Psilocybin for Depression; What’s the Best Direct Oral Anticoagulant?

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 the best direct oral anticoagulant, effect of unplanned pregnancy on maternal and infant outcomes, psilocybin for depression, and hormone therapy for prevention of chronic disease in postmenopausal women.

Program notes:

0:40 Hormone therapy for chronic disease prevention

1:40 Lower risk of colorectal cancer, diabetes and fractures

2:40 Is there a rationale to take this?

3:40 Timing hypothesis

4:40 Careful not to exclude vasomotor symptom relief

5:10 Unintended pregnancy and outcomes for mother and child

6:10 Higher risk of low birthweight

7:12 Depression and psilocybin

8:12 Development of a relationship with a therapist prior

9:12 Casts doubt on utility in long haul

10:25 Direct oral anticoagulants for atrial fibrillation

11:41 Apixaban seems best

12:49 End

Transcript:

Elizabeth: Another look at hormone replacement therapy.

Rick: Is unintended pregnancy associated with any adverse maternal or infant health outcomes?

Elizabeth: Can psilocybin help in a single dose with depression?

Rick: And what do we see when we compare direct, oral anticoagulants?

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

Elizabeth: How about if we turn right to JAMA and take a look at this perennial issue of hormone replacement therapy? This is yet another statement by the USPSTF, the United States Preventive Services Task Force. In this case, they took a look at 20 trials and 3 cohort studies in their analysis. They were looking at both estrogen by itself or estrogen plus progestin in women who both retained their uterus and those who did not. They looked at outcomes relative to a host of other conditions that may develop in the subsequent years after a woman began to take hormone replacement therapy.

Their Ns, as you would suspect, were really quite large — about 40,000 or so in the trials and in the cohort studies over a million. If you lacked your uterus, you were taking estrogen alone. If you still retained it, it was estrogen plus progestin.

Let me start first with the combination therapy because that’s more common. There was significantly lower risk for colorectal cancer, diabetes, and fractures. There were increased risks for invasive breast cancer, gallbladder disease, stroke, venous thromboembolism, and probable dementia. In women who were taking only estrogen, they had increased risk for gallbladder disease, stroke, venous thromboembolism, and urinary incontinence.

Now, they do note that these follow-ups are fairly short, somewhere between 7 years and 5 years. They basically say use of hormone replacement therapy or hormone therapy in postmenopausal persons for primary prevention of chronic conditions is not something that they recommend.

Rick: The average age at menopause in the U.S. is about 51 years and we know that chronic conditions appear after menopause like cardiovascular disease, cancer, and osteoporosis, fracture. This task force said, “OK, is there a rationale for taking hormone therapy, either estrogen and progesterone together or estrogen alone, for preventing these in asymptomatic postmenopausal women?” As you said, overall when you look at benefits and risks, they are recommending that we don’t do this.

Now, this doesn’t, by the way, refer to women who are taking hormone therapy for management of post-menopausal symptoms — such as hot flashes or vaginal dryness — and it doesn’t apply to people that have had premature menopause because their ovaries stopped working, or they have had surgical menopause where their ovaries have been taken out. What we do know is if you want to prevent chronic disease there are things that we know we can do that are effective and aren’t harmful: watching our blood pressure, using aspirin if you’re high-risk, screening for diabetes, a healthy diet, and physical activity.

Elizabeth: I have to applaud the USPSTF for also identifying some of the limitations of this particular analysis. There is this issue of timing, of when do you start taking this hormone therapy? Should you start taking it early during menopause in order to reap the most benefits?

They acknowledge that there could be something to that. They also say almost all of these trials had high attrition or low adherence to medications. That was true in 40% to 50% of participants who discontinued use of medications during the trials. Finally, they say that the mean age of their participants included studies with women who ranged from 50 to 79 years, which is older than the mean age of persons experiencing menopause.

Rick: The USPSTF also says, “OK, do we have high certainty, moderate certainty, or low certainty about these recommendations?” Despite the limitations you mentioned, they concluded there is moderate certainty that the use of combined estrogen and progesterone or estrogen alone has no net benefit. This is the fifth time the USPSTF has looked at hormone therapy for chronic conditions and in none of those times, even with the limitations you mentioned, has it shown to be of net benefit.

Elizabeth: I think you brought up a really important thing before we started to record, and that is that we need to be very careful in promulgating these recommendations because there are many women who do have vasomotor symptoms who end up not taking hormone therapy, even though it probably could help them based on things like this.

Rick: Right. Again, this applies to asymptomatic women who are trying to prevent chronic disease, not to those that have severe perimenopausal symptoms who may benefit from being on hormonal therapy for at least a short period of time.

Elizabeth: Let’s stay in JAMA and turn to yours.

Rick: We are going to ask the question, “Is there an association of unintended pregnancy with adverse outcomes to the mother or the infant?” Unintended pregnancy is common in the United States. As many as 45% of pregnancies were unintended. When we say unintended, that means they were planned for later, so they either occurred earlier or the mother never intended to become pregnant at all.

These investigators looked at epidemiologic studies that were relevant to the U.S. population — that compared key outcomes for the mother and for the baby — looking at unintended versus intended pregnancies, 36 different studies and over half a million participants.

What they found is that compared with intended pregnancy, unintended pregnancy was associated with a higher risk of depression for the mother, either before or after pregnancy, about a 40% to 50% to 60% increased risk. There was an increased risk of interpersonal violence, about 15% versus 6% in unintended versus intended pregnancies, and a higher risk of infant low birth weight, preterm birth. Those occurred about 10% to 20% more commonly in unintended pregnancies. It does look like unintended pregnancy is associated with adverse maternal and infant outcomes.

