Hey, it's the Psychopharm Podcast. Today, I'm super excited about our guest. It's Dr. Chris Akin. Dr. Akin is a psychiatrist who's an assistant professor at both NYU and Wake Forest. He's the editor-in-chief of the Carlat Psychiatry Report and co-host of the Incredible Carlat Podcast. Before I even met Dr. Aiken, I considered him a mentor just because of his incredible work on the Carlet Psychiatry Podcast. So the Carlet Podcast is really a must-listen for clinicians looking for clear, engaging, and practical updates in psychiatry.
Dr. Aiken also recently started a new practice with the goal of bringing psychiatry to the primary care office. And they're currently hiring psychiatrists, NPs, PAs, and therapists in Virginia, Tennessee, North Carolina, South Carolina, Georgia, and Florida. A potentially great opportunity, head on over to com to learn more. Let's jump right into the podcast.
I've been really interested in this idea of whether any of our treatments actually address underlying causes in psychiatry.
Symptoms or root issues.
Yes, root issues, an almost dangerous word that we never use. And I was wisely taught by my mentors in the 1990s that we really don't know how our medications work. And this so-called idea of a serotonin transporter problem or deficit of serotonin or excess dopamine is very hypothetical and not well proven and that we don't know that our drugs are addressing the underlying causes. So not to go about...
saying that we do. Now, a lot of people didn't heed that warning and did go about saying that we do, and there's been a lot of backlash in our field against that. Most notably a year ago, an article came out criticizing the serotonin hypothesis, which I think really made psychiatry look bad, because we've got to be honest about when we are treating underlying causes versus treating symptoms.
Mm-hmm.
Yeah, I definitely saw that paper shake. Even talking to friends and family, feeling like all of psychiatry was demolished by that. There's a lack of understanding that your average psychiatrist doesn't think that way, but occasionally you do see practitioners pitch things as if it's as simple as low and high serotonin or high and low norepinephrine. Yeah.
Yeah. Just an easy way to make sense of things, but deceptive in a way. I don't like to use that as an explanation for people personally.
Yeah, and I found that, although I can understand it might enhance people's engagement with the treatment if we do that, if we make it mechanistically understandable, but I found it a different way to engage in treatment as I focus more on the neuroprotective aspects of which most medications save benzos and stimulants have and Because when we talk about neuroprotection, we are actually guiding them to do things in their own life that improve their brain health.
Things like exercise and Mediterranean diet and better sleep all protect the brain. So I like to link the mechanism to things that empower them rather than making the mechanistic explanation sound like something that makes them depend purely on a drug to boost their serotonin.
I do like that. It sounds like almost like an ACT flavor thing that you're pointing towards treatment goals or treatment processes that pretty much most people would value, right? Their actual health. How does that play out more specifically, if you don't mind sharing? Let's say, let's pretend you're in the session with a patient. What kind of approach do you take? What do you say to them?
Oh, it's very straightforward. I show them pictures. There's popular ones by Husseini Manji from NIMH, which show the brain before and after neuroprotective interventions. Often I have pictures from Depakote and Lithium and SSRIs. So basically, the patient is seeing that there's more neuro connections after treatment. And then I'll talk about how lifestyle interventions, which I let them choose from, I give them a menu and I don't want to overwhelm them.
So I have them really just do one intervention can augment that as well.
I really like that. It really shows that you think about long-term when you're thinking about treatment. And it's a really good paradigm for thinking long-term with treatment, not using medications like... It helps you explain why a medication like a benzodiazepine, which subjectively the patient will experience less anxiety in the moment, why that's not a treatment we'll go towards because we're thinking long-term. We're not thinking about how you're going to feel today and tomorrow.
We're thinking about your overall mental health throughout the trajectory of your life.
We'll definitely want some of those links to be put in the description once we're over so people can look at those.
Yeah, and on the other side, we might have a different discussion if we're talking about coming off benzos to give them something to empower them to come off. There are studies that correlate those with clinical experience, meaning if people come off a benzodiazepine, they tend to have greater self-confidence, better concentration, less depression, and all that's from clinical observational studies. That correlates with what we see on the PET scan, which is that the brain is healthier six or 12 months after coming off of benzodiazepine.
