High ADHD Medication Doses Tied to Psychosis; Rapid Tests for Malaria

TTHealthWatch is a weekly podcast from Texas Tech. In it, Elizabeth Tracey, director of electronic media for Johns Hopkins Medicine in Baltimore, and Rick Lange, MD, president of the Texas Tech University Health Sciences Center in El Paso, look at the top medical stories of the week.

This week’s topics include youth, opioids and emergency medical services (EMS), good news for women with triple-negative breast cancer, a lack of benefit for rapid malaria tests, and risk associated with high-dose amphetamines in adults with attention-deficit/hyperactivity disorder (ADHD).

Program notes:

src:4src High-dose prescription amphetamines and psychosis

1:4src Compared to hospitalizations for other conditions

2:4src Stay under 3src-mg dose of dextroamphetamine equivalents

3:3src Characteristics of opioid overdose, EMS encounters, and U.S. youth

4:3src Almost all in 18-24 age group

5:31 6src% occurred at home

6:32 Rapid malaria test and child mortality

7:35 Each associated with increased antimalarial drugs

8:35 Issue with the study

9:15 Triple-negative breast cancer treatment

1src:15 Pembrolizumab or not

11:18 Adverse events related to treatment

12:36 End

Transcript:

Elizabeth: What’s going on with prehospital encounters for opioid overdose among U.S. youth?

Rick: How does the availability of malaria rapid tests affect children with fever and childhood mortality?

Elizabeth: Good news for women with triple-negative breast cancer.

Rick: And the risk of psychosis and mania with people who take prescription amphetamines.

Elizabeth: That’s what we’re talking about this week on TTHealthWatch, your weekly look at the medical headlines from Texas Tech University Health Sciences Center in El Paso. I’m Elizabeth Tracey, a Baltimore-based medical journalist.

Rick: I’m Rick Lange, president of Texas Tech University Health Sciences Center in El Paso, where I’m also dean of the Paul L. Foster School of Medicine.

Elizabeth: I’d like to turn first to the American Journal of Psychiatry looking at this notion of prescription amphetamines and psychosis. These, of course, are used for ADHD.

Rick: Right. What’s happened is among U.S. adults, and we’re going to talk specifically about adults, there has been a fivefold increase in amphetamine prescriptions from 2srcsrc4 to 2src19 for the treatment of adult ADHD.

These amphetamines change the chemical availability of dopamine in the brain. Some of them stimulate dopamine release, and others inhibit its metabolism. Dopamine excess can also be associated with psychosis and mania. The real question is in adults that receive prescription amphetamines, are they at an increased risk of having either mania or psychosis when they are being treated for ADHD?

These investigators looked at electronic health records of individuals ages 16 to 35 who were hospitalized at a Harvard psychiatric hospital for incident psychosis or mania from about 2srcsrc5 to 2src19. Then they compared them with those that were hospitalized for other conditions.

When they looked at over 1,3srcsrc individuals and compared them with twice as many individuals that didn’t have it, the use of prescription amphetamines within the past month increased the rate of psychosis or mania about 2.5-fold. There was a dose-response relationship. Those who received more than 3src mg of dextroamphetamine equivalents had about over a fivefold increase in incidence of psychosis.

Then when they looked at specific types of amphetamine, they realized that not all of them were associated with it. For example, the one that’s commonly used in the U.S., methylphenidate, also known as Ritalin, was not associated.

It seems like the association is real. It’s biologically plausible. There is a dose-response relationship. It’s more likely to happen in individuals over the age of 22 and those who take higher doses.

What I want our listeners to be aware of is that this can occur because oftentimes people with psychosis or mania don’t have any insight into their problem. For prescribers, if we can stay under the dose of 3src mg [dextroamphetamine equivalents], there is not an increased risk.

Elizabeth: When you cease taking these high doses, does that resolve the mental health issue?

Rick: That was not addressed in this particular study. It’s presumed that, in fact, is what happens.

