Psychiatry & Psychotherapy Podcast - Practical Psychopharmacology with Dr. Goldberg

Episode Date: November 30, 2021

Special guest Dr. Joseph F. Goldberg is a psychiatrist and clinician researcher with over 180 publications and 3 books. This episode focuses on his newest book, written with Dr. Stephen M. Stahl,  Practical Psychopharmacology: Translating Findings From Evidence-Based Trials into Real-World Clinical Practice. In this episode, we discuss psychopharmacology and his approach to psychiatry.  By listening to this episode, you can earn 1.75 Psychiatry CME Credits. Link to blog. Link to YouTube video.

Hello and welcome to the Psychiatry and Psychotherapy Podcast. I'm here to talk about getting rid of burnout, increasing job satisfaction, and feeling like an expert in what you do. One thing that created a lot of burnout and angst for me was trying to get continued medical education right at the last minute. So why not join the CME membership and do CMEE while listening to this podcast. Go to Psychiatrypodcast.com, sign up, sign in, take the test, and the certification is email to you in seconds. All right, before we start this episode, I am going to go through potential conflicts events. interest. So I, David Puder, have no conflicts of interest to report. I do not receive any money from pharmaceutical companies. The person I will be interviewing, Joseph Goldberg, has several conflicts

of interest to report, including royalties from his books, American Psychiatric Publishing in Cambridge University Press, consultant fees from buy Excel, jazz pharmaceuticals, Lundbeck, Ostrica, Sage Pharmaceuticals, and Sonvillon. And he is on Speaker Bureau of Abbey, Ardivis. Archimines, intracellular therapies, and son-ovion. I looked at this episode and I thought about the things that we discussed and the medications that are made by these companies. And I think that we pretty fairly discussed the medications. And I do not think that there is undue sort of bias that has leaked into this episode

despite his receiving money from these pharmaceutical companies. So if you would like to read more about this episode, we always give a handout in the resource library. And I will also say that in this last one month before the New Year's, if you sign up for continuing medical education or the emotion connection, microexpression training, I will send you a free psychiatry and psychotherapy podcast T-shirt. So I hope that you can enjoy that. it is the best cotton I could find. I enjoy wearing mine, and I hope that you enjoy wearing yours. All right, here let's start the episode. So welcome back to the podcast. I'm here with Dr.

Joseph F. Goldberg. He is a psychiatrist with over 180 publications, three books, one of which was pretty important for my practice, actually. It was called Managing Clinical Side Effects of medications. And then he recently came out with a book this summer called Practical Psychopharmacology. It's just great having you on the podcast to talk about your new book. Thank you, David. A real pleasure for me to be here. Yeah, so I wanted to start off. Kind of tell us a little bit about yourself, how you entered into what seems to be like clinicians slash researcher, and then we'll go talk about the book a little bit. Sure. So I see myself as a kind of a hybrid.

I went to medical school to become a research psychiatrist. I was a psychology major working in a research program, and I thought clinical psychiatry research back in those days was just the coolest thing ever. And to get the best training, you'd go to med school, become a psychiatrist, and then you could do clinical trials, you could do research on phenomenology, and that was my vision. And so I did it when I went to med school, did my psychiatry residency, and then a a fellowship and then ran a research program for many years at Payne Whitney Clinic in New York, Cornell. It was involved with a lot of clinical trials and bipolar disorder. And all the while

sort of maintained a private practice, but there's a mindset that comes from being a clinical investigator. You think about patients differently. It's very, it's very sort of objectified. Does the patient meet the criteria for a diagnosis? Yes or no. Do they have a clinical profile that's suggestive of a response to a particular pharmacology, yes or no, or rather, to what extent do their features conform to good responsiveness to a certain drug. So to kind of take out the notion of guesswork or what people call trial and error, over the years, I guess my research mindset has bled into my clinical life of thinking about really every patient as a clinical trial and objectifying their symptoms, using measurement-based care, knowing what the literature says to support the value of a certain drug over another drug and its pros and cons. And this sort of is an offshoot from the side effects book in terms of managing risks and

benefits because everything has side effects, even plasebos have side effects. So really kind of looking at the patient, not as a diagnosis, but rather more in a kind of an Oslerian way, you know, listen to the patient, they'll tell you what's wrong, gauging all the characteristics that are going on, phenomenology-wise, history-wise, family history-wise, past treatment-wise. And then in the second book, what I like to sort of call crafting a bespoke regimen, really comes out of the research mindset. That is, are you a candidate for this treatment? The same way a surgeon might say, are you a candidate for bypass surgery?

Or an oncologist might say, are you a candidate for a certain anti-neoplastic? I kind of foster the same mindset. And so these two books together are the yin-yang balancing of tolerability and pros and cons and risks and benefits with the tailoring of treatment to a given unique patient. Yeah. One thing I really liked about your book on managing side effects and medications was you have this analytical perspective and you go symptom by symptom. So like let's say a patient has dizziness. It's like you have a chapter on, you know, a section on dizziness. it's like here's how you approach dizziness and you know a lot of people a lot of residents occasionally will say to me I feel like in psychiatry or medical students will say I fear in psychiatry I'm going to lose being a doctor and um your approach is very much you're still a doctor

you're managing all different body organs at the same time although you're focused on the brain you know and the mind I sure hope so um It would be a real shame if people lost that perspective because, you know, the drug does what the drug does. It's not selectively honing in an anyone organ system. It's many. And so the physicianally approach in psychopharmacology is really knowing the entirety of what the drug's effects are on the body and the body's effects on the drug. And to tell you the truth, that's what makes it gratifying and interesting. Otherwise, you know, you're just sort of randomly prescribing SSRIs for any and all forms. of depression or atypical antipsychotics for so many things. But really, you know, sort of gauging for this given patient who may have particular sensitivities to side effects, who may be a poor metabolizer at certain cytochrome P450 enzymes and therefore at greater risk for certain kinds of side effects, who may have somatic features, who may have cognitive features, who may

have anxiety features. It's really crafting a regimen with knowledge of what the effects of drugs are and should be. So the other tie-in I think of from what you were saying was how we know cause and effect. And this is very much around clinical reasoning. This is, you know, if I give you a medicine and you say you're dizzy, how do I know if that's because of the medicine or because of something else? Or for that matter, if I give you an SSRI and you get suicidal, how do I know if that was iatrogenic or the natural course of things? So cause and effect is really fascinating to me. It's a very doctorly clinical reasoning kind of thing. It's how do you, how do you know, the patient comes to you and says their complaints and you're trying to determine if those

are primary illness symptoms, possible side effects, the natural course of things, or who knows, something else. That's what makes it fun. Yeah. Yeah, along those lines, it's hard as a physician to think that a patient will worsen from something that we give to them. I've had a couple provider patient situations that have come to me where they've gotten a side effect from a medication and the psychiatrist immediately thinks it's something other than the side effect from the medication. Have you seen that? You know what I'm talking about? It's almost like psychologically, we don't want to believe that we made this person worse. Plenty. And so the temptation is, I must encounter this at least a few times a week,

is if something is not going well, is that because of the intervention or despite the intervention or because of something else that's getting missed. And here I'll just mention, I think psychiatrists bring to bear a unique physicianly perspective on things by virtue of their training, if I can say that, because it can be very tempting in other areas of medicines who, as people sometimes say, blame the psych meds. Something's going wrong with the patient. Oh, it must be a side effect of the medicine. And I saw somebody not long ago who was having tremor and weakness. And they actually saw a neurologist who had said, well, it must be their depocote that they're taking their dival products, even though the level was low. And, you know, go see the psychiatrist about, you know, the side effects. And so they came to me for a consultation.

I'm doing a really detailed history. And, you know, it doesn't sound like depocote's side effects. It's not the kind of tremor that you get from depocote. You don't really get weakness from depocote. And, you know, we did a little more digging maybe than the neurologist did. And there was some bladder and bowel issues. And I ended up sending her to a neuromuscular specialist. And, you know, unfortunately, she ended up having ALS.

So what was touted as a possible side effect, you know, you talk about with the medical students asking if you lose your doctorhood, heck no. You are always listening for what's going on medically or could be going on medically when it comes to deciding what's a psychiatric symptom, what's a medication side effect, And let's not forget the realm of everything else like neuromuscular diseases that could be masquerading as side effects or symptoms. That's good. That's good. I want to, before we get to your book, I wanted to ask you a couple questions from some of your articles. I think this will also help our audience understand who you are.

And so in 2004, you were the primary author in a preliminary, randomized, double-blind placebo-controlled trial of primaprexol added to mood, stabilizers for treatment of treatment-resistant bipolar depression. And what was your thought process that led to using a D2, you know, D3 agonist? And my second question would be, is this still something that you use for bipolar depression or have your thoughts changed over time? Oh, excellent question. I'll try to keep my answer under 30 minutes as best I can. So, Pramapixel, you know, like so many things in psychiatry, there was an element of serendipity. In Parkinson's disease trials, there were anecdotal observations of improved sense of well-being and mood. And in particular, around inertia, amortivation, apathy, things that you might think of as deficits in the ventral striatim reward pathway,

for which a lot of clinicians might say, ah, I use a stimulant, or maybe buproprion, or, you know, something, or patients might themselves, you know, favor more stimulating kinds of compounds. So when some early work came out with Pramipixel, back in those days, I hung out with people like Robert Post and Mark Fry, and we had sort of a collective interest in this. So we together published a couple of cases on this. And that was the motivation to actually go to the Brain and Behavior Foundation and get a grant to do a randomized trial, which we were successful doing. And so the interest was not just, here's something to try, but rather, bipolar depression often involves atypical features, lethargy, motor retardation, slow detentional processing. So one of my other books is on cognitive dysfunction and bipolar disorder.