It's funny, Dr. Aiken, I think I'm going to have to take a page from your book because I do a similar thing, but I'm a pessimist. You know, I'm a real negativistic guy. I tell people without the mood stabilizers, they might suffer brain damage. I tell them that their psychotherapy will not progress well if they're on the gabapentin based on the evidence. But we're often saying the same thing, I think, in our separate clinical practices.
And I think that your approach inspires more hope.
But I'm here today to talk about something different, which is I went about to write a book on difficult to treat depression, similar concept as treatment-resistant depression. And I had a lot of trouble organizing all the treatments. So we have several dozen treatments that might work. They all have small controlled trials that show some promise once we get beyond the usual algorithmic-based interventions that have much better evidence and I don't want anything in this podcast to steer people away from treatments that we have the best evidence for in treatment-resistant depression.
So let me review those first. The best evidence goes to ECT, TMS, TMS. antipsychotics, particularly aripiprazole has the best evidence and the biggest effect size, lithium, thyroid supplement, and the ketamines, esketamine and ketamine. So those would be our top line interventions. And after that, we have things with small trials, basically. So the book is going to feature a lot of those. And I had trouble organizing them because they're all so different.
They're all like their own character, their own personality with different mechanisms and different kinds of evidence. But as I sorted through them, I noticed something stood out to me that shocked me. Some of these actually address what patients have been asking me for for years, which is the deficit model. Patients would love to know that they're deficient in a hormone, and boosting that hormone is going to improve their mental health, that it's that simple.
And so I go on a limb here and hesitate to say, but it sounds like we do have a few treatments that address kind of a deficit model in psychiatry where people are deficient of something and we can give them a treatment to boost that up.
This is actually funny. In one of our previous podcasts, Dr. Fu was talking about this in a totally different angle in regards to, I think, Lacan. We were saying the patient has a lack and the provider can provide it. Just a funny link.
It's a compelling way to feel, I think, and think about treatment. And definitely something that is at the gut for a lot of people when they come in. Yeah, I'd love to hear more. Which elements do you feel like we can more confidently say we're giving something that someone might be missing?
They are the folate treatments, folate vitamins, omega-3 fatty acids, probiotics, light therapy, vitamin D, and possibly some hormonal therapies, which I don't recommend psychiatrists do. But if you're really deficient in testosterone, testosterone supplementation can improve mood. And for women in the perimenopausal years, we do have some evidence that taking hormone replacement therapy improves mood.
Wow. So, I mean, right at the outset, and by the way, I'm familiar with your work, on social media. I use your website. But I think that a lot of people not necessarily being as familiar with these possible interventions would be immediately skeptical to hear about them. They would say, this isn't the treatment algorithm. This is not what we usually go to. And they're unproven. How would you feel and respond to those professionals?
Very good point. And in a lot of cases, they're right that these don't have as robust evidence as we have for, say, aripiprazole in depression. And on the other hand, a lot of times when we do have that evidence, they just get shunted over to medical specialties who take care of them for us. So let's start with that one, which is vitamin D. There have been so many trials of vitamin D in depression.
And a lot of people tell me, They call it vitamin D for disappointing because that's how it looks when you meta-analyze them all together. But at the CARLAT report, we peeled away the studies dividing them based on whether they were actually supplementing a deficit or just giving vitamin D willy-nilly. And it looked like there is a real benefit if the patient is low in vitamin D. Today I'm only going to talk about depression.
So we're talking about depression. And that specifically when the trials enrolled people whose vitamin D level was less than 20. So the cutoff is usually 30. So we're talking really low. Then they were able to detect a benefit.
Yeah, and that's actually something I've been doing myself, the vitamin D. You mentioned how often if something works, primary care, they end up taking over management. In my experience, at least in my practice population, primary care is not managing a vitamin D at all. A good point. It's mixed, obviously. Some do. But yes, I began testing vitamin D routinely for all my patients. And yes, the level of severely low...
The amount of severely low vitamin D is, I think, would be surprising in a community population, especially in underserved people, very common. So I've been supplementing.
Yeah, Dr. Reagan, I'm curious because of the things you mentioned, which ones do you test for? Yeah, I guess how do you address, you know, vitamin D is something that is commonly tested for, but a lot of the other ones, you know, methylfolate. A lot of times I start treatment without having any sort of idea of their status on that. Excellent.
