Psychiatry & Psychotherapy Podcast - Psychopharmacology Mediators With Dr. Goldberg

Episode Date: March 8, 2022

Dr. Joseph F. Goldberg is a psychiatrist and clinician researcher with over 180 publications and 3 books. This article focuses on his newest book,  Practical Psychopharmacology: Translating Findings From Evidence-Based Trials into Real-World Clinical Practice. In this article, we discuss psychopharmacology and his approach to psychiatry.    By listening to this episode, you can earn 1.5 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 CME 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, welcome back to the podcast. I am joined today for part two with... Dr. Joseph Goldberg. He is an amazing psychiatrist who was previously on talking about his new book, Practical Psychopharmacology. And we had decided that we would do another episode because I didn't feel like we got to everything I wanted to get to. And I'm also on with a resident at Loma Millenn University, Maxwell or Max Schauerman. He is a, what, third year now, third year psychiatry resident and I asked him to join us to kind of have a voice for the residents who listen to this maybe you know ask questions based off of what he's going through in the

trenches of impatient outpatient so thanks for coming on guys pleasure thanks for having david just have to do conflicts of interest myself and dr showerman do not have any conflicts of interest Joseph Goldberg have any conflicts of interest Joseph Goldberg have has the following conflicts of interest. He's a consultant of by Excel, jazz pharmaceuticals, Lundbeck, Ostrica, Sage Pharmaceuticals, Sonvian.

He's a speaker bureau at Abbe, Archimé's, intracellular therapies, and sonvian. Probably pronouncing those wrong. All right. I'm curious what kind of feedback you got, Dr. Goldberg, from your,

anyone who listened that you know, to our previous episode, if you had anything you wish you would have said or wish you would have talked about? Well, a few of my residents said, oh, wow, that was you on that program. How cool. And I heard things that were consistent from things that I teach in Psychoform. I guess a lot of it was sort of broader picture, how to think about psychopharmacology. The things I've been writing about are not so much dry reviews of how to treat depression or here are the FDA-approved drugs, but more how to think about patients in a very practical way, hence the title of the book, and then how to pair up and match up the right treatment for the right

patient as opposed to what is your algorithm for this diagnosis. So some of the feedback that I've gotten has been maybe breath of fresh air to not hear about algorithms or about, you know, what is your first line choice for bipolar depression or picking a drug in isolation, you know, should I use lithium or what's the best atypical antipsychotic, but rather how do you match up the right treatment for the right patient, which is really my message? Yeah, yeah, it's hard to make blanket statements when there's so much nuance. And what we were talking about last episode was a lot about moderators and mediators was what

we were going to focus on this time. So moderators are kind of like characteristics. of the patient that will change the way treatment will be effective or not effective or make treatment more difficult? Yeah, anything you want to say on moderators, just as a review? Just say baseline characteristics about a given individual that might favorably influence or negatively influence outcomes. So this is beyond diagnosis. You could say, here's somebody with major depression, period. And we've got three dozen things we could try, or you could say, Here's somebody with early onset, highly recurrent, major depression with comorbid anxiety,

with a positive family history of suicide attempts, and a personal history of childhood trauma. How might that influence your thinking? How might that lead you to consider whether there's a role for one or more medicines in the mix if there's comorbidities, how to craft the regimen? So these are baseline characteristics that, you know, when you meet the patient, when you're doing your diagnostic interview, you're not just going through the checklist of DSM symptoms, but you're really trying to sort of niche the presentation of this patient and having an awareness of those moderating factors because they'll influence your

thinking. For instance, anxiety, notorious negative predictor of outcome or moderator of outcome in major depression. Some things have been shown to work better than others. So one is forewarned and forearmed. Oh, I know you have this comorbidity or substance abuse comorbidity. I'm going we anticipate a certain likelihood that this treatment will work for you. Or a moderating fact, actually this gets into mediators, features that occur after the treatment started, but you could historically look back on past mediators like non-adherence. So you've stopped every medicine you've tried within about a week of starting it. Those non-adherence would mediate outcome. You could have the best treatment in the world, but if you're not going to take it, then

that'll put the kibosh on it. So you're meeting a new patient, and rather than say, well, this is your diagnosis, and I think this would be the best treatment for you. However, given that previously, you've had difficulty sticking with something. We can't just say what's the best medicine in an abstract kind of way without considering what prompted you to stop medicines before. That's sort of tailoring it more of the patient. Yeah, so mediators are things that are going to get away in the treatment being successful. And I think that when I was just thinking about the idea of mediators, the first thing that came to me, it was non-compliance, right? It's like, and lo and behold, you have like a whole table on things that are linked to non-compliance.

Max, what do you think about that one? Is that something you see a little bit? All the time, yeah. Non-compliance has to be one of the biggest moderator, excuse me, mediators that we as clinicians face, especially with psychotropics, facing stigma around psychotropics and the side effect burden, it's very difficult to get our patient populations on board. And it must feel disempowering all around. I mean, the patient sort of rests control away and says, I'm not going to do what you're asking me to do. And we, the clinician, are sort of trying to force fit. But, you know, I really think this is going to be a helpful medicine for you.

What can I do to, you know, help encourage you or engage you to take it? Or rather, you know, can we collaborate in some way to figure out what's gotten in the way of, of you're taking it. I find non-adherence kind of a fascinating area because it spans everything from side effects to misinformation. That is, I don't think I need this drug anymore or I'm fine for insight, wrong attributions about this medicine. I heard it has this terrible side effect or I'm scared. One paranoid patient once told me he wouldn't take anything that's manufactured in a laboratory. It was just so much paranoia per se that to, you know, this is a sort of dance we had to do around empathizing with his paranoia and at the same time trying to

instill some sense of, I want to help you with your distress about this, but I appreciate and recognize the fear factor that's holding you back from accepting the treatment. So to me, this is the challenge for astute clinicians to sort of get in there with the patient and try to figure out sort of you and me against the world. How can we help, how can you help you help yourself rather than, you know, me force you to take this pill? Yeah, there's something like kind of revolve about the idea that I'm going to force you to do anything, right? And it's like, I think this is where that therapeutic alliance is so powerful building the trust. I almost expect patients to be non-compliant at this point. And I don't, I feel like I've been able to work through my frustration pretty well from that where it's like, okay, let's talk about it. Like what happened, I'm glad that you were able to be. truthful with me about what's going on. You know, that's great.

And just kind of roll with whatever their goals are. I was looking at one of your tables, table 3.3 where you went through the percentage completing an entire study. And it was like 9% for some of these drugs. I'm like, what the heck? Yeah, that's a conundrum. I mean, to think about long-term studies, patients or clinicians will ask, well, is there long-term

control data with drug X? You know, keeping somebody in a randomized controlled trial for many, many, many months and asking them to adhere to treatment and they can't have misdosis and then, yeah, it's really hard to do. So dropout is inevitable. But at the same time, it really makes it hard to say with confidence to ourselves or our patients, we know this is how this drug works compared to a placebo for, you know, more than nine, months or a year if studies find that 90% of people drop out, that's probably more a reflection of real life than an indictment on the drug. But it does limit our ability to say, here's the

evidence base of using this atypical antipsychotic for, say, more than two years. We don't have that evidence base. So that is where evidence-based medicine sort of diverges into, this is as far as the data go, and now we have to extrapolate. And that's doable, but it's not the same as saying, I've got years of data. Yeah, and I think it's the same for diet studies, from what I've seen. It's like compliance was 40% on this diet. And then you look at what they actually ate. And it was like, oh, they were actually not following this diet very closely. And I wonder why the effect size is not great for this study. But, you know, if I could pick up on something you're just saying, David, about therapeutic alliance in a very tangible way, not a

fluffy, you know, way, but quite meaningfully. Something that we don't do in clinical trials is really try to engage the patient. In fact, in clinical trials, I've lived in the clinical trials world, in the practice world, you're actually trying to minimize the therapeutic alliance because that can inflate placebo response. So you don't spend a lot of time talking with the patient. You're kind of down to business. In real life, you know, studies try to minimize a placebo response.