Maybe next time we can talk about that. So slow detention processing is part of what you inherit with bipolar disorder. And people often wonder if they have ADD, but they could just have the cognitive problems of bipolar disorder. So the interest here was if you gave somebody a D2D3 agonist and assuming that they're not psychotic and they're not manic because you don't want to give them something that's that's going to agonize mesolimbic dopamine if they're psychotic or manic. would you make inroads in adedonia, anergia, amortivation, apathy, all those deficit states that we often associate with a typical depression?

And so our proof of concept study showed a large effect. It was a small proof of concept study, but it looked very promising and was a significant difference. And right about the same time, the NIMH did their own study, Carlos Serrati, with Prampexel in bipolar 2 depression,

had about the identical findings around a 67% response rate. And so we got really excited about this. And my postdoc at the time, Kate Burdick, who's now vice chair at Brigham in psychiatry, did some further work down the road looking at cognition in Pramipak. So it actually improves cognitive functioning in bipolar disorder. So all this was way cool until the patent died. And as you know, once a patent dies, that's the end of the line for drug development.

So there's really been no further extensive work on it. it. Oh. Which is to say that it's kind of a, I don't say it's a well-kept secret, but it's, it is a well-understood secret weapon. My friend Jan Fawcett, a former mentor of mine who's now out in San Antonio, in New Mexico, was very enamored with Prima Pekyll. He published a really interesting studying the American Journal of Psychiatry a few years ago in highly treatment-resistant major depression, both unipolar and bipolar. And what I liked about Jan's study, which nobody ever knows, I always talk about his study, it's the only study, I think it's only study I know of, where the average number of failed responses previously was five in the current episode. So when we talk about TRD, you know,

we often say you didn't get better with one or two or three. And I often see people in my practice for consultations who've been on many medicines that have not worked. And so Primapexel actually has moved up quite a few notches because from an evidence-based perspective, certainly based on Jan Fawcett's data, you can say to somebody, this has been shown to work when five other things haven't. Even ECT, I won't make any promises. But his data and ours as well included ECT unresponsive patients. So I really wish the patent hadn't died. Maybe somebody will invent, I don't know, an I patch or a nose drop or something that'll create a new patent for it. But this is This is one of those molecules that I think was very interesting for a niche kind of patient

and had very encouraging initial results, but the trail ends when the patent dies. Well, the trail and this podcast does not end. We did two episodes on lithium. We did one episode on Depakote. So we try to cover the meds, which are very effective, but no one is coming to your door and telling you to exercise for your mental health. So that's what we do in this podcast we talk about. all the things that there's no money behind.

Indeed, and yet it's reality. Quick comment, there was that neat paper in Lancet, I think, last week looking at new depression cases in COVID and one of the biggest predictors of new cases of depression was sedentary lifestyle. Yeah, unfortunately, one of the biggest risk factors for COVID is obesity, too. Yep. And so, you know, I wish that, I wish all my patients would exercise. Unfortunately, I don't have a high success rate in getting them to exercise initially. You can think about sort of, I think of doctors as presenting information to patients.

You know, I've been citing that Lancet study to patients saying, oh my gosh, you know, there's a 26% increased rate of depression pre-COVID and one of the biggest predictors is just not moving. You know, sitting is the new smoking and in COVID when you're home. You know, here's something that's evidence-based. Now, I'm not here to browbeat you. I'm here to tell you that here's something you can do and, you know, pick, pick whatever activity it is. It also gets in the issue of how much do medicines do versus lifestyle issues. And here, too, I think, is a very doctorly kind of thing, especially as a psychopharmacologist. You know, there are times I will say to someone, you know, here's what medicines can do and here's what medicines can't do. And there's a marriage.

And we have to talk about lifestyle. We have to talk about the things that go beyond just a specific pill. Ideally, these are elements that we bring together to try to optimize physical and mental health. Yeah, wonderful. I want to show you, since we're on Zoom here, I'll pull up this study. It's called a randomized control trial of dietary improvements in adults with major depression, the Smiles trial. Uh-huh, uh-huh. I don't know if you've seen this one, but they took a group of people and ended up be, I think, 30 in each group.

Yeah, and was 33. and they picked people who had a poor diet, and they put them on this 12-week treatment, and they found an effect size of negative 1.16, which is very significant. Impressive. And the control, they actually gave like a befriending therapy, so they had time talking with people.

So the control was decent. You know, it wasn't just a wait list. Interestingly, I was looking at in this study because I was like, what? So they went on like a more Mediterranean diet. Like what did they actually change? You know, I'm always interested in these diet studies. Like did they actually change their diet that much?

You know, at the end of the sort of results here, let me pull this up. So here's what they actually got these people to change. So these people had 1.2 more whole grains per day. 0.5 more fruits per day, basically. 0.5 more dairy per day, 0.4 more units of olive oil, one more fish per week, and 20 less what they would consider unhealthy foods.

So the fried foods, the, you know, those sort of highly processed foods. So 20 less. That was it. That's what created the effect size of like one point, basically one standard deviation, change from where they started.

30% went into remission just from diet. Fascinating. I have to look at the study because I don't know it. But I'd wonder, too, if there's an element of you're doing something proactive and that in itself may have some beneficial effect on mood. Depression tends to lead people in these very helpless, passive kinds of stances and to think, all right, I'm going to do something, whether it's exercise or following a greater degree of structure, you know, behavioral activation, the way cognitive therapists talk about.

I might wonder, fascinated with the actual logistics about the food intake, but, you know, I am doing something. I am, I'm proceeding on a course, is an anti-helplessness stance. And to the extent that that's in the spirit of overcoming malaise and lethargy and empowerment, maybe another element. Yep. Yeah. I like, I like your, I like your thought there. Okay, another question from another study of years. In a 2009 article titled Depressive Illness Burden Associated with Complex Polypharmacy in Patients with B-BOLD,

from the step-BD, you found that using, that use of traditional mood stabilizers is associated with fewer co-therapies, meaning things like lithium, divaprochs, or carbamazepine, was not found in patients with, four or more agents. How did this paper change your perspective in treating bipolar patients? So I, one of my interests, I'm glad you asked about this, one of my interests is around polypharmacy and not just two versus one drugs, but people that are on many, many medicines. We just published, a resident of mine just published a paper a few months ago on extensive polypharmacy. It was a

literature review. She found 22% of bipolar patients take four or more psychotropic. drugs. And, you know, sometimes that's very thoughtful. We put together combinations elsewhere in medicine, you know, cancer, infectious disease, hypertension, where, you know, it's very, very thoughtfully put together, not necessarily so much in psychiatry. We sometimes just kind of make assemblages of things or what I, in my newer book called pharmacological hoarding, where people just wind up on medicines and then you kind of do a sort of a roll call of why is every drug in the regimen, and if you can't account for it, that's, that's problematic. So in the step study, we found a few things.

One was that if you were on core mood stabilizers, you tended to not need as much in the way of other medicines. And just a side note to that, there was another study after step called the litmus study, the remnants of step went on and published a paper looking at just, what if you include lithium in a regimen? Does that influence outcome? And one of the findings from that study was it ended up, you took less in the way of atypical antipsychotics, dosing-wise, or even just necessity-wise, just by having any lithium in the pictures. So one point is core mood stabilizers like lithium and divalproate, though they're no longer marketed because there's no, you know, the patent's gone and, you know, it's inexpensive and there's not marketing, you know, really can make a dramatic difference.

I mean, when a patient fits the candidacy bill for responsiveness, to a drug like lithium or dival prox, you can fix them. I mean, it's a wonderful feeling when you say, you know, you are better. I mean, just not just improve, but, you know, in remission. So that's one core piece. The other element from those studies was we found that depressive illness burden tended to drive extensive polypharmacy. And I think if I remember right in that study, we found, let's see, what was it, for every

depressed, I forget exactly, for every depressive episode you'd had, the number of medicines you were taking one up by a certain increment, meaning we throw the kitchen sink at depressed bipolar patients. And when we looked at polypharmacy in step, you know, the max we saw coming in, there was somebody on 26 medicines, psychotropically. What to say? So if depression drives a lot of that

and if we may shy away from mood stabilizers and we know antidepressants tend to not be that helpful for bipolar depression, You know, maybe we end up with cluttered, hoarded polypharmacy in some instances where depressive illness burden is a driver, and maybe some of them are more core treatments like lithium or dival prox over antidepressants might spare some of the burden that comes with lots of meds. And lots of meds means more side effects, means poorer adherence, means greater cost. And if you're not even getting better, what's the point?

Yeah, yeah. It's one of my pet peeves too. I'm glad it's one of your pet peeves. We had a, I'm still medical director of an IOP partial program, and we just had a patient graduate on one medication, Prozac, 40. She came in on, like, seven medications. And I think that's what I see from a lot of the longer-term partial IOP program studies, like, I don't know if you've seen some of the mentalization-based partial programs. Like, where upon like five,

year follow-up, they're on a ton less meds, whereas if they just got like, you know, intermittent therapy or, you know, in and out of the psychiatric hospital, they end up on a lot more meds. So I like the notion of personnel rosters on several levels. One, it engages the patient as a partner. So you and I will sit down and say, it's time for performance review. Our payroll consists of the following five medicines. You are their supervisor. Let's review what. each medicine is doing. And you, the patient, tell me, what do you perceive? What is this drug doing? What is its job description? Why is it on our payroll? And if we can't account for that, then the job security

of a certain drug may become jeopardized. In my experience, patients really take to that concept. It's very empowering. It's not saying, why do I have to be on these medicines? It's rather, what are these medicines doing for you? And if we can't justify, you know, you're on this drug because it helps with anxiety. You're on this drug because it counteracts weight gain. You're on this drug because it really helps with psychosis. Okay, then, you know, the drugs keep has been earned and let neither you nor I question, why are you on this medicine? So it really helps with adherence. When patients themselves can say, I take this medicine for this reason, and it is or isn't helping. And if it's not helping, you know, then I look at the patient and do a, you know, gesture. You know, we have to

think about finding an alternative candidate for that job description because, you know, this employee is just not measuring up. Yeah, that's good. That's good. I'm sure your patients trust you enough to not have any placebo effects of getting off of a medication as well, right? Because it's like, you know, sometimes it's like, I feel like this medication represents this previous psychiatrist relationship to them. And they're like, they've gained like some attachment to it, like, because of this person that prescribed it. And so there's like the psychological aspect of holding on to the meds as well. You know, I think one of the things I love about being a psychiatrist is you embrace your doctorhood,

but you also have a psychological awareness of things. And medicines, like so many things, can also be transitional objects and we can have internalized meetings of things. And I would never, actually in one of these books of mine, I give an engagement. example of a patient who was on an old medicine for years and goes to a new doctor and the new doctor says, you know, why are you on this old medicine? It's got so many side effects and starts changing things around and one wrong thing after another happens. And the patient went from being on an old first generation antipsychotic to seven new things. Oh, no. And, you know, is like, leave it alone. I mean, the patient's attached to the drug. They're happy with it.