Yeah, great point. And I don't recommend testing for any of these. And that's in some ways where the hypothesis falls apart. And the other hole in this hypothesis is that most of the trials, in fact, nearly, well, most of the trials have enrolled people without testing for a deficit. So it's interesting that the research comes from deficit model. But the trials don't enroll people like that, particularly like omega-3.
There is evidence that low omega-3 is linked to depression. But every omega-3 trial I've seen has just given it to the entire population. And you can actually test for omega-3. So I would love to see a world where we test for it. By the way, with omega-3, we also get closer to the mechanism of how it's working because they've looked at PET scan images of the brain before and after omega-3 and bipolar disorder.
And what they see is that the brain cells are just more fluid and they move more fluidly, which is more flexible, which is interesting because that's what a lot of the research is showing is people are more flexible. They're less irritable when they take them. And we know that omega-3 is rich in the skin, and the skin and the brain are derived from the same original cells, the ectoderm.
So what I'll tell patients in this rough analogy is that... If they think about a leather car seat, it's been sitting out in the sun, they never oil it, it's going to get all crackly and crusty and broken. And that's what the brain looks like without the proper oils. When we don't get enough omega-3 in our diet, which most of us don't have, the brain substitutes the other ingredients like cholesterol to make up for that in the lipid membrane, resulting in lipid membranes that are a bit like a car seat that's been sitting out in the sun.
Car seats are leather, which is skin. So we oil our skin, we oil our brain, and as a result, we're more flexible and less irritable.
I love that visual. The thought of my brain being crusty, I'm going to go buy some fish oil. I love that the fish oil, we're really keeping that thing nice and lubricated.
It's a compelling area. I remember I came curious about it actually because I had a colleague who did his own research study. He found signal for a psychotic disorder. That's how I kind of got to the fish oil issue. One area of frustration for me clinically is that I would say even maybe the majority of readily available commercial fish oil does not match the types that are being used in the research.
How do you handle that for your patients?
That's very important. And I want to emphasize besides this compelling visual data, there are about, I remember about 30 controlled trials of omega-3 and depression. And they only show a benefit if we look at the ones that used high levels of EPA. The analyses are now recommending that it have at least twice as much EPA as DHA. Those are the two types of fish oils. And you're right, most brands have more DHA.
And when I learned this about 10 years ago, I switched all my patients, and some of them did get better and notice a difference. One of them went to Europe and forgot his fish oil and felt worse. So I did see some differences, and I have a website, com forward slash supplements, No kickbacks or anything on that. I just put products up that have been clinically tested by consumer labs or other groups for product integrity and that also have the right ingredients.
So I like to make supplement prescriptions as scientific as we can. Otherwise, they're not going to work and the patient's not going to have as much belief that they're going to work.
This is a silly question. We see a lot of, especially podcasters, pushing supplementations. What would the Dr. Aiken mental health supplement, what would be in it?
Oh, I don't know. I think probiotics, omega-3, and methylfolate are where we have some of the best evidence for depression. Other conditions, so it varies by condition. And it's interesting that I realize we've landed on a lot of complementary and alternative therapies here, which wasn't my intention. And I will say that zorenolone is a prescription medicine which possibly addresses the deficit model, enough so that you ought to explain that to patients.
That one's been FDA approved for... postpartum depression. And it was developed out of a theory that allopregnenolone levels fall in the postpartum period, and that disrupts the GABA circuits, which causes depression. So they created a synthetic version of that steroid, and they give it to women who have postpartum depression with rapid benefits. So there's another kind of deficit model going on on the pharmaceutical side.
Yeah, that is an interesting and under-researched area, right? The neurohormone systems and how they affect people. Probably alongside the postpartum depression FDA-approved treatment that you just mentioned. The most remarkable one that I've seen anyway in clinical practice is appropriate treatment of PMDD. you know, premenstrual dysphoric disorder, I've seen some night and day differences for select patients where that does seem to be their circumscribed problem when they get on the right monophasic combined oral contraceptive.
But I just wanted to go back, by the way, when we're talking about supplementation, this is in addition to the standard treatments. Is that correct?