Real life, we try to maximize the placebo response by doing everything we can. So whether or not you're formally doing a psychotherapy with a patient, you can certainly draw on some psychotherapeutic skills to try to engage in the process. And I like the way you talked about forecasting non-adherence in a very non-judgmental way. I'll go even farther than that. I will say to patients, look, most people at some point have a hard time staying with medicines. It's human nature. It's part of life for a variety of reasons. So I sure hope that if there comes a point where you're on the fence about sticking with this, tell me.

Maybe I can help. Very non-judgmental, but it's more against, sort of you and me against the world, that lets you and me figure this out. So rather than you're the last person I'm going to say this to, it's maybe the first person. Maybe I can come up with, you know, a strategy. I'll certainly empathize with you. You know, what a pain in the neck to take this medicine. It's got this side effect.

I was meeting with the patient this morning who had a really wonderful response with a metazepine augmentation, but she's having weight gain with it. I was saying, that really stinks, you know, I wish we had the perfect drug. She'd been on many other things that were not helpful. This was especially so. And I presented it, you know, together, Ardala, what do you want to do? And the first thing she said was, well, I don't want to stop the medicine. It's really helping.

Okay, fine. So let's talk about the options from there. And just, you know, sort of joining with the patient, I think, is a very key element in trying to anticipate the mediating effects of non-inherence. I can also empathize with providers who, you know, spent decades learning this stuff. And then, you know, we have this great plan and this person's not adhering to this plan. And then you're not getting the outcome you want based on your conceptualization of their non-adherence. So I think for the providers out there, it's like how do we have patience for the process, patience for ourselves, if we are for

frustrated, realizing that this is why probably frequent visits at first are good, especially if you're starting something new. You know, think about what I was thinking about was moderators are like on day one. You're trying to figure out when they come in what their moderators are to base your choice on what med you're going to start. The checkups are really an ongoing sort of assessment of the mediators. And of course, you're re-looking at the moderators if you're going to start something new. But the checkups, like you're looking at things like noncompliance, you're looking at things like, you know, do they have changes in side effects or, you know, are they having early response?

They're getting some initial good response from this med. You know, you're looking at these mediators. Not to mention life stresses. Two patients I met with today, both of them had deaths of close relatives. And what was interesting, these were both people that I'd recently started on medicines, and we were talking a lot about the difference between depression and grief and the ways in which they're able to sort of weather the losses that they're incurring. And both of them were saying, you know, this doesn't feel like depression.

This feels like sadness, which is normal. Yeah, like if someone, if you just start a med, and then they come back two weeks later, and then they've had a huge stress, well, of course, they're not going to be feeling better. Like, irrespective of if this med is going to be helpful or not. It's a big part of the totality, right? Even if somebody's had, you know, they lost their job,

they got sick, you know, COVID. So I think we're always sort of contemplating, let's call it stressful life events, once the treatment has begun, vis-a-vis how's the recovery from the ailment? Now, that's said, I'll add one more spin to this. And I have to acknowledge my friend Stephen Stahl for pointing this out. It talks about life being a stress test.

And you're not really just asking, so how are your symptoms and are you better and what's your rating scale? But rather, I'm really interested in how you do when you're under fire. Just like a cardiologist puts you on a treadmill, they're not as interested in whether you have chest pain at rest. They want to see if it's provocable, angina, under stress. And in a similar way, when something stressful happens, once a treatment has been. started. That's where the rubber meets the road. That's where I'm especially interested in your resilience because really good pharmacology or for that matter, really good psychiatric treatment I think doesn't just reduce symptoms. It tries to build resilience, which gives patients kind of a leg

up against potential mediators that could otherwise thwart their efforts. Yeah, I could see that, especially like if you look at like neurotic, like on the Big Five personality type, antidepressants have been shown to be helpful for people who are higher neurotic so we tend to think of people who are higher neurotic as their higher stress reactivity so our medications our treatment exercise diet all that stuff getting good sleep should decrease the effect that a given stress would have on someone so we we look at this as well in our partial program if someone gets restressed towards the end of treatment, how do they respond to that stress? And one way we've known that the treatment has been helpful is if they get restressed, like the same conflict with the boyfriend

that's been going on every time that sends them into a suicidal tailspin. Now it happens, and they're a lot more stable. Maybe they're frustrated, but it's not like they're suicidal. So, yeah, I see that. And you know, it can be so gratifying to point, that out to a patient. We're sometimes very cautious about pointing out improvements. But in that instance, I have to tell you, this bad thing happened to you, and you are sounding so different about how you're managing it now compared to a year ago, are you aware of your own strides that you've made? And if not, let me point them out to you because we're reflecting back what our observations are to the patient. You know, you're not as stressed. You're problem solving. You don't have tunnel vision

about this. You know, let's assume your executive functioning has improved so you can see alternative solutions for problem solving. The emotionality that was there before is not overriding your decision-making and you're presenting things in such a very methodical kind of way. It's, to my mind, a very wonderful confluence of psychopharmacology and psychotherapeutically informed treatment. Yeah. Yep, that's good. We should, I want to talk a little bit more about non-compliance You have here some demographic factors related to non-compliance, younger age, female sex. That was a surprise to me, actually. I would expect males to be less compliant.

But you put female sex, unemployment, higher levels of education. That's like, oh, maybe these aren't, are these all lower compliance? Like, does higher levels of education decrease someone's compliance? This is box 5.5, by the way. Thank you. I got to turns with the right page in the book myself. Partly wrote, partly I write books because I can't remember things. I have to write them all down. So there's a secret. So, you know, non-adherence varies across diagnoses. So many things vary across diagnoses. Side effects can vary across diagnoses.

Anxiety patients will differ than depression patients with the very same drug on things like sedation or insomnia or nausea. So that's sort of interesting. The demography here, I believe, is, this is in depression, right? So, you know, these are things that have been identified in the literature, some of the demographics around age and sex, social supports. Some of these may be intuitive, like, you know, adverse effects are a predictor of non-inherence, core insight, predictor of non-inherence. Some may be sort of proxies for severity, like early age. onset is often taken as a proxy for just severity of illness because early age and onset tends

to portend a more severe illness. And some of them, you know, like sex, you know, may or may not be robust findings. So I think one of the issues here, and this is probably particularly important for anyone who's, you know, sort of coming at this notion of moderators for the first time, is it's not like this is carved in stone. These are things that have identified in clinical trials that you want to be aware of. It doesn't mean that every female patient that comes your way, you're going to say, oh, you are in a risk group. No, no, no, no, I don't do that.

But in your head, you might make a profile. Gee, the next young, female, cognitively impaired, psychotic, poor social support, substance using unemployed, you know, women with depression that I see who's made a suicide attempt, you know, apart from saying, okay, risk for low adherence, this is also just a more severely ill patient. a lot of collinearity and crossover with things like non-adherence and severity, which makes it complex into relationships.