Yeah. We often think about we're rating symptoms and we're measuring is the patient better, but one of the measures I like when I evaluate if a medicine is helping is the same thing my ophthalmologist says to me when he refracts my lenses. He says to me, are you happy? Can you see well? And there are times where he'll give me a lens prescription that doesn't exactly conform to what he thinks my diopters should be, but I will say to him,

Yeah, I see better out of these classes. And that's the bottom line. If the patient says, I'm happy with this regimen, we'd be remiss to not pay attention. Yep. Yep, don't mess with success. Yeah. Okay. In a recent, there was a recent article that was published that you wrote a response to, I think it was Gahmi at all 2021. It's a talopram for bipolar depression. And I have always wondered, are we really looking at bipolar? In my practice, when I was seeing a lot of outpatients, insurance, I think I had three true bipolar patients that I was like, if these people stop taking their meds, they're going to get manic,

they're going to end up in the hospital. When they enter into the hospital, you put the mood stabilizers on. It takes them like three or four days to fall asleep in a normal way, otherwise they're up for like four hours at night, the first couple nights. So like, are we really looking at true bipolar? because it seems to me that with true bipolar, CELACSA would be like, Cetalopram would be not a very good medication.

What's your thought on this war of both diagnosis in research and SSRI for that population? Oh, boy. Okay, David, another question I'll try to answer in less than 30 minutes. You ask really, really probing questions. So let me try to be succinct. So there's a few pertinent pieces here. You touch on the one about diagnostic.

rigor. And this two goes back to what the point I try to make in the practical psychopharm book is a really good psychiatrist or psychopharmacologist wants to adopt the mindset of a clinical trialist by saying, you know, what's my confidence in the diagnosis? So a clinical trialist does a skid or a mini. They go through symptom by symptom, duration criteria, symptoms not accounted for by something else. You actually apply the DSM. If there's another XM, if there's another explanation for these symptoms, then I can't attribute it to this. So it really tries to invite rigor. That's very time-consuming. If somebody's floridly manic, they come in the ER and they're screaming and yelling, it takes two seconds to make that diagnosis. Bipolar 1 mania had the best

interweater reliability in the DSM-4 field trials. It was obvious. The taxi driver on the way to the hospital knows what's going on in the vac seat. But then when we get into this sort of newer concept of the spectrum, or what some people call soft spectrum, it gets mushyer. So what if you don't make the duration criteria or you don't have enough symptoms? On the one hand, you could say, well, maybe that's a form froust presentation, as we call it in medicine. You know, if you need five symptoms to make a diagnosis of lupus, you only have two. What is that? Or if you only have, gosh, I don't know, the criteria for pancreatitis includes seven things and you only have three of them. So there are times we'll say it's in the spectrum, and I think that's very fair and noosologically accurate.

But it does get murky because if we over attend to more nebulous symptoms like food swings or impulsiveness, that's like saying sneezing puts you in the infectious disease spectrum. It's too mushy. So one thing I like about randomized clinical trials, and my friend of Siragami's work, I think, speaks to this, is the rigor, with which diagnoses are made. So when you read a research study that's a randomized trial, especially from someone like Nassir, it means that there's been a really rigorous process of saying, you know, you've made it into a study.

When you're doing clinical trials, it's been shown about nine out of ten people that screen never get in because they just don't meet the definition or it's a little nebulous. You know, there's this thing, bipolar disorder unspecified, or maybe it's like lithophymia or just something that's not clear cut. And a problem with the not clear cut is when we extrapolate from rigorous trials. So if someone does a rigorous trial with any psychotropic where you bet your bottom dollar, the patient met the DSM definition, now you take it into your shop and you see people with mood swings,

or you see people with impulsiveness, or you see people with novelty seeking, or you see people whose therapist says, I wonder if they have, quote, a mood disorder. kind of a hegy, hegy sort of way. And then it's a big extrapolation to go from the randomized rigorous trial literature to those patients. So clinical trials have the advantage of saying rigor. And when I see a patient, one of the first things I try to do is clarify, is there a rigorous diagnosis or is there more of a, you know, you don't really fit. And plenty of people just don't fit. The DSM is imperfect. And there are people for whom we can describe psychopathology, but it just doesn't neatly fit. So it's a big extrapolation from the rigorous studies to those patients.

Now, separate and secondary to that is, so what about this hullabaloo with antidepressants? And if you know Nassirigami, he is a very strong opponent of the use of antidepressants. He and I have, I think, debated on various stages in various pre-COVID settings on this issue. His view, which is I would say not so much the mainstay view, is that antidepressants have a directly deleterious effect on outcome and bipolar disorder, either by destabilizing mood in the short run or accelerating cycles over time. The other view, which is a little closer to mine, is that we don't really have a database saying that antidepressants work. It's like giving antibiotics for a virus. there's never been a positive placebo-controlled study with any antidepressant, a traditional monoaminergic antidepressant, saying that it works better than a mood stabilizer.

So does that mean that antidepressants are dangerous or just that they're really not shown to be that helpful? Mine is more the latter view. His is more the former view. And in his study that we published in J. Clin-Syke, he makes the point that satylopran was no better than a mood stabilizer alone. for bipolar depression. And last point here, we have to get into the weeds a little bit.

It is true. His study found that giving somebody a mood stabilizer like lithium or valproate was as good as adding on acetalopram. So he said, what's the point of using the SSRI? It doesn't add anything. But the dilemma is that there was a pretty big effect with the mood stabilizer alone. What he called the placebo arm had well over a 40% response rate. And the problem is you can't really interpret a study when the placebo arm has a very

high response rate. But in this case, placebo was mood stabilizer plus placebo. So his study was actually more interesting than many people realize. His study really said, in my view, if acetalopram adds anything above and beyond lithium or valproate, it's a subtle, modest effect. Now, because lithium or valporeate both have antidepressant properties. But last point on this, and then I'll shut up when I was talking before about profiling candidacy for treatments. So I've written a lot about the idea of candidacy for antidepressants. And you can enrich or cherry pick the likelihood that this particular patient is going to do all right with an antidepressant. You can't just say, do you use antidepressants in bipolar depression? You have to sort of delve into literature and say

you're on better ground using an antidepressant in a bipolar two than a bipolar one patient who has no mixed features at all, no recent mania, that means they were euthymic before now depressed, no rapid cycling, meaning four episodes in the last year. They've never historically gotten manic with an antidepressant before because there's some interesting genetics data that says if you get manic with an SSRI, you may be a genetic subtype of the illness, which is a sort of interesting area. And one or two other factors. And when you get down to it, that's a small minority of bipolar patients. And Nasir likes to say when we talk about these things, Joe, you're talking about 10% of people that are candidates. So what's the point of that? And I respond to him saying,

Nasir, lithium works super well in 10% of bipolar patients. So it's the same thing. We're always looking at candidacy. Tamoxifen doesn't work for all cancers. Ace inhibitors don't work for all forms of hypertension. So what's wrong with kind of winnowing down candidacy? So my view, and I'll shut up in a second. My view is if we could really describe, describe, describe the features of the patient, we could choose our treatments in a more informed way beyond just the diagnosis. Yeah, and that's kind of getting into your book and what I see is kind of this, the basic argument inside the book is if we knew, it's like if you look at studies and learn how unique treatments can affect different populations differently,

it can give you more information to do psychopharmacology in a more nuanced way. Isn't that cool? I mean, isn't that how surgeons and oncologists and infectious disease doctors choose from among their options? They don't just randomly say, let's throw something against the well and see if it sticks. They actually go by criteria. We don't have biomarkers the way they do. We don't have tumor markers and receptor positive or negative malignancies. but we have a lot of clinical markers.

