey Institute of Neurosciences and Mental Health, the University of Melbourne, Boehringer Ingelheim, and private donation. Dr. Zhao disclosed that he has received grants from the Australian Commonwealth Government and the University of Melbourne and personal fees from Boehringer Ingelheim.

[email protected]

SOURCE: Zhao H et al. Stroke. 2020 Feb 12. doi: 10.1161/strokeaha.119.027843.

In its first year of operation, a mobile stroke unit in Melbourne demonstrated substantial savings in time to commencement of both thrombolysis and endovascular thrombectomy (EVT), results from a prospective study showed.

“While previously published data from MSU [mobile stroke unit] services in Europe and North America show substantial reductions in time to thrombolysis of approximately 30-45 minutes, little is known about the clinical impact on EVT,” first author Henry Zhao, MBBS, and colleagues wrote in a study published in Stroke.

Launched in November 2017, the Melbourne MSU is based at a large comprehensive stroke center and operates with a 20-km radius, servicing about 1.7 million people within the city of Melbourne. It is staffed with an onboard neurologist or senior stroke fellow who provides primary assessment and treatment decisions, a stroke advanced practice nurse who provides clinical support and treatment administration, a clinician who provides CT imaging, and advanced life support and mobile intensive care paramedics who provide transport logistics and paramedicine support. For the current analysis, MSU patients who received reperfusion therapy were compared with control patients presenting to metropolitan Melbourne stroke units via standard ambulance within MSU operating hours. The primary outcome was median time difference in first ambulance dispatch to treatment, which the researchers used quantile regression analysis to determine. Time savings were subsequently converted to disability-adjusted life years (DALY) avoiding using published estimates.

Dr. Zhao of the Melbourne Brain Centre and department of neurology at Royal Melbourne Hospital and his colleagues reported that, in its first year of operation, the Melbourne MSU administered prehospital thrombolysis to 100 patients with a mean age of nearly 74 years. More than half of the patients (62%) were male. Compared with controls, the median time savings per MSU patient was 26 minutes for dispatch to hospital arrival and 15 minutes for hospital arrival to thrombolysis (P less than .0010 for both associations). The calculated overall time saving from dispatch to thrombolysis was 42.5 minutes.

Over the same time period, 41 MSU patients with a mean age of 76 years received EVT dispatch-to-treatment time saving of 51 minutes (P less than 0.001). This included a median time saving of 17 minutes for EVT hospital arrival to arterial puncture for MSU patients (P = .001). Overall estimated median DALYs saved through earlier provision of reperfusion therapies were 20.9 for thrombolysis and 24.6 for EVT.

“The benefit in EVT patients was primarily driven by prehospital MSU diagnosis of large vessel occlusion, which enabled bypass of a local non-EVT center directly to a comprehensive stroke center in almost 50% of patients with large vessel occlusion,” the researchers wrote. “Even when patients were located close to an EVT center, MSU pre-notification and facilitated workflows achieved a reduction in hospital arrival to arterial puncture by one-third. Furthermore, the time saving was seen despite the majority of EVT patients receiving repeat imaging in hospital to visualize the extracranial circulation.”

The study is scheduled to be presented at the International Stroke Conference on Feb. 20.

The Melbourne MSU received funding from the Australian Commonwealth Government, Victorian State Government, Royal Melbourne Hospital Neurosciences Foundation, Stroke Foundation, the Florey Institute of Neurosciences and Mental Health, the University of Melbourne, Boehringer Ingelheim, and private donation. Dr. Zhao disclosed that he has received grants from the Australian Commonwealth Government and the University of Melbourne and personal fees from Boehringer Ingelheim.

[email protected]

SOURCE: Zhao H et al. Stroke. 2020 Feb 12. doi: 10.1161/strokeaha.119.027843.

In its first year of operation, a mobile stroke unit in Melbourne demonstrated substantial savings in time to commencement of both thrombolysis and endovascular thrombectomy (EVT), results from a prospective study showed.

“While previously published data from MSU [mobile stroke unit] services in Europe and North America show substantial reductions in time to thrombolysis of approximately 30-45 minutes, little is known about the clinical impact on EVT,” first author Henry Zhao, MBBS, and colleagues wrote in a study published in Stroke.