Yes, all of these have been studied with the exception of Lightbox as in addition to the standard treatments. Yep. And I'm not proposing any of these as cures for depressions or like if people with depression just took these, they were going to cure. I want to be clear about that. A lot of these have small effect sizes. Even when we get the most potent omega-3s, we're talking about an effect size of
3 to 4, which is actually similar for SSRIs. So not that different. Light therapy, though, is probably underutilized because people think of it as a light therapy. And I think that's starting to change. For example, last year, JAMA Psych, which is our top scientific psych journal, published an analysis of light therapy in non-seasonal depression. and showed that it augments antidepressants with a good effect size. In fact, the effect size for light therapy is in the range of
6 to 9. So we're talking about a larger effect, a big effect for this one. And is it addressing a deficit model? That was the whole point of seasonal depression is there's a deficit of morning light. So you have to give this in the morning, not the afternoon. And that's how it treats depression. As to how it works in non-seasonal depression, this is where it gets interesting.
And it starts to explain my major criticism of this theory, which is, well, then why does it work for just all comers regardless of deficit? these treatments I've mentioned today, it seems that the deficits are so widespread, either in the general population or in depression, that they're just going to work regardless of testing for it. And as an example of that, we see a lot of dysbiosis, that's problems in the gut microbiome in people with depression.
So you probably don't need to test for that. You can probably assume that it's there and give a probiotic. Probiotics have good studies to treat depression. That was also shown a year or two ago in JAMA Psych. So a lot of this stuff is moving into the more mainstream journals that I mentioned here. Looking at these, but back to light therapy. Yeah, like I believe that I'm deprived of light in the summertime because I spend most of my life indoors.
So it doesn't really surprise me that this would work in summer depression as well, even in a deficit model. But it's possible that it might just be that giving an extra dose of light is beneficial. So that's where my theory falls apart. Yeah.
Well, I mean, I think that's a compelling one, though, especially the light, because while the good commercial light exposure ones, we really want to blast people with something that we know works, you know, they can be a little expensive. I think it's a low cost intervention. And I do this to combine light exposure with behavioral activation, something that we know to be effective for depression. And I simply ask patients to make a point, make a goal to get out every morning and walk around in the daylight.
you know, regardless of the time of year, if it's not too nasty. Easier for me where I am, but not necessarily accessible to others, depending on where they are. And some might need the light box. So whatever works, right?
What part of the country do you practice in?
Oh, over in the west, southwest. So easy, you know, to not suffer the winter.
That's a good point. And there is a trial of just in winter depression, walking outdoors for an hour a day. I apologize. I don't remember where the trial was done because that's very important. But to that point, maybe we have an international audience today. So let's go over that. Yeah. We get the highest rates of seasonal depression up north. When you get down to around the latitude of South Carolina in the US and below, it starts to go down.
By the time you get to Florida and below, and now we're talking about the equator, there's no detectable seasonal depression in the winter. And in fact, in those regions around the equator, for some reason, we don't understand they tend to have a reverse pattern, if anything, where they might have more summer depression. But once we go below the equator, we're coming back to the old tune. So in Australia, what's the lowest point of Australia is Tasmania.
It's almost toward the South Pole. And that's where you have the highest rates of seasonal depression in Australia.
It's compelling to look at communities and how they might differ in seasonality or in things. It also brings to mind the little signals we have about lithium, right? There's some reason to believe that that might operate on the deficit model. What do you think about lithium at the deficit model?
Well, if your patients ask about that, because it is a legit question, like, are you saying that I have a deficit of lithium? Why don't we test for it? You can tell patients that if animals, or I guess people, are completely deprived of lithium, they have raised animals in lithium-free environments, they die. For reasons we don't understand. So there is lithium a little bit in all of us.
It's not very detectable. I'm not aware that you can measure it. But it's doing something for our life that we don't know what. That doesn't mean that giving extra lithium is addressing a deficit. But with lithium, we can speak a little more to... treating an underlying problem which is different from correcting a deficit so on that respect lithium is one of the only psych meds that regulates the circadian rhythm the genes for bipolar the closest we've come to finding the genes for bipolar is linking them to the clock genes that regulate the circadian rhythm.