And I think many of our colleagues don't fully appreciate the plethora of clinical markers that can point you in the right direction. Yeah. So it's like I want to get to that. I want to get to your kind of idea here. And maybe we should just jump there about this idea of mediators, mediers and moderators. Moderators being pre-treatment. like what are the characteristics that affect outcome mediators are factors that influence outcome

after treatment has begun like drug drug interactions or you know a whole host of things and it seems like so in chapter five you kind of lay out like here's how these you know the beginning part and the sort of process changes the outcome and we have a lot of data and a lot of the stuff that you say is like, it's, it's like we're talking about, this is what I call like the bonsai work of psychopharmacology. You know, it's not just the broad, the broad stroke of depressed SSRI, anxious SSRI. So I was thinking what we could do is we could talk a little bit about this idea of these two things and then maybe give an example, give an example of looking at just anxiety, because anxiety is not something we've covered too much in the podcast going through the different

medications that you talk about and which apply to which. Yeah. I'm so glad you brought this up. This concept that you touch on called moderators and mediators is another what I call well-kept secret that many of our colleagues are just unaware of. And I have to credit our colleague in the field, Helena Kramer from Stanford University, who coined the term. And was really, she's a biostatistician and just vastly underappreciated for what she's

done for psychopharmacology. Nobody knows her name. And yet she is the person who said, you can't just treat a diagnosis. You can't just do a clinical trial and say, everybody goes in and gets this treatment versus that treatment and what's the outcome without looking in a more granular way at who the patients are. So what she calls moderators are baseline characteristics that influence outcome. That could be things like severity, crinicity, a number of prior episodes, history of trauma. Your TSAH. One saw a patient with depression whose TSAH was 70. That was easy. Family history. You know, some drugs are more responsive if there's a family history. Lithium's a really good example. There's nice data saying that first-degree relative response to lithium

bodes well for your response. So this to me is what's so fascinating and engaging about practice of psychopharmacology is just putting together a recognition of somebody's moderators, all these baseline characteristics. So if I see you, let's say you have major depression, how should I treat it? Well, that's really not a good question to ask because if you're using a SSRI. No, this is your first or your 14th major depressive episode. Is it chronic or acute? Is it comorbid with, you mentioned anxiety, one of the most common comorbid conditions in all of mood disorders and a very negative prognostic factor that is a moderator. that lesson's response. Yeah, you point out it's almost like 70% in a lot of these

comorbidity. It's widely underappreciated. The practical psychophrone book was an education for me in reading through the literature for that project. Certain medicines, you actually work without being tainted by anxiety. Most antidepressants don't work as well if anxiety is present than absent. With one exception in literature, Michael Face had a study with Velazadone some years ago, which showed that whether or not you had high baseline anxiety, you did equally well. So just researching the book influenced my own practice. If I see an anxiously depressed patient, particularly if an SSRI hasn't worked, it's not guesswork. I will say, you know, the most evidence-based strategy for you would be Velazodone. Maybe that's because if it's 5H2NA, receptor partial agonism,

could talk about the circuits. But, you know, the literature is is much more compelling with it than randomly cycling through, you know, well, we could try an SNRI or we could try a different SSRI. Those are all reasonable options. But when you, when you face anxiety, you know, you want to roll up your sleeves because it just means it's going to be harder to treat. It's going to take longer to treat. The Starr-D study showed anxious, depressed patients seldom got better within six weeks. and in our fast-paced psychopharm lives, if you're not better in two seconds, let's change the treatment around. No, no, no, no, no.

Anxious depression is a long-haul phenomenon. So it doesn't mean it's not treatable, but it means it's a harder task. Okay. On that point, you talk about measurable improvement at two weeks of 20 percent is a good indicator of future success of medications for major depressive disorder, bipolar depression, schizophrenia, panic disorder, generalized anxiety. disorder, how are you measuring 20%? And then also, does that, like, are you saying that the anxiety is going to improve a little bit by 20%? Because sometimes I see anxiety gets worse. Like,

what's your thoughts on that? Wonderful questions, David. Thanks for posing it that way. So I am a believer in measuring things. My research background, you can't take the research out of the clinician. And if I was an internist, I couldn't eyeball your blood pressure. I'd have to measure it. If I was an ID doctor, I've got to see your white cell count and know what your temperature is. And if I'm treating your depression, I need some metric to track it. I can't just say, are you less depressed? That is, it's certainly a relevant question, but it invites so much subjectivity. So I really urge and encourage colleagues to have some grasp on measurement-based care. However you want to do that, quick and easiest is probably

the PHQ9, the personal health questionnaire nine. Is that a good session to session, you know, is there any research to support that session to session that's been validated? Oh, you are probing. All right. The answer is no. The PHQ9 has not been, you are on the run here. PHQ9 has not formally been shown to measure change over time. We use it more as a screen for depression. and truth be told, it's not a bad quantification of the DSM symptoms of depression. And so it stands to reason that if your DSM symptoms of depression are less frequent and less intense, your pHQ9 will come down. But no, you are absolutely right.

No one's done a study with that. If you really want to be rigorous, and this is where I just think a little bit harder for a busy practitioner who's not a researcher, you'd want to do a scale that's been shown to be sensitive to change over time. And that would be something like the Montgomery Aspera depression scale or the quids, the quick inventory for depression symptoms. It's just most practitioners never heard of those scales or don't know what they mean. And they are a little more involved. So that means you are going to have to carve out the time in your session to say to the patient, I want to formally evaluate your depression symptoms.

And just like if I was a research assistant, we're now going to take the next 10 minutes of your session. And I'm going to ask you specific questions about intertension, subjective sad, sadness, outward signs of sadness, and go through those symptoms, because that is a validated measure of change over time. If I was doing a research study, you're completely right. If I'm looking for a metric in the real world, I'm going to fudge it a little bit and say, you know, the pHK9 takes about one minute to fill out, and it's not a bad proxy. And for that matter, you know, you could also deviate a little bit from the rigor and just say to the, patient, keep a visual analog scale from zero to 10 and track your depression every day and tell me what the numbers are. Yeah. So, you know, if you're a researcher, the rigor matters. Your point is extremely well taken.

If you're a clinician, though, I just hate it when somebody's on a given medicine and time goes by and the question is asked, are you better? And the answer is, I don't know. So anything that captures this is helpful. Right. No, I think with my psychotherapy patients, I'll do the OQ. 45 because the outcome questionnaire 45, they can do it before session.

And I won't do it every session, but I'll do it every month or two months, just to show them that change is occurring, because that's what's what's been used in psychotherapy studies. I don't have a good answer for you on what I would use. And maybe I need to have you back and go through the quids in the Montgomery and think through, like, is that something that clinicians could actually use? I personally, I mean, Or do you think the pHQ9 is good enough?

I think it's good enough for the clinician's purposes. Because, you know, look, if you're doing a rigorous clinical trial and you want to use a measure that sense that the change over time, it matters. If I'm just treating, you know, Bob, and Bob's depressed, and his pHQ9 goes from a 30 to a 12, that means a good enough. That's good enough for me. And likewise, if his pHQ9 goes from a 30 to a 26, we're not getting anywhere. So this 20% rule that you mentioned, which I'm rather fond of because it's been replicated now in a number of studies, as you mentioned, across diagnoses, is whatever measure you're using, you'd like to see what some statisticians call a just noticeable difference. That is, you're not all better. If you're all better at two weeks, that's worrisome because that's a flight into health, and it may not last. But you're looking for signs like sprouting when you plant a seed that were in the right direction.

So the 20% rule, which I quote from this study by this guy named Zaghetti, says if you're at least 20% better than when you started out. So that means your pHQ9 goes from a 20 to a 16 at week two. We're on the right track. If your pHQ9 goes from a 20 to a 19, you've got to do something, whatever the something is. because statistically speaking, the probability of seeing or projecting a more robust change down the road is less. So it's in a way trying to read the tea leaves, but the concept of it, you know, you ask about how do you measure these things? It's hard to say to the patient, do you feel is 20% better? But you're looking for some just noticeable difference.

If you're eyeballing it and you're saying, well, what's better? Well, my sleep's better and my concentration's better. Okay. The spirit of the question, though, is if you're no better whatsoever at two, weeks. You got to do something. Raise the dose, augment, switch, because the probability of further success diminishes if you don't see something moving by two weeks. Okay. That's good. I like that. So, okay. And then one of the other sort of introductory themes that you bring up is you want to think outside of FDA approved medications. You talk about modafinil for ADHD, which I'd be

curious when you think about using this. You talk about pre-gabalin for generalized anxiety disorder, quitooping for generalized anxiety disorder. So tell me a little bit about this idea and anything you want to mention about those three meds. Sure will. So I'm mindful that this is, I think, a CME accredited activity. So I will call out the off-label use of these medicines. But I'd like to differentiate the notion of off-label versus what is evidence-based. So much like when we were talking about prima pexel before, which is an off-label use, by the way, outside of Parkinson's or restless legs, it's evidence-based. And like I was saying earlier, if a third-party entity, if an industry has no incentive to exploit and develop a drug, they're not going to go to the FDA.

And it's a gazillion dollar enterprise to take a new drug entity, a molecule of interest, and bring it from idea to marketplace. It's a very difficult venture. So FDA-approved drugs or the designation of FDA approval, I think, has several relevant and important points. One is it does assess safety and assures the public and clinicians about adverse effects. And, you know, if something awful is going to happen, we want to know that. So that's a good thing. But in terms of saying I'm going to use this off-label, like you mentioned quityapine for generalized anxiety or moodyapin for ADD, you know, the issue there is these are both examples of medicine.

that have been studied in randomized trials. And so they're evidence-based, but they either never were brought to the FDA to seek an indication, or the extent of the studies is not massive enough for the FDA to approve it. And this is where I think one has to be a very careful reader of the literature. You know, quatyapine has droves of data in anxiety. It's one of the best studied drugs in PTSD. And as a monotherapy from major depression, it nicely beats a placidia. But none of those are on-label uses, in part, because the FDA did not approve those uses. And there's

some backstory as to whether the FDA has some biases against the notion of a D2 blocker being used for something like anxiety because of the tolerability and safety issues with the drug. Quatyapine is not an easy drug to take. It's got a high metabolic liability and so on. Anxiety is the most common psychiatric element, affects one in four people. So the FDA has historically been hesitant to go forward with that. But there's lots of examples elsewhere where the FDA has just sort of declined to approve something. So you mentioned modafinil, for example. So there's three positive, randomized trials of modafinil to treat ADD or ADHD in kids.

It works. It's got a big effect. It works really well. However, I think I talk about this in the side effects book, turned out of almost 900 plus kids who were enrolled, 12 got skin rashes and three of them ended up being severe cutaneous reactions like Stevens Johnson syndrome. And that and that alone led the FDA to decline the new indication that was being sought for modafinil as a non-stimulant option for ADD.

Now, you and I might say, well, gee, if it worked, why not just put a box warning on it saying, hey kids, watch your skin, you know, the way we do with the motocer gene. or carbamazapine because we don't have a ton of treatments for ADD and none of us loves Schedule 2 drugs all the time and there's the weight loss effects of amphetamine which modafinil does not have so in my view it would be welcome to have an on-label use for that drug but the FDA declined to approve it and and it wasn't because it didn't work so that would be an example of an on evidence but off-label use and then that has implications for insurance and And I've had patients, I've given modafinil two for ADD, and the insurance won't approve it.