Launched in November 2017, the Melbourne MSU is based at a large comprehensive stroke center and operates with a 20-km radius, servicing about 1.7 million people within the city of Melbourne. It is staffed with an onboard neurologist or senior stroke fellow who provides primary assessment and treatment decisions, a stroke advanced practice nurse who provides clinical support and treatment administration, a clinician who provides CT imaging, and advanced life support and mobile intensive care paramedics who provide transport logistics and paramedicine support. For the current analysis, MSU patients who received reperfusion therapy were compared with control patients presenting to metropolitan Melbourne stroke units via standard ambulance within MSU operating hours. The primary outcome was median time difference in first ambulance dispatch to treatment, which the researchers used quantile regression analysis to determine. Time savings were subsequently converted to disability-adjusted life years (DALY) avoiding using published estimates.

Dr. Zhao of the Melbourne Brain Centre and department of neurology at Royal Melbourne Hospital and his colleagues reported that, in its first year of operation, the Melbourne MSU administered prehospital thrombolysis to 100 patients with a mean age of nearly 74 years. More than half of the patients (62%) were male. Compared with controls, the median time savings per MSU patient was 26 minutes for dispatch to hospital arrival and 15 minutes for hospital arrival to thrombolysis (P less than .0010 for both associations). The calculated overall time saving from dispatch to thrombolysis was 42.5 minutes.

Over the same time period, 41 MSU patients with a mean age of 76 years received EVT dispatch-to-treatment time saving of 51 minutes (P less than 0.001). This included a median time saving of 17 minutes for EVT hospital arrival to arterial puncture for MSU patients (P = .001). Overall estimated median DALYs saved through earlier provision of reperfusion therapies were 20.9 for thrombolysis and 24.6 for EVT.

“The benefit in EVT patients was primarily driven by prehospital MSU diagnosis of large vessel occlusion, which enabled bypass of a local non-EVT center directly to a comprehensive stroke center in almost 50% of patients with large vessel occlusion,” the researchers wrote. “Even when patients were located close to an EVT center, MSU pre-notification and facilitated workflows achieved a reduction in hospital arrival to arterial puncture by one-third. Furthermore, the time saving was seen despite the majority of EVT patients receiving repeat imaging in hospital to visualize the extracranial circulation.”

The study is scheduled to be presented at the International Stroke Conference on Feb. 20.

The Melbourne MSU received funding from the Australian Commonwealth Government, Victorian State Government, Royal Melbourne Hospital Neurosciences Foundation, Stroke Foundation, the Florey Institute of Neurosciences and Mental Health, the University of Melbourne, Boehringer Ingelheim, and private donation. Dr. Zhao disclosed that he has received grants from the Australian Commonwealth Government and the University of Melbourne and personal fees from Boehringer Ingelheim.

[email protected]

SOURCE: Zhao H et al. Stroke. 2020 Feb 12. doi: 10.1161/strokeaha.119.027843.

Among Medicare beneficiaries admitted to the hospital between 2008 and 2016, there was an increase in postdischarge 30-day mortality for patients with heart failure, but not for those with acute myocardial infarction or pneumonia.

The finding comes from an effort to evaluate the use of services soon after discharge for conditions targeted in the U.S. Hospital Readmissions Reduction Program (HRRP), and patients’ outcomes.

“The announcement and implementation of the HRRP were associated with a reduction in readmissions within 30 days of discharge for heart failure, acute myocardial infarction, and pneumonia, as shown by a decrease in the overall national rate of readmissions,” first author Rohan Khera, MD, and colleagues wrote in a study published online Jan. 15, 2020, in the British Medical Journal (doi:10.1136/bmj.l6831).

“Concerns existed that pressures to reduce readmissions had led to the evolution of care patterns that may have adverse consequences through reducing access to care in appropriate settings. Therefore, determining whether patients who are seen in acute care settings, but not admitted to hospital, experience an increased risk of mortality is essential.”

Dr. Khera, a cardiologist at the University of Texas Southwestern Medical Center, Dallas, and colleagues limited the analysis to Medicare claims data from patients who were admitted to the hospital with heart failure, acute myocardial infarction (MI), or pneumonia between 2008 and 2016. Key outcomes of interest were: (1) postdischarge 30-day mortality; and (2) acute care utilization in inpatient units, observation units, and the ED during the postdischarge period.

During the study period there were 3,772,924 hospital admissions for heart failure, 1,570,113 for acute MI, and 3,131,162 for pneumonia. The greatest number of readmissions within 30 days of discharge was for heart failure patients (22.5%), followed by acute MI (17.5%), and pneumonia (17.2%).