I think Max had pointed out before that a lot of these factors overlap. So it's not so easy to say, oh, you have this, this, and this moderating factor. That means that, that, that, and that. But rather, you've got a sort of a whole package. And to me, this is, I mean, here's what Max thinks about this from just seeing patients in the acute setting is how do you sort of conceptually put these things all together and sort of make a rank ordering in your head of risk factors, the same way we do with suicide. You know, in the ER, you always teach tick off in your head the risk factors for suicide, you know, severity of

depression, single, not working, poor social supports, prior attempt. Those are all moderators. You do the same thing when you're planning at a treatment plan, but I'm curious if you would transpose that same mentality of clicking off risk factors for suicide in an ER patient relative to predicting any outcome, good, bad or otherwise, pharmacologically. Yeah, I think we all do a sort of mental checklist when we're seeing a patient and we're going through these factors. And, you know, looking at, you know, just the poor medication compliance factors here, it's interesting to me that, you know, shorter duration of illness too is, is something that makes someone go off treatment because there's this, you know, they feel that they're

immediately better. They don't need to continue treatment. And then on the opposite side, when they're really ill, they're also more likely to discontinue treatment. We were looking for that sweet Goldilocks, middle population, I guess, with the best compliance. But, yeah, it's difficult with these patients, and there's lots of things to consider. And it's hard to keep all of these demographic factors in our heads. But I think with practice, they become more second nature. You know, for me, what's missing in this summary of non-inherence factors, to my surprise, is degree of efficacy of the treatment.

if I was just off the street being asked, I would think, well, I'm not going to stay with a treatment that's not working, right? I mean, why would you? And there's some data out there that speak to that. There was a DBSA study not too long ago saying that side effects and lack of efficacy with the two top reasons, depression and bipolar support alliance patients identified. But I think of response to treatment as a kind of a mediator, right? So if I'm on a medicine that's got a side effect burden or I'm questioning whether I still need it and I'm better, the efficacy is there, I'm going to rely on my psychiatrist or my health care provider to explore with me. Well, do you think you're better because of the treatment? You're wondering whether you still need it.

But what if the reason you're better is because of the treatment? And then we have to do kind of a risk-benefit analysis and decide, is it worth continuing? Much like the lady I mentioned from this morning with metazepine, who is quick to say, to me, no, I am clearly better with this drug, and I've been on a lot of others. I just don't like the weight gain. So, you know, she's not ready to ditch. And hopefully the therapeutic alliance is there that she and I can say, all right, you're a female. She's had a long duration of illness, but she's so much better. I often wonder how patients bring that into the calculus in their minds. I know I'm better. I'm confident to that. And so how does that impact you're

thinking about should I stay on the treatment? I think part of that is how. we educate them as well. Like when I give someone like an antidepressant or something, I'll be like, you're gonna feel better. Probably is gonna take three to four weeks. And just let you know, like, because this is your first episode of depression, usually we wanna wait once we get you better,

once you're out of the depression. From that point, we wanna wait about six months before we change something. I don't know if you do a, differently or longer? I do it exactly that way, and I use the fire analogy. I forget if we talked about this last time or not, but so, you know, picture an episode of a mental health problem as a house on fire, and the acute intervention is the fire department comes and puts out flames using whatever means of extinguishing, we think appropriate. Pick your favorite pharmacology, psychotherapies.

And once we got the flames out, we now say, hopefully all the flames are out, we say, okay, you are either responding to treatment, meaning you're at least 50% better than when you began, or you've remitted, better still, where any symptoms left over are minimal to none in significance. That's the acute phase, and then we go to what we'd call the continuation phase. That's sweeping up the embers. That's making sure we didn't miss anything. That's saying, you're better.

I don't want you backsliding. And that's a very high risk window for what you just described, David, about, gee, so I feel better, can I stop this now? Just like, you just cast in my broken leg. Can we take the cast off now? So we want to get people through that continuation phase. And studies would say that's about a four to six month window. So based on that, I'll say to people, your risk window for the fire coming back is about four to six months. If you're better, don't breathe on this regimen. wear the same socks and shoes every day, walk the same streets, change nothing, hold that pose. Because if we can get you to that mark, by month six, you are now declared recovered. That episode is now in your rearview mirror. It is in the background. And any symptoms that come along from this point is a new episode. And that's maintenance treatment. And maintenance treatment is we've cleaned up the fire. The fire marshal is inspected. There's no exposed wires. And now we don't

want to see a second episode. So I break it into those segments. And just, just as you say, once you're better, if you can hold that pose, the probability of a next event becomes less and less and less. Yep. I also might add what I do is I, if they have energy to make changes, at that point, I usually try to introduce more of the lifestyle stuff, exercise. Sure. You know, stuff like that, where it's like, hey, you know, do you remember back when you were in high school and you had no anxiety and you were on cross-country, it's probably because you're on cross-country. I'd be like, oh, yeah, I'll go run. And I'll be like, well, how fast are you going to go? They're like, just as fast as I was when I was in high school. No, wrong. We're going to get you,

a heart rate monitor. We're going to get you, keep you pretty low at first, right? So do it in a way where it's like not painful, where I'm not causing injuries and then slowly escalate over time. But It's that idea. Transition to you thymia. Or hyperthymia, ideally, right? Feel better than they did before. The new normal, you know, so you're not going to lie in bed until 11 o'clock in the morning anymore. You're not going to find yourself with unstructured time of the day. The lifestyle piece goes hand in hand with us. In fact, it almost would say, you know, we should fully expect that when you're feeling better. You know, what would you want to be doing that you're not doing when you're in the throes of a depression or otherwise symptomatic? And then plan for it. And this is, again, where the psychotherapeutic element interfaces with the psychopharm around behavioral activation, structuring your time, sleep hygiene, goal setting. Goes hand in hand. Yep, very good.

Okay. Another mediator is changes in cognitive function. And I think, Max, I think you had a good question about this. Yes. Yeah. from last episode you, Dr. Goldblert, you've mentioned a little bit about cognitive dysfunction and bipolar patients. And I see a lot of patients with traumatic brain injuries that our institution kind of colloquially calls frontal lobe syndrome, where patients, you know, have damage

to their frontal lobes from various means like drugs or schizophrenia or other, you know, genetic reasons, or just, you know, TBI. And how does. How does. cognitive dysfunction in bipolar look different from these other forms, if at all. I know you had mentioned that Pramapexol had an improved function in those patients. Can you share any other clinical pearls in that you found helpful for treating this issue? Yeah, so I think cognitive dysfunction is an often underappreciated correlate of many forms of psychiatric disorders. Patients may be quick to say, I think I have ADD. May I have a stimulant, please? Or I think I have dementia. oh my God. But as you as you point out, Max, you know, there are both moderating and mediating elements

to this. So someone with a significant history of, let's say, extensive substance use or TBI, or for that matter underlying medical conditions, chronic Lyme, the history of a CVA can be a baseline a fact that that's a poorer response to many things, and that's sort of to be understood at the outset. Post-stroke depression is much harder to treat than non-post-stroke depression. It's actually not a lot of literature, to my surprise, other than acknowledging how difficult it is. So if someone's starting out with a baseline substrate of cognitive dysfunction, it's going to make for a poor course over time. But then mediating-wise, if one does not see changes in cognitive functioning, persistence of cognitive deficits, either because of residual depression or because of adverse effects

of medication, or because of a comorbid undertreated executive dysfunction or ADD or TBI or anything you want to call it, we feel less good inside, less prognostically. You'd like to see changes in cognitive function go hand in hand. This is, I think, was nicely borne out in the studies with vortyoxetine, Roger McIntyre's work that showed, you know, really good response to that drug in major depression, seemed to go hand in hand with improvement in the cognitive symptoms of depression. So we look for that. And if we don't see that change or if we see residual cognitive problems, you know, poorer outcome, and it may need its own treatment. So I can say, you know, your sleep is better, your appetite is better, your energy.

is somewhat better, your concentration is not better, your motivation is not that much better. As I recognize that, I may not necessarily say, well, let's raise your SSRI. I mean, I might. I might say this is just residual depression. So I want to be sure I've optimized the dose of whatever I'm using. But if I'm parsing out in my mind, these elements of depression are better, but these ones are not, that might prompt my thinking about what more can be done specifically addressing the cognition. That might be pharmacological.