And they'll write the patient and say, this is not a use that's been shown to work. So go inform Dr. Goldberg that he's giving you a drug that's not been shown to work, even though the patient's fine. So it becomes an insurance. It becomes an insurance loophole. But I very much like our colleagues to think about not just is this on-label or off-label, because that's really more a reflection of did the pharmaceutical industry, bankroll efforts to pursue an indication, but rather, what's the evidence-based? And for that, you have to go online and look at PubMed and Google Scholar and research it. And then you can say to yourself and your patient, I'm going to give you something that's been shown to work. Whether

or not it's on-label or off-label has implications for insurance, and that's important for cost. But, you know, evidence-based is sort of what we're after. That's good. Yeah. And you also kind of talk about how you're, you're, you, you know, you kind of get away from this idea of like classifications of medications, like, oh, this is an antipsychotic. One example you give is zeprazadone under 120, 160 per day functions more as a 5H-T2c antagonist than a D2 antagonist. So then how are we viewing something like zeprazadone medication-wise and its usefulness and not usefulness? it's kind of labeled broadly as an atypical antipsychotic, but does it really, does it have a niche use in the group of medications that you would give out?

Yeah, so you can't just talk about the drug in a broad kind of way. 25 milligrams of quixopiope might help you sleep, but it's probably not going to treat psychosis. And 800 milligrams will take down your mania, but it's probably overkill if I'm using it as a set of hypnotic or an anxiolytic. So the dose, and for OCD, you know, 25 milligrams of serchylene is not the same as 300 milligrams of serchylene, which is super therapeutic off-label, but more evidence-based. So I think classifications are tricky.

This is in part why there's interest in the so-called neuroscience-based nomenclature and talking about not just, you know, is this drug an antidepressant or an antipsychotic or an anti-anxiety, but more something based on its mechanism. Because we have examples now abounding of drugs that are being repurposed, like Primapexall. So should I say to you, I'm going to give you an anti-Parkinsonian drug for your depression? Or if I'm going to give you modafinil for ADHD off-label, I'm giving you a wakefulness-promoting drug for your ADHD. And for that matter, I remember when dival proex first came out years ago, and people had a tough time wrapping their head around the concept of an anti-convulsant for mood.

And I remember colleagues saying, I don't get it. Is this for my epileptic bipolar patients? And what about migraine? Why am I giving an anti-seizure drug for migraine? So, you know, it's fascinating when you think about the extent to which particular pharmacologies, Jew or don't have an evidence base. Buproprion could be an excellent anti-smoking weight loss drug, regardless of your depression. I've had patients say to me, give me Zyban, but not well,

I don't want anybody to think I'm taking an antidepressant. Oh. It's the same thing. Or seraphim, remember that one? That was fluoxetine retooled as a PMDD, premenstrual dysphoric disorder drug. It's the same drug. So I think this is in part become more salient as more and more of the atypical antipsychotics have been examined in recent years for broadened use besides psychosis.

True. They block D2 and they have an antipsychotic effect. But some have anxiolytic properties, as we talked about. Some have antidepressant properties. Some don't. Some have anti-obsessional properties. There's very nice data with aeropiprizole and respiradone and refractory OCD. But it becomes a stumbling block when you say to the patient, I'm going to give you an antipsychotic for your Olincipine is more and more being used as a post-operative anti-emetic.

So do you say to the patient, I'm giving you a very powerful antipsychotic for your nausea. So I don't know what the best way to translate this into lay language is because patients, you know, look things up and they say, gee, this drug is used for this. Why are you giving it to me for that? And we probably need some more user-friendly way to say to our patients. So the thing I'm going to prescribe for you is based on how the drug works, what I expect it to do, and what it's been shown to do. And the fact that it got niched in a particular area, you know, go back to the MAOIs for tuberculosis, Iperiniaz it. Do we ever go around saying to our MAOI recipients, I'm giving you a tuberculosis drug now? But that's where it started out. So the history of psychopharmacology is, I think, filled with things get looked at for one purpose and get found for something else.

Lomotrogen in the early 90s. In epilepsy, there were observations of enhanced mood and well-being, and that prompted interest in exploring it for mood. Bupropropion was originally being studied as a weight loss drug by Burroughs Welcome, and they serendipitously noticed that people seemed brighter. And back then in those tricyclic pre-SSRI days, depression wasn't quite the market. And so they actively put on hold their weight loss efforts and said,

you know, maybe there's a signal with depression here. for all we know buproprione would be a weight loss drug that has off-label use for depression wow a lot a lot there shall we talk about moderators a little bit because i feel like this is kind of like we're barely touching on the meat of the book here i was thinking as i'm reading through this i'm like man we could have you back we could do like we could do a chapter by chapter happy to david i will tell you that if if anybody you know is is kind enough to buy a copy of the book or borrow one, and you read nothing else in that book. Read the chapter on moderators, because that was the first chapter that I wrote. And really, the entirety of the book grew around that chapter out of my

enamoration, really, with Helena Kramer's work. I thought it was just an epiphany. And this comes out of my, I guess, my research background. When you do clinical trials and something works or doesn't work, the very first thing you do after the publications, you say, all right, let's do the moderator, mediator paper. So let's figure out whom did it work for. Oh, it worked in left-handed people from Minnesota who wear blue jeans on a Friday afternoon. And that's the population that you want to target. My earliest research back when I was from college was on lithium and looking at where lithium doesn't work well. That was back when rapid cycling got coined as a moderator of lithium non-response. I and others did work back in the 90s talking about lithium.

in mixed states or lithium with substance use. And there's a long list of reasons when lithium doesn't work. It's not a great choice in rapid cycling, with mixed features, with substance abuse, doesn't work as well on psychotic mania, doesn't work as well in multi-episode mania, doesn't work as well in depression-prone mania.

These are all moderators and predictors of likelihood of response. And great board questions, by the way. All of those things are great board questions. I'm sure. And even more than that, when you're sitting with a manic patient and you're deciding what to give them, you know, just imagine if you were in your mind going through saying, do you, how much do you conform to the profile of a lithium responsive candidate?

You know, rather than say lithium is the gold standard, lithium should be used. Again, it's like an infectious disease, we don't just say, how do I pick an antibiotic? We say, well, what's the culture, what's the sensitivity, what's the gram stain, what's the resistance? This is our clinical counterpart. So do you have rapid cycling? Are you on your umpteenth episode? How severely ill are you? Are you mania prone or depression prone? Do you have psychosis? Do you have OCD? I have to make an argument for why I want to give you what I gave you. Quick example. Years ago, I saw a new patient who comes in for an appointment after she was in the hospital, just left the hospital. I forget exactly long ago.

But she comes in, she sits down, she has a like a scarf on. She takes the scarf off. She flounces it in the air and she makes a little, little thrown. for herself and she sits down and she looks at me and she says, is that my chart? And I said, yes. And she said, may I see it? And I asked, uh, why? And she said, well, they're making a documentary about me on television and I thought I would autograph my chart for you because I'm going to be very famous someday and you're going to make a lot of money with that chart if I autographed it for you. My point is I didn't have to ask her any diagnostic questions. She answered everything. And the reason why I said lithium is your drug, without asking her a single question, is because she displayed what Nasiragami calls Cade's disease, euphoric, expansive, grandiose, non-disporic mania.

And lithium is the treatment of choice in that situation. The grandiosity, the self-aggrandizement, the expansiveness. You know, Mannix, who sort of almost make you want to laugh. You smiled when I even told the anecdote, it cries out for lithium, and it's not arbitrary. That's a really, in my opinion, important example of moderators, where you wouldn't just say, how shall I treat you? We've got a zillion options for mania, but this is different. This is saying you have a clinical profile. And, you know, she had me at hello, or she had me at, may I autograph my chart? That was the instant I knew, you know, you're going on lithium. Moderators. Okay, let me run through some of the moderators, just to give people an idea.

Baseline severity. Crucial variable because, now I'm going to put my researcher cap on. When you look at a clinical trial, somebody does a study of drug X versus placebo, and you're interested in whether it works or not, baseline severity is a pretty important differentiator of separation from placebo, meaning low severity inflates placebo response. meaning more severely ill patients are not placebo responsive. You remember those criticisms that antidepressants are no better than placebo.

I think there was a piece on 60 minutes some years ago and a lot of press claiming that antidepressants are no better than placebo. Well, what they were really getting at, little did they know, was that baseline severity is an important moderator that discriminates separation from placebo. So if you enroll in a clinical trial more mildly ill patients, you'll get a high placebo response rate. That doesn't negate the efficacy of the antidepressant, but it does mean mild depression is more placebo responsive. It's going to be harder to show an effect. So this is a really important point because it's not nullifying the effect of the drug.

It's saying you're not going to differentiate it from placebo in more mildly ill patients. Or severely ill patients, if you're better with drug X, I have much more common. that this is a solid improvement, then if you were mildly ill, you have a PHQ 9 of 10. Yeah, you know, the natural course of your illness is going to get you better. If I give you drug X, how confident can I be when your pHQ comes down to a two? That's because of what I gave you or just because you were mildly ill. So baseline severity is important to researchers. It explains failed trials.