The overall rates of observation stays were 1.7% for heart failure, 2.6% for acute MI, and 1.4% for pneumonia, while the overall rates of emergency department visits were 6.4% for heart failure, 6.8% for acute MI, and 6.3% for pneumonia. Cumulatively, about one-third of all admissions – 30.7% for heart failure, 26.9% for acute MI, and 24.8% for pneumonia – received postdischarge care in any acute care setting.

Dr. Khera and colleagues found that overall postdischarge 30-day mortality was 8.7% for heart failure, 7.3% for acute MI, and 8.4% for pneumonia. At the same time, postdischarge 30-day mortality was higher in patients with readmissions (13.2% for heart failure, 12.7% for acute MI, and 15.3% for pneumonia), compared with those who had observation stays (4.5% for heart failure, 2.7% for acute MI, and 4.6% for pneumonia), emergency department visits (9.7% for heart failure, 8.8% for acute MI, and 7.8% for pneumonia), or no postdischarge acute care (7.2% for heart failure, 6.0% for acute MI, and 6.9% for pneumonia). Risk adjusted mortality increased annually by 0.05% only for heart failure, while it decreased by 0.06% for acute MI, and did not significantly change for pneumonia.

“The study strongly suggests that the HRRP did not lead to harm through inappropriate triage of patients at high risk to observation units and the emergency department, and therefore provides evidence against calls to curtail the program owing to this theoretical concern (see JAMA 2018;320:2539-41),” the researchers concluded.

They acknowledged certain limitations of the study, including the fact that they were “unable to identify patterns of acute care during the index hospital admission that would be associated with a higher rate of postdischarge acute care in observation units and emergency departments and whether these visits represented avenues for planned postdischarge follow-up care. Moreover, the proportion of these care encounters that were preventable remains poorly understood.”

Dr. Khera disclosed that he is supported by the National Center for Advancing Translational Sciences of the National Institutes of Health. His coauthors reported having numerous disclosures.

[email protected]

SOURCE: Khera et al. BMJ 2020;368:l6831.

Among Medicare beneficiaries admitted to the hospital between 2008 and 2016, there was an increase in postdischarge 30-day mortality for patients with heart failure, but not for those with acute myocardial infarction or pneumonia.

The finding comes from an effort to evaluate the use of services soon after discharge for conditions targeted in the U.S. Hospital Readmissions Reduction Program (HRRP), and patients’ outcomes.

“The announcement and implementation of the HRRP were associated with a reduction in readmissions within 30 days of discharge for heart failure, acute myocardial infarction, and pneumonia, as shown by a decrease in the overall national rate of readmissions,” first author Rohan Khera, MD, and colleagues wrote in a study published online Jan. 15, 2020, in the British Medical Journal (doi:10.1136/bmj.l6831).

“Concerns existed that pressures to reduce readmissions had led to the evolution of care patterns that may have adverse consequences through reducing access to care in appropriate settings. Therefore, determining whether patients who are seen in acute care settings, but not admitted to hospital, experience an increased risk of mortality is essential.”

Dr. Khera, a cardiologist at the University of Texas Southwestern Medical Center, Dallas, and colleagues limited the analysis to Medicare claims data from patients who were admitted to the hospital with heart failure, acute myocardial infarction (MI), or pneumonia between 2008 and 2016. Key outcomes of interest were: (1) postdischarge 30-day mortality; and (2) acute care utilization in inpatient units, observation units, and the ED during the postdischarge period.

During the study period there were 3,772,924 hospital admissions for heart failure, 1,570,113 for acute MI, and 3,131,162 for pneumonia. The greatest number of readmissions within 30 days of discharge was for heart failure patients (22.5%), followed by acute MI (17.5%), and pneumonia (17.2%).

The overall rates of observation stays were 1.7% for heart failure, 2.6% for acute MI, and 1.4% for pneumonia, while the overall rates of emergency department visits were 6.4% for heart failure, 6.8% for acute MI, and 6.3% for pneumonia. Cumulatively, about one-third of all admissions – 30.7% for heart failure, 26.9% for acute MI, and 24.8% for pneumonia – received postdischarge care in any acute care setting.