And we know that lithium normalizes the expression of those clock genes. What that means in practice is that if you give a patient lithium, it's not sedating. It's not going to make them fall asleep. Only 1 in 28 people get sedated on lithium. But if they're an extreme night owl, which a lot of people with mood disorders are, it'll gradually correct that so they have more of a normal circadian rhythm.
Now, you talked a little bit, I mean, in a similar regard in regards to deficit versus still helping out things, you know, thyroid replacement. We know hypothyroidism is a cause of depression. And we also see it on the treatment-resistant depression or the difficult-to-treat depression algorithm. Yeah. When it's used in that regard, is it fixing an underlying deficit? Or do we have a way of thinking about why thyroid hormone replacement would be helpful in that area if we don't see an observable deficit in the hormones?
Yeah, thyroid is one where we don't have good studies to answer that. But there are some studies suggesting that people with depression, not all, but some of them, they're not absorbing the thyroid into their cells as well as they should be. So this theory, and I want to emphasize it's just a theory, is it's almost like insulin resistance. Like depression is a form of thyroid resistance. And just like we give people with because they're resistant to it, we pump up the thyroid in these patients with depression.
They then get more thyroid entering into their cells, particularly in the brain. That's why we tend to prefer T3 triiodothyronine cytomel, because it's more brain active. So the idea is there that you may be correcting a deficit with giving thyroid, but we don't have definitive proof of that, so I didn't include it in that chapter. The places where we have evidence of a deficit, and the deficit here is pretty widespread in the population of depressed people, so we're generally not testing for it, are folate vitamins, omega-3s, probiotics, light therapy, and possibly some hormone treatments like testosterone and hormone replacement therapy.
Now, the one we haven't talked about is the folate, and that's one of the best ones for depression. It's not FDA approved, but the product is FDA cleared as a food supplement for depression, and that's methylfolate. And that's the Deplin, is that correct? Yes, it is brand name Deplin, although it's available generic and you can get it. The proper dose is 15 milligrams a day, which is available through several products on Amazon for just about $5 a month.
So your patients can now afford it where it used to be difficult. It used to be more like $30 a month. So two things have changed with folate vitamins if you're using them. One is that we've had some large trials in the last five years showing that folic acid did not work as a supplement. Whereas in the past, we had small trials showing it did. So there's always been this debate, should you use folic acid or methylfolate?
And now all the methylfolate trials I'm aware of are positive. And we do have large trials showing it works. So I would go with that one.
Is there a very little familiarity with the mechanism here? Is there a idea about why the folic acid ones would be negative, but the methylfolate might be effective?
Yeah, good point. And this gets into why the deficit is so widespread. You don't need to test for it. So the idea has to do with the MTHF are enzyme which converts folic acid into its brain active form. And without that enzyme working properly, you're not going to get enough in the brain. So the idea of the deficit model here is it might not be you don't have enough folate, but that you don't have enough of the enzyme converting it.
into brain active folate, which is necessary to make most of the monoamines that are involved in depression, that's serotonin, norepinephrine, and dopamine.
And then the methylfolate then would be the more brain active form already?
Yep, so you're bypassing the need for that enzyme to operate functionally as well. Now, I want to emphasize that some people actually test for that enzyme, and you're welcome to do that on the gene site assay, but there's so many different ways that this can go wrong in the body. that I don't think you need to test for folate levels or the enzyme to just use it and see if it works.
So in summary, the testing is not going to tell you. In fact, most of the genetic tests out there don't actually test for the gene that we know from clinical trials is important in the mechanisms. I know that sounds weird, like why are they testing the wrong gene? But there are many different genes for this MTHFR. So I generally don't do that. A lot of times patients bring that data in, and that will steer me more towards this.
But there's lots of cases where methylfolate might be the right treatment. I'll go over two that are relatively easy to identify. Studies have found that if you have a BMI over 30, you're more likely to respond to it. And if you have inflammation, which can be measured through an inexpensive test of high sensitivity C-reactive protein, HSCRP. And if that marker of inflammation is three or more, you're more likely to respond to methylfolate, You're also more likely to respond to, I should say, to need higher doses of omega-3.
There is a study showing that you had to go higher if you had inflammation all the way up to 4,000 milligrams a day of the EPA and the DHA, where most people take 1 to 2,000. So you're pretty much doubling the dose.