Elizabeth: Well, it clearly needs to be addressed in a follow-up study. Then how often does someone require higher doses in order to manage their ADHD?

Rick: Again, this particular study doesn’t address it. What this would suggest is either to have a limit, to screen for it, or to use a prescription amphetamine like Ritalin that’s not associated with psychosis or mania. What these authors highlighted was that high doses of these amphetamines are commonly prescribed in the U.S., and in their patient population about 12% of individuals who had a prescription for amphetamines had the higher dose.

Elizabeth: Let’s turn to JAMA, “Characteristics and Trends of Prehospital Encounters for Opioid Overdoses Among US Youth.” This began in 2src18, the data, and then they followed it through 2src22. They looked at EMS encounters and they looked at the database of the National Emergency Medical Services Information System (NEMSIS).

They were looking at encounters for youth younger than or equal to 24 years of age during this time period. They were taking a look at youth opioid overdoses by age group, sex, the Child Opportunity Index — which is a composite score — census division, location, urbanicity, naloxone doses administered, disposition, and level of care.

A rather daunting number of youth encounters were consistently reported during this time period, just shy of 9 million encounters reported by 5,6srcsrc-plus agencies, and in this subset almost 92,srcsrcsrc youth opioid overdose encounters. Almost all of these were in the 18 to 24 years of age group. For males, which was 65%-plus, having occurred at a private residence, almost 6src%, and had at least one dose of naloxone, 66%-plus.

There were increases in this number over this time period. There were 81src and 1,538 encounters, respectively, in January 2src18 and February 2src2src.

Interestingly, there was an increase previous to the pandemic that has actually gone up and stabilized, and has remained higher than the pre-pandemic levels. Also noteworthy, I think, is that those adolescents age 12 through 17 years of age were the only age group with a significantly increasing trend both before and during the pandemic.

Our problem remains, appears to be persistent at the level that it is, and clearly calls for intervention.

Rick: Here is one thing I was surprised at is that about 6src% of these occurred at home. That means if we’re going to strategically place naloxone, for example, which we know is effective, we need to make sure that it’s available at home.

Elizabeth: I would just note that one of the stories that I’m actually reporting on this week is about a class of synthetic opioids that are called nitazenes that are making their way into the United States, and these are about 4src times more potent than fentanyl. One of the things that’s true about it is that it requires a huge dose of naloxone in order to reverse that. My concern about this recommendation is, gosh, with all the adulterants that are in fentanyl and heroin these days, are we going to give parents and other people who might be found in the home enough naloxone to actually achieve a successful reversal?

Rick: Although when someone has an opioid overdose, we’ll never know what opioid is responsible or what the adulterants are, what’s really important is the prehospital administration of naloxone. For those that aren’t familiar, it can be given intranasally now; it’s a nasal spray.

Elizabeth: Remaining in JAMA, then.

Rick: How do rapid malaria tests affect children who have fevers, and does it affect their mortality? We’re talking specifically about Sub-Saharan African countries. Between 2src1src and 2src21, there were 3.5 billion malaria rapid detection tests sold and 82% of those were in Sub-Saharan Africa.

Before we treat a child for malaria, we want to make sure they have malaria. The rapid detection tests are available, and they are relatively inexpensive. They cost about $1 per test. They are very easy to administer. It can be done by a community health worker.

Does the availability of those change how kids are treated, and does it affect their overall mortality? They looked at a data set that looked at rapid detection tests to 165 representative household surveys across 35 different countries, 4 million child-year observations, and over a quarter million febrile illnesses. These are children under the age of 5 between 2srcsrcsrc and 2src19.

Each additional rapid detection test they distributed per child younger than 5 was associated with an increased risk of blood testing and increased anti-malarial drugs, about 1.5% points, and increased use of antibiotic dose, about src.4% points, and a decrease in child mortality, about src.3 deaths per 1,srcsrcsrc child years.