Dr. Khera and colleagues found that overall postdischarge 30-day mortality was 8.7% for heart failure, 7.3% for acute MI, and 8.4% for pneumonia. At the same time, postdischarge 30-day mortality was higher in patients with readmissions (13.2% for heart failure, 12.7% for acute MI, and 15.3% for pneumonia), compared with those who had observation stays (4.5% for heart failure, 2.7% for acute MI, and 4.6% for pneumonia), emergency department visits (9.7% for heart failure, 8.8% for acute MI, and 7.8% for pneumonia), or no postdischarge acute care (7.2% for heart failure, 6.0% for acute MI, and 6.9% for pneumonia). Risk adjusted mortality increased annually by 0.05% only for heart failure, while it decreased by 0.06% for acute MI, and did not significantly change for pneumonia.

“The study strongly suggests that the HRRP did not lead to harm through inappropriate triage of patients at high risk to observation units and the emergency department, and therefore provides evidence against calls to curtail the program owing to this theoretical concern (see JAMA 2018;320:2539-41),” the researchers concluded.

They acknowledged certain limitations of the study, including the fact that they were “unable to identify patterns of acute care during the index hospital admission that would be associated with a higher rate of postdischarge acute care in observation units and emergency departments and whether these visits represented avenues for planned postdischarge follow-up care. Moreover, the proportion of these care encounters that were preventable remains poorly understood.”

Dr. Khera disclosed that he is supported by the National Center for Advancing Translational Sciences of the National Institutes of Health. His coauthors reported having numerous disclosures.

[email protected]

SOURCE: Khera et al. BMJ 2020;368:l6831.

Among Medicare beneficiaries admitted to the hospital between 2008 and 2016, there was an increase in postdischarge 30-day mortality for patients with heart failure, but not for those with acute myocardial infarction or pneumonia.

The finding comes from an effort to evaluate the use of services soon after discharge for conditions targeted in the U.S. Hospital Readmissions Reduction Program (HRRP), and patients’ outcomes.

“The announcement and implementation of the HRRP were associated with a reduction in readmissions within 30 days of discharge for heart failure, acute myocardial infarction, and pneumonia, as shown by a decrease in the overall national rate of readmissions,” first author Rohan Khera, MD, and colleagues wrote in a study published online Jan. 15, 2020, in the British Medical Journal (doi:10.1136/bmj.l6831).

“Concerns existed that pressures to reduce readmissions had led to the evolution of care patterns that may have adverse consequences through reducing access to care in appropriate settings. Therefore, determining whether patients who are seen in acute care settings, but not admitted to hospital, experience an increased risk of mortality is essential.”

Dr. Khera, a cardiologist at the University of Texas Southwestern Medical Center, Dallas, and colleagues limited the analysis to Medicare claims data from patients who were admitted to the hospital with heart failure, acute myocardial infarction (MI), or pneumonia between 2008 and 2016. Key outcomes of interest were: (1) postdischarge 30-day mortality; and (2) acute care utilization in inpatient units, observation units, and the ED during the postdischarge period.

During the study period there were 3,772,924 hospital admissions for heart failure, 1,570,113 for acute MI, and 3,131,162 for pneumonia. The greatest number of readmissions within 30 days of discharge was for heart failure patients (22.5%), followed by acute MI (17.5%), and pneumonia (17.2%).

The overall rates of observation stays were 1.7% for heart failure, 2.6% for acute MI, and 1.4% for pneumonia, while the overall rates of emergency department visits were 6.4% for heart failure, 6.8% for acute MI, and 6.3% for pneumonia. Cumulatively, about one-third of all admissions – 30.7% for heart failure, 26.9% for acute MI, and 24.8% for pneumonia – received postdischarge care in any acute care setting.

Dr. Khera and colleagues found that overall postdischarge 30-day mortality was 8.7% for heart failure, 7.3% for acute MI, and 8.4% for pneumonia. At the same time, postdischarge 30-day mortality was higher in patients with readmissions (13.2% for heart failure, 12.7% for acute MI, and 15.3% for pneumonia), compared with those who had observation stays (4.5% for heart failure, 2.7% for acute MI, and 4.6% for pneumonia), emergency department visits (9.7% for heart failure, 8.8% for acute MI, and 7.8% for pneumonia), or no postdischarge acute care (7.2% for heart failure, 6.0% for acute MI, and 6.9% for pneumonia). Risk adjusted mortality increased annually by 0.05% only for heart failure, while it decreased by 0.06% for acute MI, and did not significantly change for pneumonia.