I give in the book the example of Lomotrogen, if I can spend a second on that. The reason why Lomotrigine never got a... its FDA indication for bipolar depression. Well, it's because it didn't work. But the reason it didn't work for acute bipolar depression, it isn't like that the drug didn't work. It's that the placebo response was crazy high, moderated by baseline severity. So there's a section in my talks about this. If you took mildly ill or moderately ill depressed bipolar patients, the success rate with thromotogene or placebo is about 45%. But if you take severely ill depressed bipolar patients, the success rate with placebo drops to 30 percent. And that allows separation

from the active drug. So when clinical trials enroll more mildly ill patients, and that's one of the first things I look at if I'm reviewing a study and the finding is negative, drug X didn't work, did they shoot themselves in the foot by having low baseline severity patients? So that's important as a research, and that also goes into, I think, Dr. Gami's study is he had somewhat low baseline severity in his satalopram study. So he kind of invited a placebo effect. And the placebo effect is real. At MGH at MGH at Mass General, they do open trials of placebo and they get response rates of 70%. You know, I tell the patient, I'm going to give you something. It doesn't have any active medicine in it, but some people find it to make them better and it's well tolerated.

you go, seven out of ten people get better if their baseline severity is not high. So that's the research conception. The clinician conception, sort of toggle back and forth with your mindset. Am I research or am I clinician? The clinician mindset is if I have a severely opatient, they're not going to get better with placebo. They're going to have a harder time getting better because baseline severity is just tougher to treat. But if I do see improvement, it's more durable because they sort of pass the acid test of a more severe form of the illness. And lastly, it also may take longer. So when I was saying before, anxiety buys you more than six weeks for depression,

chronicity buys you more than a six-week trial. You know, we go around saying an adequate trial is four or two six weeks sometimes, but in more severe forms of the illness, it's going to take longer. So the clinician has to sort of know this is a profoundly depressed patient, a moderately depressed patient, or a mildly depressed patient, it's going to influence the outcome. Man, it just jumps into my mind. Ketamine, do you think, what are your thoughts on ketamine for, like, would you consider that if someone was severely depressed?

I sent someone in for ketamine, severely depressed, pretty anxious, haven't sent too many patients, but this one fit the bill. And it hasn't seemed to help, but I wonder if you got enough. Like, is ketamine one of those things that you need to carry it out for a long time before you give up on it? This may be beyond. No, no, I got to pull out a page. So the short answer is probably not. It either works or it doesn't.

My ketamine guru colleagues will tell me things like if by three infusions you haven't shown much improvement, the odds are pretty low. not zero but pretty low. So you'd like to see something happening by three infusions. If it's S ketamine, you know, provado, the nasal spray, the studies are a little more generous. They go out to 28 weeks in judging response. And I actually got a bootleg graphic from a poster that I pinched in the book, which shows that the week-to-week-to-week success rate. So you can actually measure it week by week.

This is with S-Ketamine, the nasal spray. Okay. And what this graph says, which our podcast listeners can't see, but at day two, there's significant separation from placebo, but the response rate is 17%. That's day two. Okay. By day 15, it goes up to 26%.

Still beats placebo. By day 22, it's up to 45%. Still beats placebo. And by day 28 response is 58.7%. All beating plus. placebo. So there's kind of a linear progression, at least with S-ketamine, meaning if you're not better on day two or even day eight or day 15, you're not out of the woods. You want to, the induction period goes on for several weeks. And this is why, because you can still see accrual. It tapers off

at a certain point. So after about 28 weeks, if you haven't hit success, time to cut bait. But now here's where things get more interesting. So I got to invoke another concept in this lovely book. If you finish reading chapter three and you like it, go to, sorry, chapter five on the moderators, go to chapter three on interpreting literature, because to me, one of the biggest epiphanies in my research for this book was this, looking at effect sizes. You can't see this, and our podcast listeners can't see it. But in chapter... I love, I talk about effect sizes quite often. So this, I have to say, this, this blows my mind. You know, you talked about the effect size and the study before with diet. So a large effect size means that whatever you do is very clinically

meaningful. It's not just significantly better than a placebo. It's got wallop. It's got a dramatic effect. Think of what's a large effect size. No, no, I mean, clinically speaking, amoxicillin for strep throat. Anesthesia, right? Unambiguous. You're going to sleep if I give you propofal. It's not, you're sort of asleep. You're a little busy. You know, profound effect. Closopine. Pretty big effect. So if we look at effect sizes, this is what was the epiphany for me, among the biggest effect sizes in psychopharmacology, intravenous ketamine for major depression, large effect size, over one. That means, you know, if the patient's not getting better with ketamine, it doesn't mean you're out of luck, but it does mean I've given you a 16-inch

gun, you know, a really big caliber weapon. And if that hasn't worked, again, we never want to take away hope ever, but we also want to be sort of non-random. So it sort of begs the question, what do you do after non-response to ketamine? Well, there's lots of things that you can do after non-response to ketamine. You might do ECT. You might do an M-A-O inhibitor. You might do, there are some newer forms of TMS, theta-burst, ultra-brief pulse, even beats ECT, you know, the data with psilocybin. Just saying if you use a big gun treatment like ketamine, you probably then don't want to to go down, and it doesn't work, you probably don't want to go down from a four-door limousine to a two-door compact or a low-effect-sized treatment. So you didn't get better with IV ketamine,

and let's give you peroxitine. That's a low-potency drug. And when we look at this, you know, SSRIs for depression have effect size of about 0.3. That's okay. It's not great. But throw in the moderators, all right, you know, who's going to have a bigger effect? Somebody who's, you know, not chronically ill, not as severely ill, not with a lot of treatment non-response, certainly didn't fail IV ketamine. And your patient who failed IV ketamine is going to be a tougher, a tougher challenge. So you'll want to think about your next treatment based on what's got a large effect size. Say it again, theta burst TMS beats ECT. Yeah. So, so, you know, those of us who are sort of trying to follow the pipeline, TMS itself is modestly helpful.

It works in about one in three people. It does not have a large effect size. It's about as good as an SSRI. It got its FDA indication for treatment resistant depression, but, you know, it's not an IV ketamine. It's not ECT. It's inferior to ECT. It's about as good as an SSRI. So it works, but, you know, no 16-inch caliber gun. tweaked versions of TMS are now sort of occurant. And the group at Stanford, Alan Chatsburgh group, published a study a year or two ago using theta burst technique for TMS in treatment-resistant depression with a very large effect size. I can try to pull up the study, actually, since we're on Zoom.

and it worked even in ECT non-responsive patients. You don't run down to the urgent care center and ask for ThetaBurse TMS. It's not quite in Doc in the Box, you know, mall treatment centers. It's an experimental approach, but I take it as an example of how the field is moving in directions where we're hopefully going to have more impactful treatments in times to come. So fingers crossed, if ThetaBur's, you know, TMS gets replicated and proves to be viable, useful, and closer to something like ECT, which plain old TMS is not, that would be quite stupendous.

While you pull that up, IV ketamine, is there evidence that you know of increasing the dose? Not to my knowledge. Ketamine seems to have a distinct effect at different doses. So its psychedelic effect is different from its anesthesia effect, is different from its regional pain effect. And my understanding from the IV ketamine gurus is that roughly 0.5 mix per kilo is about what you aim for. And I'm not aware of any data that says higher dose does more for you. So I think like so many things, it either works or it doesn't. And, you know, nothing works for everybody.

Okay. So it's an early study that points at something that's potentially promising. And a nuance or an improvement above and beyond the existing technology. A little bit like the H coil is sometimes thought to be more penetrant in TMS. I'm not a TMS expert, but I think trying to refine the technology, especially in very hard-to-treat patients, is quite the challenge. We don't have a lot of treatments for very refractory patients. Vagal nerve stimulation. My friend Scott Aronson is a real expert in VNS.

And when he published his study in the American Journal a couple of years ago, he told me he often saw people with 12 non-responses to prior things. So, you know, what do you do with someone who's taken a dozen treatments and they know better? And you're trying to maintain hope. You know, you don't want to just say, well, you haven't tried Louvox, haven't tried Remmeron. because there's no real database that says the effect size makes you expect a bigger effect. You could go for bigger effect-sized drugs, MEO inhibitors, for example, a lancebein-fluoxygen combination, ECT, very large effect size. And as we start to look to the future for things like psychedelics, perhaps, or Xeranolone,

there's all kinds of interesting new things on the horizon. But for those of us who see people where many other things haven't worked, I think it's important to not just say, well, let's randomly pick something, but rather what's the chance of success? That's good. That's good. Well, I feel like we're going to have to do a part two because I feel like we barely cracked open that even the moderator mediator section. And I want to get to anxiety. But I also want to be cognizant of your time here. Let's try to jump into anxiety because I feel like, so to kind of summarize the moderator, mediators, mediators section. You go through things like age, chronicity, early age of onset, episode number, duration of untreated illness, sex, race, ethnicity, baseline anxiety, trauma history, childhood trauma history. So you go through all these things that influence how well different medications are going to work. Anything on those that you want to just throw out little clinical pearls real quick on things that have made a huge difference for you in your practice. Yeah, well, I think from a general perspective, just knowing that one should inquire about the kinds of characteristics you just mentioned puts you ahead of the curve above and beyond saying, I have your diagnosis and I have your Hamilton score and that's it, or have your rating scale score on current cross-sectional symptoms.

Because you know much more about the patient and their history with those moderators, you know, in your hip pocket. of them all, you know, I guess I would have to say number of failed responses in the current episode is maybe the biggest one. My ECT colleagues like to tell me the same is the case in their experience when I ask them, suppose someone has not responded to umpteen treatments, what's the chance of ECT? And they roll their eyes and look at me and say, Joe, you know the answer to that question. It's same as everything else. You know, if you wait too long to use a large effect size treatment, it's not going to work as well. So that, again, does not mean tell the patient, sorry, bud, can't help you.

You're out of luck. But it does mean, I think, having some transparency about saying, look, you know, many things have been tried. Let's figure out if they were adequate trials. Sometimes people have been on lots of medicines for all of a day, right? You know, I took this and then somebody called me this way. Oh, I took Searcherlane and I was a zombie the next day, so I stopped it. I don't know what that means, but I don't count that as an adequate trial of anything. And so patients who tell us an intolerance occurred or they weren't on the drug long enough.