That's a big one. It's an interesting area. I'd love to continue to monitor the development of evidence. You know, folate in particular reminds me of sort of the odd research signal. I believe there is one study where lamotrigine's antidepressive effects were attenuated by supplementation of folic acid, which I don't think we understand why. But obviously, it's likely that it's implicated in mood conditions.
Yeah, some things that will help us understand that study, that was a very large trial, and it surprised the researchers, is that folic acid is not at all natural, and it can produce byproducts if you're not converting it well, which could be depressive or block lamotrigine's mechanism on its own. So they have linked that particular finding you're referring to people with certain genes. They're not genes that we test for, so it's not going to help us.
But we are starting to understand that I believe that's a limited population, but a real one. So I'll tell you a story. There's a study showing that Depakote works better in mania if given with folic acid. And we know that Depakote tends to deplete folate, so it makes sense to give it. So okay. So I didn't know what to do. I had a patient on Depakote and Lamotrigine, and he was depressed, so I recommended taking folic acid.
I didn't tell him anything else about the study that you just mentioned, which had just come out. He called me back a week later and said, Dr. Aiken, I don't know what's going on, but I feel like I did before I ever took that Lamotrigine. I feel way worse. It feels like I'm missing Lamotrigine. And I was like, whoa, because this guy really loved his lamotrigine and it changed his life.
So I said, please stop the folic acid. And he went right back to slight depression instead of major depression. So it can have a clinical relevance.
Very interesting.
Very cool.
I did want to go back. You mentioned, you know, CRP can be predictive. Do you ever test for it or do you just assume, I mean, there's certain conditions that we would almost presume that they have high CRP, autoimmune conditions, you know, patients with obesity are more likely to have higher CRP. But would you ever test for it?
Yeah, I usually test for it. It's pretty inexpensive and it's great to show the proof to the patient. Plus, if it's elevated, then we can talk about anti-inflammatory lifestyle. And now they have an extra motivation to pursue that. To which I'll tell them, if you do these things, we're talking Mediterranean diet, good sleep hygiene... mild exercise, so 30 minutes every other day of walking briskly, for example.
And other stress reduction techniques like mindfulness, if you do these things, your CRP is going to go down. The other part of it is I advise people not to just tell me that they did these things because I'm not going to test their CRP again unless they've really rigorously done them. And that brings a level of honesty into the conversation that otherwise isn't there. So we wait.
And it's been wonderful to see, like, we test a year later and their CRP does go down. But to your question, I've been surprised many times by how people, like... overweight, smoking, sedentary, poor diet, and your CRP is normal. I just can't believe it. Okay. So the body is complex. Some of the risk factors that indicate you might have a high CRP are stress, depression. Well, that's why they're here.
But also any chronic medical illness, obesity, and any recent injury to the body. which would be like surgery, attack by a virus or an infection, bodily injury. And this one, I've recently added it to the list, postpartum. So inflammation is higher in the postpartum period, and that's where some of these might come in handy to use in that period.
Yeah. I mean, it's a fascinating area, but it's also frustrating to me. Basically, the psychiatric system, the mind, the brain, and steroids, hormones, that whole system. The testing is not necessarily reliable. Our science is not necessarily so good in finding out about it, but we know it's implicated as classically as the HPA axis experiments and testing for depression and Let's go to the hormones. What do you do about the hormones?
Do you recommend anything? How do you feel about the lack of reliability of the laboratory tests?
Well, let's get to the hormones. So you mentioned the HPA axis, which is so critical to understanding the pathophysiology of depression. And there were even studies showing that, I apologize, I forget the name of it, but it's commonly called the morning after pill. So trying to treat depression through that corticosteroid pathway just made total sense from the mechanism you're reminding us of. But those studies, which are industry-funded, didn't pan out.
It collapsed. So they never got FDA approval for what looked like, I think it's methapridnazone, if I remember right, that looked like a very promising therapy for treatment-resistant depression. So when it comes to hormones, thyroid shows up in most analyses of treatment-resistant depression as an effective treatment, whereas meds we commonly use like mirtazapine and bupropion to augment don't show up as effective. So we live in this weird world where this is a little off the subject, but I should make mention of this.