“The study strongly suggests that the HRRP did not lead to harm through inappropriate triage of patients at high risk to observation units and the emergency department, and therefore provides evidence against calls to curtail the program owing to this theoretical concern (see JAMA 2018;320:2539-41),” the researchers concluded.

They acknowledged certain limitations of the study, including the fact that they were “unable to identify patterns of acute care during the index hospital admission that would be associated with a higher rate of postdischarge acute care in observation units and emergency departments and whether these visits represented avenues for planned postdischarge follow-up care. Moreover, the proportion of these care encounters that were preventable remains poorly understood.”

Dr. Khera disclosed that he is supported by the National Center for Advancing Translational Sciences of the National Institutes of Health. His coauthors reported having numerous disclosures.

[email protected]

SOURCE: Khera et al. BMJ 2020;368:l6831.

Low serum levels of hydroxychloroquine (HCQ) among patients with systemic lupus erythematosus are associated with a threefold increased likelihood of physician- and patient-reported nonadherence to the medication. In addition, routine monitoring of HCQ levels are associated with improvements in adherence and disease activity.

Alexander Raths/ThinkStock

Those are two key findings from a systematic review and meta-analysis published in Arthritis Care & Research.

“HCQ is recommended for all patients with systemic lupus erythematosus (SLE, or lupus) to reduce disease activity and improve damage-free-survival,” the authors, led by Shivani Garg, MD, of the University of Wisconsin–Madison, wrote in the article. “Yet, up to 83% of lupus patients are nonadherent to HCQ commonly because of poor understanding of benefits of HCQ, lack of motivation to continue therapy, and inflated concerns regarding side effects from HCQ use.”

For their analysis, the researchers drew from 17 published observational and interventional studies that measured HCQ levels and assessed adherence or Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) in adults with SLE. They used forest plots to compare pooled estimates of correlations between HCQ levels and reported nonadherence, or SLEDAI scores. Patient-reported nonadherence was defined as less than 80% medication adherence reported, and physician-reported adherence was estimated based on physicians’ interpretations of the previous month’s adherence as reported by patients during clinic visits.

The study population consisted of 1,223 patients. Dr. Garg and colleagues found a threefold higher odds of reported nonadherence in patients with low HCQ levels (odds ratio, 2.95; P less than .001). The mean SLEDAI score was 3.14 points higher in a group with below-threshold HCQ levels on a priori analysis (P = .053), and 1.4 points higher in a group with HCQ levels below 500 ng/mL (P = .039). Among all patients, those with HCQ levels 750 ng/mL or greater had a 58% lower risk of active disease, and their SLEDAI score was 3.2 points lower. “Our study support levels greater than or equal to 750 ng/mL to be clinically meaningful and statistically significant to identify disease flare (change in SLEDAI greater than or equal to 3 points) and predict active disease (SLEDAI greater than or equal to 6),” the authors wrote.

In an interview, Michelle A. Petri, MD, MPH, took issue with the HCQ goal of 750 ng/mL or greater recommended by the authors. “I think that was premature,” said Dr. Petri, professor of medicine at Johns Hopkins University, Baltimore. “We presented data at last year’s ACR [which showed] that the level needs to be higher than that to prevent thrombosis. But it is important to open the discussion that HCQ blood levels are not just for nonadherence. I believe they will help us to reduce retinopathy, and also to make sure the dose remains in an efficacious range, such as what is needed to prevent thrombosis.”

Dr. Petri, who also directs the Hopkins Lupus Center, said that the study’s overall conclusions confirms the need for blood testing for HCQ to identify nonadherence. “Everyone remembers the saying of the [former] Surgeon General Dr. C. Everett Koop: ‘Drugs can’t work if patients don’t take them!’ – in particular, blood levels which represent what the patient has taken in the last month. I call blood levels the ‘lupus A_1C.’ ”

She added that HCQ blood levels have utility for nonadherence, prediction of retinopathy, and prevention of thrombosis. Such tests “are now much more widely available, including by some large national laboratories such as Quest Diagnostics, as well as by Exagen. No more excuses.” LabCorp plans to start offering HCQ blood level testing by the middle of 2020, she said.