So we do want to clarify, you know, if there was adequacy of past trials in part so we don't reinvent the wheel. We're not going to, you know, if somebody says I was on drug X for all of a week and not better so I stopped it, that doesn't count. Drug X is still on the candidate list of options. But if someone's really been on meaningful trials that haven't worked, I will tell patients we have to be very realistic. The probability of success is much more limited than if you had not had that experience. It doesn't mean we can't try new things and we should try new things, but we also have to sort of acknowledge the here and now of you're coping with the chronic condition. And you might like a paper I wrote some years ago in J. psych called when further pharmacotherapy is futile. I was having an alliteration day that day.

And it talks about how do you try to maintain hope when someone's been on lots of things and they're not getting better. And it becomes disingenuous to say, well, let's try etatalopram. You haven't tried that before with no awareness as to the likelihood that that's going to do something. And it also, in my view, it also raises the risk of what I'd call an operant conditioning paradigm that is every time you try a medicine and there's a negative consequence, you don't get better, it's demoralizing. So how can I look you in the eye and say, I know you've been on 15 things, but you haven't been on this? So to me, that means saying moderators wise, if many things have not worked, let's call that the most overarching moderator. Is my diagnosis right? You know, I think you have depression. Really, you have heroin addiction.

I saw somebody recently, oh, I'm manic, I'm manic, I'm using cocaine every day and I'm manic. Well, tell you what, let's have you stop the cocaine and then we can reassess the mania. Or somebody with a high TSA or somebody with lime or somebody with some confounding variable. So non-response, you have to sort of try to grasp what might be going into that in terms of adequate trials, accurate diagnoses, comorbidities. Yes, you're depressed, but you're also using cocaine. So that's going to be a negative moderator. Because then you start to map out what's viable.

I have to jump on that. Do you believe in chronic Lyme? Oh, do I believe in chronic? Do I believe in it? Do you think that that's a real issue? I've encountered patients. I'm practicing in Connecticut, not far from old Lyme, so I tend to get somewhat over-representation.

of that clientele. I think chronic Lyme does persist and often, it does occur and often persists with fatigue, malaise, lethargy, arthrales, a lot of physical disability. I guess if you speculate about CNS Lyme, you could question, is your depression not getting better because of some, you know, brain inflammation, the same as if you had lupus cerebritis and you're not getting better. But when I've seen patients with bona fide lime, not Western blotten, negative, but some clinician nevertheless thinks that they have a tick-borne disease. But, you know, the real deal, I see it with a lot of physical complaints. And I have people that are physically very debilitated. And the arthrales in particular can be very debilitating, which is, I would call a mediator.

So, you know, something that happens after you've started your treatment. You're cruising along, doing well, but then you get felled by some other problem. You know, I have patients who've gotten COVID and then had long haul COVID and they're having cognitive problems and there's this malaise and the anosmia and their depression is still better than it was but their quality

of life is not as good as it was and they just never quite regain the level of vitality that they had so something that comes along and disrupts the potential best outcome. Mediators are things that muck up good outcome so that means getting sick with something

that means side effects can be mediators, they'll torpedo your response or cause non-adherence, drug abuse, getting pregnant, getting fired, getting hired. And, you know, the clinician wants to be ever mindful of the variations that occur over time in judging response, someone who's had a major life event, an adverse event, and they get depressed. I don't know that I would say, oops, we better raise your dose of medicines. We probably want to evaluate the context of what's going on, since mediators can be so influential. Yeah.

Yeah, I think there was one study that came out, I think UCSF, where they looked at, you know, do antibiotics help people who think that they have chronic Lyme and they found that there was no difference with like three months of antibiotics versus no treatment. I'm no expert here, but my impression is that it is a very difficult mediator in psychiatric disorders as someone happens to have chronic Lyme. I had a patient who had cardiac lime, and it didn't get diagnosed for a while. I'm not sure how they actually did diagnose it, but he was having dyspnea and weakness, and the cardiologists were saying, oh, it's your depression, go back to your psychiatrist,

and something wasn't adding up, and then eventually, I think it may have been an MRI, found something. Interesting. So we have to be mindful of these things. We, so I had a good friend who was an infectious disease doctor out in San Francisco, and that's one of the, there's a big Lyme disease center out there, cash pay, very expensive, and he would get the people who had years of complications of antibiotics. So if you're listening to this and you're thinking about that, just realize that there's,

there's some people, some infectious disease doctors who do not believe that the patients are needing to be treated with years and years of antibiotics. Are they saying that it's not clear the antibiotics on the remedy or are they questioning the diagnosis? They're questioning the diagnosis and some people think it's psychosomatic. I've had a number of patients through my IOP and partial program who come in with Lyme disease and get off all the meds and do great just with psychotherapy. It looks more like fibromyalgia for those people. Now, you're in Connecticut, you're in a place where Lyme disease is higher, so maybe I need to look at that and be open to that. But from what I've heard from a couple people,

including infectious disease doctors, for this one particular guy in UCSF, is that they get kind of the patients with huge complications and they think they've been poorly treated. Well, so let me just throw out, if I can, another important moderator, which is somatization. Patients who are very somatically preoccupied are very hard to treat. And I know no psychotropic drug that helps that, but I know plenty of that

make it worse. So the second the patient swallows a pill, they can feel pain over here or something. And, you know, one of the chapters in the book talks about the placebo effect, and I think it's worth pointing out what's called the nocebo effect, which is side effects from an inert substance. So patients who are prone towards somatization are at very high risk for adverse effects from inocuous substances. And so there may well be some overlap, particularly if there are not clinical diagnoses, and it's not so easy to make a hard and fast diagnosis when there's things like fibromyalgia or chronic fatigue syndrome. If someone is very somatically preoccupied, you run the risk of, oh, I'll give you this, I'll give you that, and then they get worse.

and oh, I can't take that again. You gave me 100 milligrams of gabapentin, and I got the worst headache of my life, and I got urinary retention, and edema, and chills and sweats and tremor. And what? What? That's a marked nocebo response, and that's almost a contraindication to pharmacology. Yeah. So I've been running this program for psychosomatic patients now for about eight years,

and psychosomatic and real medical issues. And so we see like psychogenic seizures, fibromyalgia irritable bowel, chronic fatigue, occasional Lyme disease. Now we're seeing a lot of the COVID long haul. Not that it's purely psychosomatic. I'm not saying that, but we see them in the program

because it's a mixture of medical patients and psychiatric issues. Our effect size is around two to three. With psychotherapy? With a lot of psychotherapy. I mean, I'm cleaning up their meds as well. They're coming in on a polypharmacy a lot of the time. You know, a lot of the times they're on like a tricyclic plus an SSRI or an SNRI,

which is kind of, I'd be curious what you thought on that is. I usually clean it up. I think it's redundancy. Choose one or the other type of thing. Usually get them off of amotryptylene and on something with less side effects. Anyways, so I just have to sort of insert my hesitancy. to buy into the narrative, I think there's always going to be a narrative that's changing

that the psychosomatic patients fall into because there's so much stigma for the psychosomatic patients, I think we should have a lot of compassion for them. But when there's new culturally appropriate ways of manifesting their illness that gets them empathy and validation, they often will change the naming of it. Yeah, anyways, I don't know if you have any other thoughts on that or we could jump to it.

No, I completely agree. I mean, I think, you know, I'm quite fascinated with nocebo effects, patients who, you know, report feeling harmed by treatments or or just have a plethora of physical complaints that don't conform to any particular pattern in the side effects book. I think I mentioned when you're trying to assess causality, when someone gives you, you know, opposing mechanisms like, oh, I'm having dry mouth and diarrhea. Really? I mean, you know, it's either one or the other, or I'm disparate symptoms that don't have an understandable common pathophysiology is where I think the psychiatrist's mindset kicks in and saying, gee, this doesn't add up. It's paradoxical effects, which can happen, but, you know, somebody who says, oh, whenever I take lithium, I get manic. Uh-huh. or, you know, clonazepam makes me very agitated.

Okay, well, let's not give you a clanasopam. You sell me, oh, amphetamine makes me very drowsy. I think I need a higher dose. So we're sort of trying to see beyond the complaint, trying to gauge how the person processes it. And people can have all kinds of idiosyncratic ideas. I've had patients, I've sort of seen a lot of people, I guess, with side effect sensitivity complaints who come along.

And we'll have all kinds of videos. ocratic ideas like, gee, if I mix and match an XR with an IR of this drug, and I take it with food between 930 and 10 a.m., you know, wearing blue socks, it works, but only then. Can you explain that, Dr. Goldberg? Why is it that I have to wear blue socks? And so the ritualizations that we attach to to treatments. Oh, yeah. You look back at mesmer, you know, take people, give them ritual, have authority, an aspect of magic, you know, dose to actually, you said, what? do people want miracle mystery and authority? You know, they don't want freedom.

And so sometimes placebo is, it works for people, homeopathy, right? Quick, quick anecdote. It was once doing clinical trial with somebody with a tricyclic antidepressant. I like the secondary means, by the way, the tertiary means don't mix well with other stuff. But I think this was a decipramine trial.

And this person got much better from their depression. Then they, so here's my research mindset. Then they randomized. for relapse prevention into drug versus placebo. And we didn't know which it was. And over the next few weeks and months, this person started complaining of sexual side effects. So back in those days, I think I gave him,

I don't know, you know, him bean or something. And they started complaining of dry mouth. So I gave them, you know, something for dry mouth. And then they started complaining about something else. They ended up being getting put on like three or four concommonant medicines for all these side effects. And at the end of the study, as you can guess, the blind got broken. Care to guess?

This fellow who was euthymic throughout the maintenance phase was on placebo. I had to tell this person, you don't have dry mouth, you don't have sexual side effects, you don't have constipation, you don't have any of these side effects because you're taking an inert substance. You are not depressed. You don't need an antidepressant. You're not having side effects. You don't even need a psychiatrist. They were very upset by the reality.

by the reality of that information. I'm paraphrasing how I said it. It wasn't that harsh. But, you know, the reality was the brain's a really funny thing. This person was experiencing all kinds of phenomena, clearly. And here was me saying you're not depressed. You're not having side effects. How do I validate their distress?