Elizabeth: All of this, of course, part of the burgeoning evidence looking at the full range of reproductive services and trying to preserve those for women.

Rick: That’s one issue, reproductive services, either contraception or, in many areas around the country, the use of abortion. But it also highlights the fact that there are other things we should be doing to reduce preterm birth, increase depression screening, and reducing different types of family violence.

Elizabeth: I think it’s one of the really sobering and daunting aspects of pregnancy that that is the time when a woman is most likely to experience violence.

Rick: It is. In fact, the authors mentioned that interpersonal violence is experienced by approximately a third of women in the U.S. during their lifetime. The chance of interpersonal violence in unintended pregnancies is as high as 15%.

Elizabeth: It certainly speaks to the need for comprehensive services for women who are pregnant for sure.

Rick: Elizabeth, that’s right.

Elizabeth: Moving on. Let’s go to the New England Journal of Medicine, another very common issue, and that’s depression. They were using a single dose of psilocybin for treatment-resistant major depression. We have talked about psilocybin a whole lot in the last, now, what do you think, decade or so?

In this case, they had a single dose of a proprietary synthetic formulation of psilocybin and they did this at 3 different dosages: 25 mg, 10 mg, or 1 mg, which was the control.

Their primary endpoint was a change from baseline to week 3 in their score on the Montgomery–Åsberg Depression Rating Scale (MADRS). It ranges from 0 to 60, with higher scores indicating more severe depression.

It’s 79 participants in the high — the 25-mg group, 75 in the 10-mg, and 79 in the 1-mg. They had the model where they did psychotherapy, I’m going to call it, and development of a relationship with a therapist previous to the administration of the psilocybin, so that that person could be comfortable and knew what to expect.

They looked at a number of outcomes, including suicidal ideation or self-injury in all dose groups. The high-dose group did experience better remission of their depression, somewhat of a dose-response in this group. It wasn’t very durable in comparison to other strategies for treating depression, including medicines, and really did not appear to be that much better.

Rick: When we use these drugs for people who had cancer, they seemed to help their depression. Now, there are 180 different studies that are currently being undertaken looking at psilocybin and LSD, and MDMA. As you mentioned, these are sessions that take 6 to 8 hours of treatment. It was tremendously involved and intensive, therefore costly. It really casts some doubt about the long-term benefit of these drugs in treatment-resistant depression.

Elizabeth: Right, so let’s just review some of the numbers. Their response at week 3 was 37% in the high dose, the 25-mg group, 19% in the 10-mg group, and 18%. We know that there is that substantial placebo response with regard to depression that we have talked about so many times before. That sustained response, however, at week 12 was 20% in the 25-mg group, 5% in the 10, and 10%, interestingly, in the control group. Then they also reported some adverse events including suicidal ideation. The other curiosity for me about this study was it was conducted in 22 sites in 10 countries.

Rick: That was over a 2-year period too, by the way. It was a big effort. That’s why the data I think are very robust, but the results aren’t nearly as robust.

Elizabeth: I would finally say that the editorialist notes that the United States has failed to prevent conflation of biomedical and commercial marijuana enterprises, and expresses concern that this should not be repeated with psilocybin because there is a lot of energy behind that right now.

Rick: Yep, the message is don’t try this at home. Let’s talk about anticoagulants or blood thinners.

Elizabeth: Sure, and that’s in Annals of Internal Medicine.

Rick: We’re going to talk about these because the current guidelines recommend using anticoagulants and particularly what I’m going to call direct oral anticoagulants. Some people call them DOACs. Instead of the older warfarin or coumadin, the dose-response is much more predictable — therefore you don’t have to monitor the blood levels — and there is less of a bleeding risk than with coumadin in people that need anticoagulation, specifically for atrial fibrillation, that irregular heart rhythm.

There are 4 direct oral anticoagulants that are on the market right now: apixaban, dabigatran, edoxaban and rivaroxaban. Is one any better than the other?

We’re going to look at people that have newly diagnosed atrial fibrillation. They are going to be put on 1 of these 4 medications and we’re going to look at their risk of having a stroke, which we’re trying to prevent, or a systemic embolism versus the risk of intracranial hemorrhage, bleeding in the brain, or gastrointestinal bleed.

The investigators looked at five electronic healthcare databases, which covered 221 million people in France, Germany, the United Kingdom, and the United States. They were able to find over 500,000 put on one of these four agents.

What they discovered was that apixaban was associated with a lower risk of gastrointestinal bleeding, but there was no difference at all in terms of their ability to prevent stroke or prevent a systemic embolization. The highest-risk group are those over the age of 80, and even then, apixaban had a lower risk of bleeding, but was just as effective.

Elizabeth: What about cost?

Rick: The cost is relatively about the same.

Elizabeth: It’s sounding like we got a clear winner here.

Rick: There are no direct head-to-head comparisons among these agents. This to my knowledge is the largest and probably best comparison among the agents.

Elizabeth: Since we are seeing so many more people on these agents, I think this is really an important piece of information.

Rick: It is. I mean, the number of people that are affected by atrial fibrillation is about 33 million people worldwide. Almost all of those people should be on a direct oral anticoagulant.

Elizabeth: Good news. On that note then, that’s a look at this week’s medical headlines from Texas Tech. I’m Elizabeth Tracey.

Rick: And I’m Rick Lange. Y’all listen up and make healthy choices.