In their manuscript, the study authors acknowledged certain limitations of their analysis, including the fact that there were only four studies that measured HCQ levels and nonadherence or SLEDAI. “Second, most of the studies that examined the correlation between reported adherence and HCQ blood levels were performed in Europe, and there was only one small U.S. study,” they wrote. “Therefore, generalizability for our findings could be limited because of differences in cultural beliefs, social issues, and insurance/medical coverage in populations from diverse countries.”

The study authors reported having no disclosures. Dr. Petri disclosed that she has conducted research on HCQ that was funded by the National Institutes of Health. She has also conducted research for Exagen.

[email protected]

SOURCE: Garg S et al. Arthritis Care Res. 2020 Jan 31. doi: 10.1002/acr.24155.

Low serum levels of hydroxychloroquine (HCQ) among patients with systemic lupus erythematosus are associated with a threefold increased likelihood of physician- and patient-reported nonadherence to the medication. In addition, routine monitoring of HCQ levels are associated with improvements in adherence and disease activity.

Alexander Raths/ThinkStock

Those are two key findings from a systematic review and meta-analysis published in Arthritis Care & Research.

“HCQ is recommended for all patients with systemic lupus erythematosus (SLE, or lupus) to reduce disease activity and improve damage-free-survival,” the authors, led by Shivani Garg, MD, of the University of Wisconsin–Madison, wrote in the article. “Yet, up to 83% of lupus patients are nonadherent to HCQ commonly because of poor understanding of benefits of HCQ, lack of motivation to continue therapy, and inflated concerns regarding side effects from HCQ use.”

For their analysis, the researchers drew from 17 published observational and interventional studies that measured HCQ levels and assessed adherence or Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) in adults with SLE. They used forest plots to compare pooled estimates of correlations between HCQ levels and reported nonadherence, or SLEDAI scores. Patient-reported nonadherence was defined as less than 80% medication adherence reported, and physician-reported adherence was estimated based on physicians’ interpretations of the previous month’s adherence as reported by patients during clinic visits.

The study population consisted of 1,223 patients. Dr. Garg and colleagues found a threefold higher odds of reported nonadherence in patients with low HCQ levels (odds ratio, 2.95; P less than .001). The mean SLEDAI score was 3.14 points higher in a group with below-threshold HCQ levels on a priori analysis (P = .053), and 1.4 points higher in a group with HCQ levels below 500 ng/mL (P = .039). Among all patients, those with HCQ levels 750 ng/mL or greater had a 58% lower risk of active disease, and their SLEDAI score was 3.2 points lower. “Our study support levels greater than or equal to 750 ng/mL to be clinically meaningful and statistically significant to identify disease flare (change in SLEDAI greater than or equal to 3 points) and predict active disease (SLEDAI greater than or equal to 6),” the authors wrote.

In an interview, Michelle A. Petri, MD, MPH, took issue with the HCQ goal of 750 ng/mL or greater recommended by the authors. “I think that was premature,” said Dr. Petri, professor of medicine at Johns Hopkins University, Baltimore. “We presented data at last year’s ACR [which showed] that the level needs to be higher than that to prevent thrombosis. But it is important to open the discussion that HCQ blood levels are not just for nonadherence. I believe they will help us to reduce retinopathy, and also to make sure the dose remains in an efficacious range, such as what is needed to prevent thrombosis.”

Dr. Petri, who also directs the Hopkins Lupus Center, said that the study’s overall conclusions confirms the need for blood testing for HCQ to identify nonadherence. “Everyone remembers the saying of the [former] Surgeon General Dr. C. Everett Koop: ‘Drugs can’t work if patients don’t take them!’ – in particular, blood levels which represent what the patient has taken in the last month. I call blood levels the ‘lupus A_1C.’ ”

She added that HCQ blood levels have utility for nonadherence, prediction of retinopathy, and prevention of thrombosis. Such tests “are now much more widely available, including by some large national laboratories such as Quest Diagnostics, as well as by Exagen. No more excuses.” LabCorp plans to start offering HCQ blood level testing by the middle of 2020, she said.

In their manuscript, the study authors acknowledged certain limitations of their analysis, including the fact that there were only four studies that measured HCQ levels and nonadherence or SLEDAI. “Second, most of the studies that examined the correlation between reported adherence and HCQ blood levels were performed in Europe, and there was only one small U.S. study,” they wrote. “Therefore, generalizability for our findings could be limited because of differences in cultural beliefs, social issues, and insurance/medical coverage in populations from diverse countries.”