I mean, obviously you want to validate their distress. And yet you know it's not, you're not being harmed by the drug because you're not taking a drug. You know, in my experience with this population, I rarely will say to them, it's all all in your head. You know, like that's sort of like you're only dry, you're only having the dry mouth because there's something about you got put into fight and flight. Maybe you thought the medication was real. You had this belief and then that belief led to you to be in a stress state. The stress state led you be dry mouth constipated from being in that sort of fight and flight place. I don't know. You know, like what do you think? I step back and marvel at the brain and talk to patients

about something called the somatosensory cortex, which is responsible for integrating information about physical sensations and what that means. And then I give them examples of things like phantom limb phenomenon or how is it that when your arm is asleep and you touch it, your brain doesn't realize that that is your hand. The brain has some way of processing phenomena that's contrary to objective realities sometimes. So if you tell me that you're having, I don't know, tremor from a side effect. I may not be able to explain that physiologically, tremor from something that, I don't know,

pick a drug that does not cause tremor. I can't think of an example left hand. But my thought is this is an implausible side effect. I'd never say to a patient, I hope, that's implausible or that can't be. But I would say, you know, this is a tough one. It defies explanation. You know, first and foremost, safety first.

So I want to make sure that, you know, you're safe. you're noticing this unusual side effect. Rest assured it is causing you no medical hazard. It's not like Stevens Johnson syndrome or myocarditis. So partly I'm here to differentiate. I make a point in the side effects book, serious side effects from annoying side effects. So if somebody is telling me that they're having,

I don't know, yawning or dry mouth, you know, rest assured that is not life-threatening and it is in no way medically hazardous, but it's uncomfortable. And, you know, then, you know, what do we do about it?

So if I think that there's a high degree of somatization, you know, I may fall back on some psychotherapeutic skills and not challenge the validity of their experience, but rather to commiserate fully with it and point out that, you know, the brain is this phenomenal computer that we don't fully understand. Let's take away the thing that we think is causing you harm and let's just watch and see what happens. And I often tell residents when they meet a new patient at the beginning of the year, For heaven's sakes, don't change anything in the first few weeks. Because you don't know what the patient's going to attribute as cause and effect. Yeah, I have therapeutic alliance, right? If they feel connected with you, they tend to do better. Actually, you know, I'm very curious on your thoughts on this one study.

It looked at psychiatrist effect. Have you ever heard of this idea? Where they look at the different effects of different psychiatrists, the effectiveness of the different psychiatrists. So in this one study, they were looking at amypremine versus placebo. Uh-huh. And what they were looking at was, does one psychiatrist do better than another psychiatrist?

Interesting. And, you know, in psychotherapy, they've done a number of these studies, like, you know, does psychotherapy do better? Or is one psychotherapist better than another psychotherapist? Mm-hmm. So they've done a number of these studies in psychotherapy, and they found that, yeah, lo and behold, there are these, like, super shrinks. There are these psychotherapists that are doing in one article.

It was 10 times better than the average therapist, but not in general. The bell curve is actually pretty narrow in effectiveness of therapists. But it is fascinating. You touch on, let's call it, the nonspecific aspects of treatment, and whether that's the meaningfulness of the placebo effect, you know, what a third, of antidepressant response is placebo. So, you know, when clinical trials get done, staff are instructed to not inadvertently make supportive comments to patients, not spend too much time, kind of be fairly cold, or at least business-like. You end up telling the patient, wow,

that must be really difficult for you. How are you coping? How are you managing? What are your supports. If you introduce accidental supportive psychotherapy, you contaminate the drug effect. And so it wouldn't surprise me that with a given psychotropic in the hands of different clinicians, you know, you're not a vending machine. How you present it may be more the cherry on the cake, the drug that leads up to how did you get there in terms of how you're, how you empathize, your therapeutic alliance, do you instill a sense of hope, you know, all those factors that that can differentiate good therapists from, quote, less good therapists. Okay.

So here we have an NIMH study that looked at depression. And this was a secondary analysis of it. And so they had nine psychiatrists treating 112 patients, randomized to amypremine versus placebo. And I'll show you the, here you go. So you saw some of these psychiatrists, like Psychiatrist 1 had a much more effective decrease of the BDI, Beck Depression,

inventory than Psychiatrist 9 here. Actually, Psychiatrist 1, amypremine was better than Psychiatrist 9. Oh, no, psychiatrist 1, placebo is better than psychiatrace 9. Mipramine, yeah. And I've never seen any other study repeat this type of, you know, like model, like, you know, It would be nice to have more studies like this, I think, looking at secondary analysis of these datasets. So if you're listening to this and you need a research project, there you go. Yeah, this is fascinating. Did they explore some of the characteristics of psychiatrist one versus nine?

So speculate? Unfortunately, they didn't. They just showed the, they call it the proportion of variance due to the BDI score, due to medication was 3.4%. The proportion of variance of the BDI score due to psychiatrists was 9.1%. So in this study, it was a little bit less for the Hamdi, I think it was 5.9 versus 6.7%. Variants meaning like, you know, how much of it was the placebo versus the medication, how much was it between psychiatrist's effectiveness, right? You know, this reminds me in clinical trials, multi-site trials. The heterogeneity across sites becomes important, and certain sites that enroll patients

are sometimes looked at as outliers for either disproportionately low or high response rates, either to drug or placebo. It's a kind of a macro level of the same thing you're talking about here. If Joe Schmo's site in Idaho gets stupendous results, and Sam Smith's site site, in Sahara, you know, has just, you know, a really inflated placebo response rate. And this site over here has just, you know, nobody getting better at all. It makes it hard to ascribe cause and effect to the drug because something's going on. And if you're an investigator or worse, if you're the sponsor of a study, you start pulling your hair out saying, now what do I do? Do I ditch

this site? Do I say that they were, you know, an outlier? There was a recent study just published in the journal Effective disorders with a new molecule. called SCP-4199, which found that it worked in Japan, but not Europe or the U.S. Oh. Explain that one. Wow. Explain that one. I mean, say methodology.

I would almost, if it was just nation-specific, Japan is such a homeo-you-you-you-you-know-I- would say genetics. There's something about the genetics of that group of people, but maybe I'm wrong. But the other thing is, I would say, is that, medication born in Japan? Because if it was born in Japan, there's some charismatic leader that is usually connected to it, right? So we can speculate from here to Doomsday, as far as, you know, what really gets patients better? And to me, this is, effect sizes are comparing the impact of a drug versus placebo. Placibos not no treatment. And there's just, in my opinion, been an underappreciation

of the things that are encompassed by placebo. Placebo is not wait list. Placebo is not nothing. Placebo is usually some level of clinical care and management. So for all we know, you know, sites that have inflated placebo responses, spent more time with patients, reimbursed them for car fare, gave them a turkey sandwich when they came in. We're more compassionate, spent more than 10 minutes. Made them believe in the treatment, the effectiveness of the treatment.

connected with them as an individual. They felt the love and care of this research team. And David, I'll tell you an irony and a paradox here. Researchers try their darnest to minimize placebo effects and clinicians try their darndest to maximize placebo effects. So if I'm treating, so if I'm treating you as a patient, I want to do every, I'm going to do cartwheels to make you feel cared about, empathy, share decision making. I will go the distance to capitalize on everything I know about the placebo response, hoping that I'll buy a few more points of variance in your BDI score. Whereas if I'm doing a clinical trial, I'm trying to minimize that. So it's a very interesting paradox. The goals are quite different in that regard. Well, but it's tough because

in research studies, you have a team monitoring this person. You have extra sessions with the person doing large number of like tests and stuff. So there's like a specialness that comes with it, right? So, yeah. Anyway, we have to, we have to wrap this up. I actually have to bring this this wonderful time to a close. I actually would love to have you back on. I think next time we'll get to mediators. And anxiety. It's an anxiety. So I apologize if you've listened to this whole episode wanting to get to anxiety. Anxiety is bad and it's hard to treat, but I'm happy to say more about that next time. And your one little, your one little thing of think about, um, Lyrica.

Oh. It was interesting. Pre-gabalin? Yes. Think about pre-gabolin for anxiety, no? And CBD. Quickly. Would you use pre-gablin?

Would you use CBD? Either is reasonable. CBD is not as evidence-based and more provisional and there's not as much quality control. Pre-gabalin has a long story, which I'll try to answer in less than 30 minutes. The manufacturer got in trouble with the Attorney General's office for making promotional claims about gabapentinoids, having anti-anxiety properties without getting the FDA's blessing. They had good data. But the Attorney General in New York decided to sue the Dickens out of Pfizer for making proactive claims off-label. In Europe, non-issue, pre-gabalin's approved in the

European Union for sociophobia and I believe for generalized anxiety disorder. It's got a large effect. It works well. The bipolar practice guidelines, can mat guidelines, acknowledge that anxiety doesn't have a lot of known effective treatments when it's comorbid and bipolar disorder. But the CanMAT authors suggest pre-Gablin is a very reasonable thing to try, and it is a good example of an off-label drug that's got a decent evidence-based to it. So you can't prescribe it off-label because it's got clinical trials. It's just, you know, Pfizer didn't spend a gazillion dollars going to the FDA to get the blessing to advertise it. Boom, there you go. Hey, it's so good to have you on If you're listening to this episode and you got through it, congratulations.

And if you get the book, please leave a review for Dr. Goldberg on Amazon. Let them know that you heard this interview and that you got the book and that you appreciate the book. Don't leave a bad review, please. That would bode poorly for future guests coming on to the podcast. But honesty is always welcome. If you have an honest critique, email me. email yes if you have a uh always yeah so yeah i will leave it there it's a pleasure meeting you and thank you for coming on thanks for having me david's been a real pleasure