If you drew a graph of the most effective therapies for treatment resistant depression from top to bottom, it would resemble the exact opposite of what is done in practice. And I'm not like putting practice down because it's kind of understandable. Like it's hard to get people to agree to ECT. It's hard to get people to go every day to TMS. Those are two of our most effective.
I'm not like suggesting everyone take ketamine even though it has a big effect size because it doesn't have lasting benefits. But it is true that at the bottom of that evidence ladder sits bupropion and mirtazapine and basically buspirone, another antidepressant augmenting. So taking two antidepressants rarely ever works better than taking one, which is what we most often do. Lithium and thyroid are certainly underutilized in that ladder, and they sit kind of in the middle of the ladder.
They don't have really big effect sizes, but they do show up as effective in meta-analyses.
Yeah. It's supposed to, it seems like it's an unfortunate reality surrounding that clinical practice, clinical treatment has to go along, uh, financial lines, legal lines, and simple risk benefit and the willingness of patients. Right. Um, the simple version of that,
for example, the one, well, the ones at the bottom of the ladder, there's a perception that, like you said, they are more tolerable. And also they're frankly FDA approved in depression. So I think we all feel more comfortable using them. And you brought up exercise. Like I want to emphasize, we could have had this whole conversation about lifestyle deficits. That's another talk. And many of those exercises does have positive trials and treatment resistant depression, even the ones that are hard to treat.
And there's a deficit for you that really works.
And so then onto the topic of sex hormones, how you talk about those, approach those, think about them.
With sex hormones, the two that I'm most concerned about are estrogen-based and testosterone-based. So I'll keep this simple. With estrogen-based, we have evidence that hormone replacement therapy improves depression when added to an antidepressant. These are small trials, and most of them used a patch. And we have more on how to use that in the CARLAT report we did in interview on that. But I don't use it myself, you know, because there are risks, like risks to the heart and risks of cancer.
So I advise them to consult with their OBGYN. By the way, schizophrenia, the same thing, we see improvements as well in that age period. But most OB-GYN doctors believe that if you use it for five or 10 years, the risk is very low and outweighed by the benefits. So most of them will go with it. That's fine. And that's estrogen specifically or- Yeah, it's hormone replacement therapy, so it's not just estrogen.
And I apologize, I forget which is the one that's most often used in these cases. But I leave that up to the OBGYN to choose the right agent. In men, this is brand new, so I've not had the chance to apply this in treatment at all, but the FDA became so worried about doctors prescribing testosterone supplements to people who barely need them. It's very popular. Yeah. And so I think we should all know as doctors, I don't claim to be an expert on this, but the FDA required the industry to do large trials to prove their safety and efficacy.
And those trials are just starting to come out. They involve thousands of patients, randomized controlled trials. And they do reassure us more about the safety. There's still some risks with them. And they did find improvements in mild depressed mood, so not clinical depression, but mild depressed mood, and of course, improvements in sexual function, which is often related to So I think we can at least tell people, and this is all done on, all these trials were done on people with verified low testosterone.
So we're not talking about going beyond the normal, but we can tell people if they have verified low levels of testosterone and they have depression, they might want to talk with their PCP about the risks and benefits of supplementation there.
Well, Dr. Adkin, it's been a pleasure. I think it's very exciting to talk about, think about, uh, Additional therapies, maybe we can call them for the difficult to treat depressions. You know, I appreciate your website and your work in terms of outlining a lot of the evidence behind things that we don't normally think about when it comes to depression. But for the patients who benefit and the patients who need it after the standard treatments, I think it's quite a good thing.
Yeah, thanks for using that word, difficult to treat depression. It's starting to replace treatment resistant. And the idea there is that we're not going to find a single treatment like a new medication that's going to pull them out of all these problems. But if we take a broader look at their relationships, their lifestyle, at these kinds of deficits, we might find ways to improve their mood a bit and help them function better in the world.
That's what the new model is about. That's great. Shifting our focus, basically, in a more realistic direction.
Awesome. Thanks so much for coming on. We really appreciate it.
All right. Good to see you both. All right.
Bye. Big thanks to Dr. Aiken for joining us. Thank you, listener, for listening, and we'll catch you back next week. Thank you.