The only survival improvements were in those areas that had a high prevalence of malaria. What that tells you is if you detect it rapidly but you don’t have all the systems in place to appropriately treat the child, it may not make a huge difference.

One of the concerns about the increase in antibiotic use is that if the rapid test was negative, they assumed it was a bacterial infection, when in fact most of them are viral. We know antibiotic resistance is a problem. It does highlight the fact that just having a rapid detection test available isn’t helpful unless you have a system that’s in place to take advantage of that information.

Elizabeth: There is nothing in this study that talks about that, about how often these kids got inappropriate meds after they got a positive malaria test?

Rick: That’s one of the issues associated with this particular study. The data set did not include which of those kids received anti-malarial agents or how quickly they received them.

Elizabeth: I guess I’m rather disappointed in that. I would also just note that, gosh, this issue of malaria and mosquitoes that are able to convey that, I suspect we’re going to be seeing this a good deal more right here in the U.S.

Rick: You’re right. We are seeing more mosquito-borne diseases here in the U.S. Part of that is indigenous to the United States. Part of that is from people coming over with malaria and viral diseases, as well as that mosquitoes can pick up and transport to other patients.

Elizabeth: Closing the loop, it sounds like this is an important issue.

Finally, let’s turn to the New England Journal of Medicine. Speaking of closing the loop, this is the final analysis of overall survival with pembrolizumab in early-stage triple-negative breast cancer. Triple-negative breast cancer, of course, I would note the bad actor doesn’t have any receptors that we can target in treatment and so is associated with more aggressive disease and higher mortality.

They undertook this KEYNOTE-522 trial. They were looking at the addition of pembrolizumab to platinum-containing chemotherapy. As I said, these are the final results for overall survival.

In this study, they randomly assigned in a 2:1 ratio patients with previously untreated stage 2 or 3 triple-negative breast cancer to receive neoadjuvant therapy with 4 cycles of pembrolizumab or placebo every 3 weeks plus paclitaxel and carboplatin. That was followed by 4 cycles of pembrolizumab or placebo plus doxorubicin, cyclophosphamide, or epirubicin cyclophosphamide. Then, following their definitive surgery, they received adjuvant pembrolizumab or placebo.

They had 784 women who were assigned to the pembrolizumab-chemotherapy group and 39src in the placebo-chemotherapy group. Their median follow-up was 75.1 months. Almost 87% of the folks who received the pembrolizumab/chemotherapy were alive and event-free compared with just shy of 82% in the placebo-chemotherapy group.

Rick: This is using the addition of immunotherapy with routine chemotherapy. This is a great example of how using therapies that look at different pathways can be beneficial when used together.

This is a 1src-year study. The early benefits that we saw at 3 years, 5 years, and 7 years extend even out to 1src years later. If it recurs, it usually does so within the first 3 years. What this study showed here is if it didn’t occur in the first 3 years, those individuals were more than 9src% not likely to have recurrence over the next 7 years.

Elizabeth: Yeah. Now, let’s talk about side effects, of course. What they did note was that adverse events related to trial treatment occurred in 77.1% of those folks who took the pembrolizumab/chemotherapy and 73% of the folks who did not. Those were largely neutropenia, decreased neutrophil count, and anemia. They did note immune-mediated adverse events occurring in 35% of the women who ended up on the pembrolizumab/chemotherapy group and in 13.1% of those in the placebo group, and this higher incidence of endocrine disorders in the group who were taking the pembrolizumab also.

Rick: Specifically, the endocrine disorder was usually hypothyroidism — i.e., a low thyroid, or hyperthyroidism. Both of those, as you know, are treatable. They are usually detected with a blood test and treatable. I consider that a relatively minor side effect. It’s certainly much better to be alive after having an aggressive cancer and you can treat the thyroid disease than not being alive.

Elizabeth: Indeed. On that good news note then, that’s a look at this week’s medical h