So one might contemplate things like stimulants or wakefulness promoting agents like armadaphanal, potentially dopamine agonist. So there's not a great data set with how to improve cognition, but Pramipixel, the D2D3 agonist that's used in Parkinson's disease has some limited off-label data in bipolar depression. And my colleague Kate Burdick, who's now at the Brigham, He's done a lot of work with this drug looking at its potential pro-cognive effects. In euthymic bipolar patients, she found that it seemed to help with social cognition and global cognitive functioning. So it's not like an, oh my God, this is going to get everything

back to baseline. But it may have some benefit for, say, a cognitively sluggish, inattentive, residual depressed patient where you're not necessarily invoking a comorbid diagnosis of ADD. And it's not necessarily going to compensate for a TBI or, you know, years of, years of cocaine abuse. So I think we have to do a very careful diagnostic assessment. That may include neuropsychological testing. Sometimes there's a role for pro-cholinergics. I've had some depressed patients who benefit off-label use of pro-colonergic drugs. like Denephazil, sometimes cognitive remediation can be helpful. But calling out sort of a standalone symptom is one of the elements that I think is an underappreciated contributor to disability

and mood disorders. Not sure if that fully answers the complicated question, but that's how I'd break it down. No, thank you for that. That was really helpful. Yeah, I think that a lot of what the Impatience sees at Loma Linda is like kind of more of the chronic frontal lobe dysfunction. That's just very hard to treat. It's not like you cure the depression. You're going to cure this issue. You know, it's like there's like 20 years of methamphetamines. Yeah.

That kind of stuff sometimes. It just makes it a lot harder to have good outcomes. And so I think the residents are just, it's hard work, you know. Sometimes you just see these people. over and over again. I do see a lot of that, you know, more chronic looking patients and especially in the emergency department and patient units. But in the outpatient world, I do have, you know, quite a few patients who, as you were saying, Dr. Goldberg, they have that improvement in their mood, maybe in their energy, but they're still that like 20% of their symptoms that are remaining and

they're looking for that final boost in their concentration or other symptom. Well, good for you for noting the distinction. You know, as you're sort of demarcating domains, you know, not just the diagnosis is better, yes or no, but this is better, that's not better. That may help you craft the tailored treatments. So you may, for instance, contemplate whether a pro-dopaminergic drug would be useful. So, you know, prime pexels. One example, stimulants are an example off-label use to target cognitive deficits, but there's, you know, there's some data. In bipolar disorder, there's one study with lorazodone, presumably through its 5HT7 antagonism effects.

That's been shown to improve global cognitive functioning in utamic bipolar patients. So, you know, there's a database there. If you're treating bipolar depression and you're inclined to use an antidepressant, one of the reasons bupropion is sometimes looked upon a little more favorably as it may help with some of the pro-motivational dopaminergic, presumably dopaminergic processes that go with inertia and sluggish cognitive tempo and slow processing. Armadaphanol has some off-label data for improving associative fluency and global cognitive functioning while treating bipolar depression. In people with bipolar disorder, the cognitive deficits seem to align along three lines.

attentional processing, executive functioning, planning, organization, reasoning, and verbal memory. So unlike schizophrenia, it's not like a global dementia type process where you see changes in motor processing or nonverbal memory or vocabulary or visuospatial memory. It seems more circumscribed. The magnitude of deficits is also less in bipolar disorder than in schizophrenia. And fun fact, cognitive deficits run in bipolar families. So my colleague, Dr. Kay Burdick from Brigham, has done studies and looked at non-affected siblings of bipolar pro-bands, meaning their mood is fine. But they tend to be a half of standard deviation below the normal population on measures of attentional processing. So it kind of makes you think part of what gets inherited isn't just the mood piece.

It may be a cognitive piece, which is sort of is interesting from a genetic. standpoint. You know, you're not just inheriting a categorical entity bipolar disorder. You could inherit many things. You could inherit attentional problems. You could inherit nocturnal dysfunction or circadian rhythm vulnerabilities. You could inherit impulsivity. You could inherit creativity. There's all these domains that we look at as clinicians and sort of judge their standalone presence like cognition and their interdependence with mood and anxiety. and thinking and so on. I like how you broke kind of your assessment

into three domains there. The attention, verbal, remembering things, and executive function. Yeah, yeah. Those three domains. And with schizophrenia, what meds do you, like if you were thinking cognitive dysfunction, are there certain meds that jump out to,

like close a being where you get excited about? I wish we had something to get excited about for cognition and schizophrenia is, you know, when the atypical antipsychotics came along and gathered some momentum, and then in the KD study, there was a great hope that we would start to see inroads in cognitive dysfunction. And, you know, the KD study was a real disappointment. It did not show, in I think Richard Keefe's analysis, it did not show improvement in cognitive domains with any of the atypical antipsychotics. I know no pharmacolism. strategy to improve cognitive function in schizophrenia. That's not to say there aren't things

that can be tried. It's just none has really stood out. I think avoiding anticholinergic, antihistaminergic drugs is one thing. So you mentioned closapine. The only drug approved for treatment resistance schizophrenia, but it's a hell of an antihistaminergic, anticholonergic burden, and we don't think of anticholinergic drugs as pro-cognitive. You know, that's an interesting thing that I brought up with Dr. Cummings. And he tended to think it still inevitably helped the cognition because the brain got you, because of the glutaminergic nature of it. In his book, he just wrote a book also with Stahl and Treatment Resistance, Schizophrenia.

He talked about for the negative symptoms, also thinking about something like Abilify. It can sometimes be helpful. But you're less excited, I hear about these. Well, I'm excited that it's an unmet need that's been identified. And given that there's not what I'd call a standard of care for how to tackle cognitive symptoms, you know, clinicians are welcome in my mind to frame a hypothesis and test it. So, oh, okay, so wait, I think, are we talking about, because in schizophrenia, I'm thinking like there's the positive symptoms, there's the negative symptoms,

and then there's the cognitive symptoms. Yep, yeah. So quickly for the audience, different. between the negative and cognitive. Are those the same things or different? There's a great deal of overlap. I mean, if you think of negative symptoms as deficit states or diminished capacity for normal processes, positive symptoms are in excess of normal processes. So I'm paranoid and I hallucinate. Negative symptoms are deficit. Flat absence of processing. That will dovetail in with slowed processing speed, inattention, low motivation. So we're

one ends and the other begins, it's a bit tough. I think it's harder to tackle the combination of slow processing speed, inertia, a motivation, apathy, negative symptoms, coupled with, oh, let's say, impaired working memory. You need both. So, you know, if you're a baseball player and you're on third base and deciding whether to do a suicide squeeze, it depends on whether you're in the bottom of the nine thinning with two out and the full count on the batter, that's a working memory task. You've got to be managing a bunch of things all at once, and most of us on a good day can't get halfway there. But you can't just run home when the pitcher throws the ball. You've got to be holding in mind those things. People with schizophrenia have

markedly impaired working memory, much more so than in bipolar disorder. And we test that in the lab with things like the end back task. We have to just remember things. Remember that old game concentration where they'd show you two like the memory game where two different animals or something right right so you have to remember where these two boxes yeah I hate I hate that game