The study authors reported having no disclosures. Dr. Petri disclosed that she has conducted research on HCQ that was funded by the National Institutes of Health. She has also conducted research for Exagen.

[email protected]

SOURCE: Garg S et al. Arthritis Care Res. 2020 Jan 31. doi: 10.1002/acr.24155.

Low serum levels of hydroxychloroquine (HCQ) among patients with systemic lupus erythematosus are associated with a threefold increased likelihood of physician- and patient-reported nonadherence to the medication. In addition, routine monitoring of HCQ levels are associated with improvements in adherence and disease activity.

Alexander Raths/ThinkStock

Those are two key findings from a systematic review and meta-analysis published in Arthritis Care & Research.

“HCQ is recommended for all patients with systemic lupus erythematosus (SLE, or lupus) to reduce disease activity and improve damage-free-survival,” the authors, led by Shivani Garg, MD, of the University of Wisconsin–Madison, wrote in the article. “Yet, up to 83% of lupus patients are nonadherent to HCQ commonly because of poor understanding of benefits of HCQ, lack of motivation to continue therapy, and inflated concerns regarding side effects from HCQ use.”

For their analysis, the researchers drew from 17 published observational and interventional studies that measured HCQ levels and assessed adherence or Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) in adults with SLE. They used forest plots to compare pooled estimates of correlations between HCQ levels and reported nonadherence, or SLEDAI scores. Patient-reported nonadherence was defined as less than 80% medication adherence reported, and physician-reported adherence was estimated based on physicians’ interpretations of the previous month’s adherence as reported by patients during clinic visits.

The study population consisted of 1,223 patients. Dr. Garg and colleagues found a threefold higher odds of reported nonadherence in patients with low HCQ levels (odds ratio, 2.95; P less than .001). The mean SLEDAI score was 3.14 points higher in a group with below-threshold HCQ levels on a priori analysis (P = .053), and 1.4 points higher in a group with HCQ levels below 500 ng/mL (P = .039). Among all patients, those with HCQ levels 750 ng/mL or greater had a 58% lower risk of active disease, and their SLEDAI score was 3.2 points lower. “Our study support levels greater than or equal to 750 ng/mL to be clinically meaningful and statistically significant to identify disease flare (change in SLEDAI greater than or equal to 3 points) and predict active disease (SLEDAI greater than or equal to 6),” the authors wrote.

In an interview, Michelle A. Petri, MD, MPH, took issue with the HCQ goal of 750 ng/mL or greater recommended by the authors. “I think that was premature,” said Dr. Petri, professor of medicine at Johns Hopkins University, Baltimore. “We presented data at last year’s ACR [which showed] that the level needs to be higher than that to prevent thrombosis. But it is important to open the discussion that HCQ blood levels are not just for nonadherence. I believe they will help us to reduce retinopathy, and also to make sure the dose remains in an efficacious range, such as what is needed to prevent thrombosis.”

Dr. Petri, who also directs the Hopkins Lupus Center, said that the study’s overall conclusions confirms the need for blood testing for HCQ to identify nonadherence. “Everyone remembers the saying of the [former] Surgeon General Dr. C. Everett Koop: ‘Drugs can’t work if patients don’t take them!’ – in particular, blood levels which represent what the patient has taken in the last month. I call blood levels the ‘lupus A_1C.’ ”

She added that HCQ blood levels have utility for nonadherence, prediction of retinopathy, and prevention of thrombosis. Such tests “are now much more widely available, including by some large national laboratories such as Quest Diagnostics, as well as by Exagen. No more excuses.” LabCorp plans to start offering HCQ blood level testing by the middle of 2020, she said.

In their manuscript, the study authors acknowledged certain limitations of their analysis, including the fact that there were only four studies that measured HCQ levels and nonadherence or SLEDAI. “Second, most of the studies that examined the correlation between reported adherence and HCQ blood levels were performed in Europe, and there was only one small U.S. study,” they wrote. “Therefore, generalizability for our findings could be limited because of differences in cultural beliefs, social issues, and insurance/medical coverage in populations from diverse countries.”

The study authors reported having no disclosures. Dr. Petri disclosed that she has conducted research on HCQ that was funded by the National Institutes of Health. She has also conducted research for Exagen.

[email protected]

SOURCE: Garg S et al. Arthritis Care Res. 2020 Jan 31. doi: 10.1002/acr.24155.