I have terrible working memory my son who's five can beat me at the game like as hard as I try he's five years old he can beat me at the game he's full of neuroplasticity and that's a good that's a good prognostic but but so that's a very

difficult task to do if you have schizophrenia where we have to sort of hold things in mind. And that's evident, you know, even in pro-dromal phases. That may be part of the hardwiring of the illness. Now, after the illness has come along, if deficit states start to compound it, you have this sort of double whammy, which is I think, you know, frankly, my own opinion is as bad as positive symptoms can be. The disability, the A-motivation, the demoralization, the suicide risk,

much more comes from the negative symptoms. We don't have very good treatments for them. And if you put the two together, it's just harder. So you've got to have the motivation and the drive to be able to pay attention to the task of, I'm on third base with two out and the bottom of the ninth and so on. The best, I have one higher functioning schizophrenia patient who was homeless at one point. Now he's, now he's in a graduate school, actually two different graduate schools at once, doing really well on clozapine pretty high dose you know still still has symptoms once in a while

and they always happen at night so we have a sleeping med he takes if he has symptoms he takes sleeping med goes to bed wakes up much better he's actually on some concerta during the morning and we found that that made all the difference for him and made him do an agreement with me on the dose if he does any other substance, then I decrease the dose the next visit. So it's kept him also sober off of other substances, which are causing him issues. I'm trying not to go into too many details here, but I'm pretty happy that he's doing well. I know it's not always the case, but it's been fun to follow him for a good decade now. And there is a literature on stimulants, both amphetamine and methylphenidate,

for negative symptoms in schizophrenia. And just looking back in the old book here, the effect size, I think, is a medium effect size. You wouldn't want to give it to somebody with flagrant positive symptoms because of the risk, obviously, for a psychotomimetic effect. And again, this is off-label use. Yeah, and I would add, when starting, seeing him once a week, I was actually seeing him for, you know, full visit, 24. five minutes. So got a real good, and pretty close to the parents. So, you know, you do these things under close, close observation. Good. Yes, indeed. And you're tracking. And just as you say, you're not just sort of saying, let me open up the spigot, here you go, and feel free to take it as

needed. But, you know, there is some limited data with amphetamines. Lysdex amphetamine came close to pursuing an FDA indication for negative symptoms. and schizophrenia, there was some positive data, but also some negative data. And then the patent died, and that was the end of that undertaking. So on a practical level, let's be practical, I think it's useful to try to tease apart things like cognitive impairment, memory-wise in particular, from attentional problems, from negative symptoms, from depression. Some clinicians conflate negative symptoms with just depression. And depression's a very feelingful state.

You're sad. There's affect. There's facial muscles moving and there's an emotionality to it. Whereas flat is the absence of emotion. In that sense, there's a deficit in processing. I also think, like, dopamine blockers I've seen make people more flat in their face. You know, obviously because it blocks like dopamine, almost. Secondary negative symptoms, as they call.

and which we think is where atypicals should work better. So, you know, people did look at things like Aripiprizole. The partial agonists, I think, you know, certainly suggest themselves as maybe having value above and beyond pure dopamine antagonists. So Carriperzine, Ariaprizole, and Brexpiprizole are all D2D3 partial agonists. They all do treat the negative symptoms subskill on the pans in the schizophrenia trials. So that's encouraging. Not with a gigantic effect, but better than placebo.

But that's not the same as saying, and now you can do an end-back task and score better than before. Yeah, so this is the nuance that I was missing. Thank you for that. And, Max, I think you were asking about olanzapine and phloxatine combination, OFC? Yeah, I was wondering if you know about any data that might suggest that helps improve cognition for schizophrenics, like similarly that we're hoping clausopine might,

I know that clausapine has all those other issues we talked about. A good question, short answer, I'm not aware of data with it, but I'm also not sure how much, you know, that one of the things I like to say to people is, I don't know, but I can look that up. That's a good one that I have to look up and see if anyone has done, even a preliminary study of OFC targeting cognition in schizophrenia patients. there was a study in treatment-resistant depression that my friend Lauren Marangel published some years ago

looking at this is slightly different than what you're talking about but looking at the kind of indifference state that people talk about with SSRIs is sort of an apathy it's not really depression it's not residual depression it's more sort of a just indifference numbing numbness yeah I hear that a lot for my patients and so Lauren Marigel had a paper in the journal of Psychiatry, early study of OFC showing, I forget the rating scale she used, but there was some uptick in motivation and drive when elancipine was added to fluoxetine. And she argued, this is at the beginning of when we were very excited about the atypicals, is that by blocking 5H2A, as they all do, you increase prefrontal dopamine. And so part of the reason why we all

thought and expected and hoped and crossed our fingers that atypicals as a class would have a pro-cognive effect is that 5HT2A blockade and the prefrontal cortex should raise dopamine exactly where you want to raise dopamine if you like a methylphenidate-like effect only it's selected for the prefrontal cortex I don't know that that's really panned out and some of it is maybe expectancy bias on our part that is I'm giving you a 5HT2A antagonist That should help your attention. Laura Marigel showed that it improved motivation in flattish SSRI recipients. But I have been underwhelmed by the extent to which any atypical has meaningfully produced the result of someone with schizophrenia saying,

you know, I am going out tomorrow and I'm pounding the pavement and I am just going to, you know, throw myself into this project. Yeah. So I think that's still an unmet need. Right. The one thing when I think about cognitive dysfunction in general, it's like what what do we think of as like long-term best life-changing outcomes for people, right? Is it medications, you know, for cognitive decline, preventing dementia? Probably not. I don't see any drugs that excite me that much. It's like exercise. I've personally been on Well, I would say underwhelm.

I have colleagues who are very fond of the notion of low-dose lithium as a neuroprotective agent that may help reduce the risk for cognitive dysfunction over time or dementia. Some of our prominent colleagues routinely advise low-dose lithium. You know, there's some data that it may have some value in minimizing risk for dementia by virtue of its neuroprotective effects. I'd like more data on that. I fully agree that people who are maintaining an active mental life and keeping themselves mentally challenged fair, better than those who don't.

I'd also add that recurrent mood disorders are a risk factor for dementia. So you will do your brain a favor by not letting it have multiple depressions. Yeah. Yeah, that would be the key thing is like, why? I talk to patients about that with completely. clients, I say, look, the goal now that you have a psychiatrist is that you never enter into another episode like you did before. So you're going to tell me early when you feel it when you're feeling worse, we're going to work together. Because yeah, there is residual damage to your brain

if you have a manic episode for 10, 15 days, you know, it's like, or psychotic symptoms. And more begets more. Just like I was saying, you know, the longer you're well, the longer you're you stay well and hold that pose, get your six months down, they get into maintenance phase, in part that's to reduce relapse risk. But also the less, people would say that prominent psychiatric symptoms are this very pro-inflammatory, non-neurroprotective state. Nothing good happens in your brain in terms of synaptogenesis or neuroplasticity when you're hallucinating, when you're psychotic, when you're having uncontrolled panic attacks, when you're having, you know, depressive episodes.

So we can only make things better by minimizing this. And it's not just the pain and suffering of a depression and getting you back on your feet now. It's to really try to spare your brain from, who knows, oxidative stress and free radicals and the neurotoxicity of mental illness. Very good. Max, any follow-up questions there? none that are jumping out of me. Thank you. I'm just enjoying the discussion.

One thing, I found this little article here. I'll show you. Resistance, training, and executive function, 12-month randomized control trial. This is one that I found that I really liked. They followed a single-blinded randomized trial of 155 community-dwelling women, age 65 to 75 years old in Vancouver, were randomly allocated to once weekly or twice weekly resistance training or twice-week balance and tone training. That was a control group. The primary outcome measure was the Stroop test and executive cognitive test of selective attention and conflict resolution. Secondary outcomes of executive cognitive function included set shifting as measured by the trail making test, part A and part B, and working memory as assessed by the verbal, digital span forward and backwards test.

Gate speed, muscular function, and whole brain volume were also secondary outcome measures. So the results were that both resistance training groups significantly improve their performance on the Stroop test compared to those in the balance and tone group. task performance improved by 12.6% and 10.9% in the once-weekly and twice-weekly resistance training group, respectively a deteriorated 0.5% in the balance and tone group. Enhaned selective attention and conflict resolution was significantly associated with increased gate speed. Yeah. Well, I think the thing that I took away from the study was that some of these frontal lobe functions, cognitive functions, improved in this strength training

group pretty significantly where there was a slight decline in the other group. I think my point is that part of the full armatarium of what we have to treat the cognitive decline is to use our powers of persuasion, our powers of compliance, right? Getting people compliant on a plan that's going to move them forward. And also our clientele, especially the serious mental illness population, you know, tends to not work out at the gym. They don't have the best diets. They often smoke cigarettes or other things. Substance use carries its own neurotoxicity. Thinking of a particular patient who was very heavy cannabis consumer and was complaining about low motivation. And I found myself, yeah, that happens. And you know, you're making a choice.

I want to make sure you understand the choice you're making. You know, if these are the things you find beneficial about heavy cannabis use, you know, you're paying a price for it. Dr. Goldberg, marijuana only does good for me, okay? You're not understanding. You're informed by drug companies. You're paid off by drug companies, Dr. Goldberg. Marijuana is what has kept me saying through all of this, okay? Actually, I'm informed by this study in the Proceedings of National Academics.

of science is that I just keep nearby on my desk for people like you, was the study from Danaden that followed heavy adolescent cannabis users over the course of 10 years and found a significant decline in cognitive functioning. And back in the pre-COVIDs when I was in the office, I had copies of this paper. I'd hand it to the patient. And I'd say, you know, look, I don't care if you believe me or not. I'm here to give informed consent, right? So I need to make sure you know the data. Those people were paid off by the drug companies. You know that and I know that. Right.

Well, look, I cannot argue with you if your mood is fine and all as well. I just have to ask one thing, which is why are you coming to see me? You know my mom forces me to come here. I won't get my allowance of $10,000 a month if I don't come here. Right, right. Yeah, that's a slow walk, that one. You know, part of what we're trying to do. to do is I guess use a cognitive approach in helping patients recognize, is there something

that they want for themselves? If what they want for themselves is blessing that it's fine to use crystal meth or, et cetera, yeah, I don't know a strategy around that one because the only way I know to get at these sorts of dilemmas is, you know, what do you want for you? And if what you want for you is to get your mom off your case, you know, I'm not sure I can be helpful to you right now. Yeah. I had a patient once who called me this real, to say, it was a prospective patient. They were saying, can you help me because I find when I take this antidepressant, I can't get the same buzz from alcohol. And I really like to drink a lot. So could you help me get off my antidepressant so I can go back to heavy drinking? I didn't know how to answer that

question. It sounded like alcohol use disorder in remission successfully treated with depression and permission, and he wasn't happy with the result. So we're always asking patients, you know, what do you want? What are you looking for? And the answers can surprise us sometimes. They may not correspond to what we assume they're looking for. My favorite was the giveaway when I asked him how he made his money. He said, oh, I sell bongs. And I was like, oh, you're, you have ADHD and you sell bongs. Tell me, do you smoke marijuana? He's like, uh, occasionally. I'm like, oh, tell me some more, like how many grams a day. He's like, well, I grow, so I have like 15 plants.

So I don't really like measure how much I'm consuming a day. I'm like, well, you know, that's probably like why you're having issues with focus and attention. And he's like, oh, no, no, no, no. The strain that I use increases my attention. I was like, well, I'm not going to be able to prescribe you, you know, an ADHD. medication if you're good yeah and i'm just going to say you know joking aside this is a real dilemma when someone is really wedded to a personal belief um and looking for affirmation that that is contrary to let's say science and wisdom a patient who came to me was convinced that the only thing that

helped his depression was was oxycodone uh and his last doctor was you know happy to prescribe gobs and gobs of it and then yeah i don't remember what happened to that last doctor but this person was befuddled that i did not subscribe to that point of view and then went on to say you know so you mean you're going to let me suffer when i found something that can work for me you doctor goberger are going to and it's it's such a dilemma because you end up saying look you know all i can do is give you my opinion and my take on what the science says and you know we may not be able to work together if we are cross-purposes. Yeah. Yeah, I usually just give them their money back and say, hey, like, here's your co-pay back, here's your cash payment back if they were a cash-pay patient.

You know, I think you should go back to your last doctor, you know? Maybe that's, I don't know any other doctors I can refer you to that are going to practice that way. So I got to ask you this, and I'll be curious what Max thinks from the residence perspective, the words that come to my mind in these scenarios are motivational interviewing and the extent to which we are trying to bring the patient to their own conclusion of something that they're not happy with and the ability to recognize that the thing they're doing is contrary to what they state their goals are. I find it both incredibly empowering to think that you could try to do that as a mental health clinician. I also find it's one of the hardest things to do is to sort of help the

patient arrive at their own conclusion that they're shooting themselves in the foot. I'm curious, actually, in your program, you know, how does MI come up in these sorts of scenarios? We were talking about not adherence. We're talking about please sign off on my substance use. We're talking about, you know, maybe personal idiosyncratic beliefs about medicines. And users are trying to persuade patient of a certain point of view, but you can't really persuade him by hitting them over the head. You have to get them to come through their own conclusion. Does that come up in your realm? Absolutely. You know, the substance using population is actually a population that I'm passionate about. I really like addictions and this comes up a lot. Patients seem to think that oxycodone helps with

depression for some reason. And, you know, we got to guide them in the right direction. And usually I start by asking, you know, how, why do you like the substance and what does it do for you? And I try to ally with them and figure out what they're seeking. And, and then I try to actually use something that helps that, helps that, that issue, you know. And I try to, you know, tie in some psychoeducation about, you know, oxycodone. It's not really working towards that, that end goal that you have. And there's some other things that we can do. What have you tried? It's a lot of role. with resistance, certainly with the initial stages and getting them to buy in. And oftentimes, they won't. And you got to hold that personal boundary and help guide them towards health. But

sometimes they don't want health. At least the health we're offering. Such a conundrum. I can picture myself sitting with someone. On the one hand, my neuroscience brain is saying, don't you realize you're down regulating dopamine in your reward pathway? And of course, you're going to be anodon. and you're going to be depressed, and you're going to think you need more and more, where you need a stimulant or some dopamine agonist because you're down-regulating dopamine. And then the other part of my brain says, I don't know that my words are going to have any meaning. It's not quite the same as when I go to the internist and want an explanation about my cholesterol because there's an emotional investment in what they're doing.

And that's, I think that's the challenge is you could sort of come at them with facts. You could say, well, look, I can only tell you what I think. I'm happy to give you, here's the paper from whatever journal or I can cite literature, I can invoke evidence-based medicine, but at the end of the day, you have a really strong emotional investment in this. And if that's something other people see as a problem, but you don't, you're kind of in a crossroads. And I guess I try to think of it as how are you the patient going to deal with this? Because after we leave here, I'm going home to my house.

You're going home to yours. what are you going to contend with when you go back home? Is it just getting your mom off your back? Or is there anything you can point to that's a negative about this? The cost, the time spent, you know, when you think about substance use disorders versus use, it means you're taking time away from your work, from your school, from other things. It's taking its toll on your life. And you're trying to engage their pre-contemplative nature to just recognize, yeah, it's true. I'm not showing up at school. Yeah, it's true. I'm in my room all. getting high and not really interacting.

That ambivalence there. So I had this patient who was in and out of partial. And one day she went to the ER and Friday, Friday evening for abdominal pain. And she got dilauded. And she comes back to me on Monday. And she says, Dr. Puter, I found what helps. It's dilated. It got me through the weekend.

And we looked at how, like, opiates actually do soothe attachment dysphoria. Like, there's studies of rats and, you know, kids, kid rats that are on opiates seek their mother less. And so there's this kind of, like, theme that I see of opiates decreasing attachment dysphoria. And so she had borderline per size disorder. This was, like, the soothe of the weekend because she was in partial five days a week. and come Friday it was a disaster because she had to wait a whole weekend to get back to the therapist to get back to her surrogate mothers and so kind of explaining this to her and why I didn't think this was a good option for her because of the addictive nature there's hypersensitization to pain with cold pain with opiates there's also hypersensitization to depressive symptoms in studies and how like initially, yeah, it does soothe, but then most of the chronic opiate addicts are in bed.

They're not interacting with the world much. I've had a lot of opiate addicts who come detox, and they've had 10 back surgeries. They detox, and then they're like, yeah, I'm not spending the day in my bedroom anymore, just lying in bed. I'm like actually, like, wanting to engage human beings. And, you know, that kind of cognitive knowledge,

and I think my therapeutic alliance with her staved her from a pretty bad, bad of addiction. But I think that's why our patients are allured into these very powerful drugs. Hitler was allured into using, I think opiates caused them issues when the supply chain

was harder to get it. But, you know, it's very, it solves a problem initially very well, which is why they end up using. but then creates other problems. Yeah, so as mediators go, I mean, I wouldn't rank order them, but I've been doing this a long time. I don't think I have ever in my career seen someone with an active substance used to sort of get better from a comorbid psychiatric ailment. You say that with pain on your face for those who can't see them.

Real pain. I mean, you feel a lot of pain for these people because you want them to get better. I have great empathy. I mean, one of my messages I hope to impart is, you know, I'm not here to be judgy. I'm here to try to help. And when I hear, you know, I'm thinking of a patient I was referred to some years ago who was shooting heroin and was depressed.

And, you know, the poor fellow's internist was saying, can you help him with his depression? And I wasn't exactly going to say, no, I can't. But I also wasn't able to say, yes, I can. I was like, nothing is going to move with this. And this individual was so wedded to the heroin. There was no ambivalence. I couldn't find a thread to pick up. Is there any element of unmanageability in your life?

Any downside to this? I mean, he was well-funded. And he ended up getting undercarditis from shooting. And he ended up having open-heart surgery and valve surgery. And it was very, very difficult because his well-meaning primary care doctor was going on about, if only you could treat his depression better, Joe. Dot, dot, dot. Maybe he wouldn't be using the heroin.

And it was just a no-in dilemma. And I was saying, I wish you were that easy. But, you know, I mean, the addiction has just so taken hold. I know no treatment that's going to help this fellow while he's using. And like, so you're giving up on him? No, I'm afraid he's giving up on himself. Right. He doesn't want to detox.

And, you know, last year there was like 100,000 deaths largely from fentanyl, but opiates, you know, overdose, accidental overdose. one of the big issues that we're facing is, you know, drug dealers do not know how to dose fentanyl. Well, so people take too much. I've had a number of patients who have had dead relatives. And I don't think there are suicide attempts largely. I think they're like accidental overdoses on fentanyl because you just can't dose it. I was talking to a fentanyl addict in the CD unit one day about this. And I said like, don't, you know, because in my logical,

brain, I was like, hey, people are dying from this. He's like, actually, Dr. Peter, but all due respect, when people find out there's a fentanyl death, they go and they try to get some more of that batch because they know it's going to be a really strong batch. And, like, my mind is, like, blown. I'm like, wait a minute, like, you're not running away from that drug dealer. Like, you're actually going to get that because you want that high. Like, this is like, okay, wow. I'm like, well, what do you do to not die? Is like, I do, like, a micro test. just of the thing to see how strong it is, you know. It's tough, man.

I knew someone once who carried Narcan on his person with a little note saying, if I am found unconscious, look in my back pocket. I mean, I guess you could say that that's an informed approach if you're going to play Russian roulette. But, you know, as we're talking about factors that can influence for better or worse treatment outcomes, you know, as we're talking, I'm thinking more that mediators can really be demoralizing. for both the patient and the clinician. It's one thing if I can say on the moderator's side, all right, you've got history of childhood abuse.

We need to come up with a psychotherapeutic way to address that. You've got a comorbid anxiety disorder. We need to have a way to address that. You've got this family history, and so I want to be mindful of that. But, you know, in terms of the things in the world that are out there that could just completely derail your recovery that will entice you. you know i i can manage side effects that's by comparison a whole lot easier but um you know

substance use which is you know neck and neck with anxiety disorders as the most common comorbidity and bipolar disorder and treating their bipolar disorder doesn't make their substance use go away it's just it is among the hardest situations i've ever encountered to try to treat holistically yeah and i think i think you're absolutely right like we can we can come at our patients with data, it doesn't necessarily help. I think going back to what Max was saying and how Max has picked up some of the psychotherapeutic skills for me. I teach most of the psychotherapy with Dr. Tar over there at the university still.

And a lot of what we emphasize is connecting with the individual, trying to find what their goals are, trying to align with them in their goals. and occasionally I would say three patients. I've had to walk out the door because we had a complete disagreement on, you know, the way of prescribing meds with their substance use on board as well. So usually it's finding those connection points, finding common goals and trying to work with them. Interestingly, in our IOP program that I run, we'll bring in someone if they're smoking marijuana. they're we'll bring them in and then we'll a couple weeks in once we have a good

therapeutic alliance then we start to get them off of it but we try to connect with them first and we found that to be very successful other programs i know they won't let people in who are using substances at all but we found that we can get people with if we if we connect with them first we can get them off once they're connected in the group they don't want to give up the group so at that point that's when i send them into detox if they're on like opiates and I feel like it's interfering with treatment and they don't need it for something we'll send them in for detox but usually we try to build the connection first it's sure not a one and done proposition and um you know I guess in terms of therapeutic

alliance building one can plant seeds along the way like you know this is a really hard problem um I will you know I will be there with you as best as I can be but You know, this is pulling things down. You've been on these low, many medicines that haven't helped. We can't really write them off because you've been taking pro-depressants with antidepressants. And so, you know, it's like, I'm the fire department, but you're the gas company. And so you're pouring incendiary on the flame, not you, but, you know, the comorbidity, the illness, the substance use. You know, it's for all we know, this medicine would work a whole lot better.

in the absence of an incendiary. Yeah, and sometimes I'll also say you don't know. Your patients won't tell you. Two years in, I remember one patient, they told me they were drinking a bottle of wine a night, and I was blown away. I was like, I did not see that coming. This is someone I saw weekly.

They had hit the level of addiction for that long. So as you keep working, sometimes when patients aren't getting better, that's when I, nowadays, I'll reevaluate, like what am I missing? Yeah. And I'll sometimes do that with the patient, again, sort of in the joining with you, you know, so you and me are in this together.

Things haven't gotten better. What are we missing? You know, can you think of anything? Have you missed any doses? Are there any particular stress that's going on in your life right now that we're not paying attention to? Smoking weed again. Bulimia is another one that's been, I think people have a harder time getting better if they're actively throwing up multiple times a day. It does cause problems of its own as well.

Comorbidity, just per se, I think, is, I don't want to say it's underappreciated, but when we talk about treatment-resistant primary disorders, it sometimes feels to me a little disingenuous to not acknowledge the reality of an individual patient who has more than one disorder. You can't just say this is treatment-resistant depression with bulimia, with PTSD, with OCD, with cocaine use disorder. This is a complex presentation of multiple ailments, and to just treat the bejesus out of their depression, right?

It doesn't work. Sleep apnea is another one for me. Like, if that's ongoing, it's going to be hard to treat the depression. They're not going to be high energy if they're active sleep apnea. Any other big ones that jump out that get in the way of treatment? So sleep apnea is one for me. Well, you should want to miss medical comorbidities.

And here, let me just remind all of our listeners that whatever your medical training is, whether you're a psychiatrist or a mid-level practitioner, you never want to lose sight of that. Gosh, I was treating a patient once with resistant depression. And it just occurred to me to check a TSA. And it was like 70. Yeah. So, yeah. Or, you know, you just hate to miss something that could be masquerading.

Yeah. So I think we never want to lose sight of our medical mindset for things, or for that matter, what's iatrogenic? So a patient who's on a, you know, you always sort of backtrack, play detective. Did a new medicine come into the picture? Is there a drug interaction that's going on? are you taking something that's an inducer of the drug? So a patient who was on something doing well and started relapsing. And they went on primadone, unbeknownst to me.

And that's a very potent P450 inducer. And so they were probably getting a lot less of whatever I was prescribing for them. So the detective work, I think, with these moderators and mediators is, you know, sort of play Columbo. Just saying, you know, something doesn't add up. And think out loud. I love to think out loud with the patient. I find it, I find it's helpful for the alliance. It helps sort of the me versus you approach.

It's more like, you know, let's think this through together, solving a puzzle. And there are times we hit on something that's very empowering. And the patient gets co-credit for the idea. Well, another moderator is if they have had like a ruin why. I don't have you seen that a lot in your practice, how that affects your choice of medications, I would be curious. Possibly even gastric sleeves in terms of absorption and with long acting drugs and dumping syndrome. Or I had a patient who had unrecognized malabsorption syndrome. They were on a bunch of valproate and not getting better. I mean, just a gigantic dose.

And I ended up measuring a free valpropic acid level and the unbound fraction was very high. So they just weren't absorbing. And you know, you always want to think. think about any and all possible factors that could interfere with an optimal drug response. The Therapeutic Alliance itself is another one, too, right? So, you know, this drug worked better when Dr. Sharman gave it to me, but now you, Dr. Puder, the same drug doesn't work as well. How can that be? So there are, you know, all these parameters that may come into play that we're not aware of. one that you mentioned in your book was neds added to lithium can increase 20% the levels

due to the arterial constriction yeah or thiasi diuretics or you know if i inadvertently cause you to have a side effect because i've added something that's let's say an inhibitor of the enzyme that your medicine goes through so again i think you'll never be faulted for taking the detective approach and just thinking out loud, together with the patient, what could be interfering with response? Of all these things, though, I would have to say that shaky adherence is probably, if I had to guess at the top of the list,

in bipolar disorder, it is the number one reason for relapse. And before we start rethinking the wheel and saying, well, let's pick a new medicine. This is why I like to forecast for patients in advance. Many people have a hard time staying with the medicines. I have hard time finishing an antibiotic prescription. And the last thing I want to do is, you know, tell that to my doctor, but this is not the confessional. So, you know, for heaven's sake, if it comes to be that, you know, you're missing a dose here and there, if you can let me know that, you know, we might be able to have to work around.

We can pick medicines with longer half-lives. You know, that's why we often pick fluoxetine and depression because of its norfoloxetine long half-life. Kriperzine has two active metabolites, the half-lives of which are several weeks. So it's almost like giving a long-acting injectable because of the long-half-lives. There are long-acting injectables. And so these are all factors that we can in our head think of in choosing. You know, if you tell me your adherence is not so good, I'll give you philoxetine, but I'm not going to necessarily tell you, well, it's because your adherence is not so good.

Right. It's not that important. I tell you that as much as I think this drug could work better for you, for among other reasons, if you happen to miss a dose or two or three, doesn't matter. Okay, Max, any dying questions before we get off? Yes. You know, I was wondering, you mentioned EEGs and inflammatory markers that could maybe moderate the treatment response and depression. And I was wondering, is that something that you would get like as a routine study when you're aware that it could be, that it could moderate the treatment?

or is this something that is like that you would have as supplemental from other neurology consults or things like that? Right, right, right. So I think these are good examples of potential biomarkers that are not quite ready for prime time yet. So, you know, there are some preliminary studies that speak to, gee, if you have a high C-reactive protein, maybe you'll do better with a tricyclic than an SSRI, for instance. That doesn't mean, that one study doesn't mean go out and do C-reactive protein. CRPs and everybody and routinely take it up. We need replication, we need larger sample sizes, before we're going to be able to incorporate that because of, it's a preliminary finding. It could be a type 1 error. It could be a proxy for something else. But some of these biomarker

studies, whether it's EEGs or inflammatory factors, I think, you know, are ways of helping shed light on the systemic nature of psychiatric ailments. It's not just patient's subjective experiences. there's measurable phenomena that we have. But as far as how that's going to guide us yet, I think that's still not necessarily ready for prime time. Pharmacogenetics might be another example. I sort of have a lively debate around this, that there are times where it can be useful,

particularly if you're concerned about trouble with tolerability or inability to break down a pro-drug to its active metabolite. You keep giving somebody a 2D6 substrate like fluoxetine or venerable. They're not getting better. Maybe they're a 2D6 for metabolizer, and they're just not going to make the active metabolite. But I don't think we have any biomarkers that are going to directly inform us about this treatment versus that. So pharmacogenetics may be the closest. I used to do a lot of genetic testing.

And then, yeah, that was one thing that I realized if they had issues of 2D6, putting them on like death venlofaxine, worked a lot better than venlofaxin. There's a reason why that's always in the green bin. It's metabolized. Nowadays, I just look at what they've reacted poorly to. And if they haven't, you know, if they were having issues with venlo-faxine, increasing the dose past 75, having some sort of side effects, palpitations, or hard stuff, that would be like, it's probably that. Yeah, so these are useful, I think, in various ways, tools.

I saw a patient not long ago was on fluvoxamine, wasn't getting better. her foxing was in principle a good choice. Ended up pharmacogenetic testing showed that she was a 1A2 ultra-rap and metabolizer. And so you do a little digging in literature. It turns out in body dysmorphic disorder, there is some preliminary data saying that a fluoxetine level over 85 correlates with the response. And so I'd suggest it to her treating doctor, you know, look, she's a poor metabolizer. She's already at 300 milligrams.

Why don't you check a level and see if it's under 85? And if it is, given that she's a PM, poor metabolizer, raise her dose past 300. Oh, I couldn't do that. I couldn't do that. She's a rapid metabolizer, if that's what you mean, right? You said rapid metabolizer and then you said poor. Ultra rapid. So she's gobbling it up too fast.

Yeah, so you can raise the dose higher. So raise the dose. Oh, no, no, that exceeds the manufacturer's recommendation. Well, but the science doesn't really follow that. If she's an ultraab metabolizer. Yeah. I've had to call and speak to pharmacists who don't want to give. stuff and the blood levels is like the evidence i think the strongest evidence blood levels um i'd much

prefer blood level than trying to guess what some person's genetic profile is going to do you're trying to build a story and it's not arbitrary you wouldn't just say well you're not getting better with maximum dose full of oxymine try something else without using some of these kinds of tests to corroborate your hypothesis yeah that's good hey well i know that you have um a date with your kiddo pick up time pick up time and uh i do have another resident who wants to get you back on to go over your side effects of medications book so we'll have you back hopefully in the future to go over that always a pleasure david anytime i have gotten a lot of appreciative comments from our last episode so thank you so much for your time coming on educating the masses here and uh yeah it's

good to good to see always a pleasure max thanks for joining us i really appreciate your input as well. Thank you. Yeah, today was a pleasure getting to meet you and chat with you and learn more. So thank you for the opportunity. Fun stuff. Cool. All right. Till next time, folks. Take care.