Psychiatry & Psychotherapy Podcast - Q&A with Dr. Michael Cummings

Episode Date: April 5, 2024

In this episode, we welcome back fan favorite Dr. Michael Cummings and ask questions sent in by listeners. Topics include Schizophrenia, Social Media Trends, and the SSRI controversy. We are thrilled to dedicate an episode that allows individuals to ask pointed questions and glean from Dr. Cummings' expertise.  By listening to this episode, you can earn 1 Psychiatry CME Credits. Link to blog. Link to YouTube video.

All right, welcome back to the Psychiatry and Psychotherapy Podcast. I am joined today with Dr. Michael Cummings. He is a, I would say, a pivotal person in this podcast series and his deep dives on psychopharmacology. And so I sent out to my email list. If you have gone on my website and looked at the extra resources, you are on my email list. And so I sent out, please send me your questions. And I will pitch them at Dr. Cummings. This is a cornucopia of questions. It's all over the place. If you like this, you can let me know, and if you want to do this again, if we get enough of those positive things, we'll do it again. So here we go. You ready, Dr. Cummings? Yes, I am. Happy to be back, and we'll see what happens. Ask, it was a lot of different areas involved. Yeah, and some of these will be rapid fire. Some of them maybe we'll speak more to. And, uh, I asked people if they wanted me to list their names or not. So if I do, I've gotten their permissions.

And, okay, so we have no conflicts of interest, me or Dr. Cummings, to report. Here's our questions on schizophrenia. Anonymous listener from Iowa says, I listen to all your podcasts and repeat them. I've learned more from you than my professors. Please speak about treating with the too long acting injector. I have a patient with severe psychosis who absolutely will not take oral, have cases that become

life-threatening because the patient believe food and medical treatment are contaminated and refuse them. These are individuals in psychiatric facilities long-term. I've had people on how-all-200 milligrams every two weeks. I've worked with flu-fenazine injections, but I've never dosed more than 75 milligrams every two weeks. Thank you. Okay, essentially this question deals with the issue of polypharmacy. There's nothing inherently forbidden about giving too long-acting injectable antipsychotics. The question is whether the combination is rational or irrational.

The first step, of course, would be to check the single antipsychotic to be sure that it is optimal, while dose can tell you something about optimal treatment, it's very limited because of the variation people have in a rate of metabolism for drugs. The better way to assess optimal treatment is to measure the plasma concentration. For example, haloperidol has an optimal range of two to 18 nanograms per milliliter. Flufenazine has an optimal range of around one nanogram per milliliter to four nanograms per milliliter. So first step would be to check to be sure that your single drug is optimal, usually in a resistant patient, meaning near the upper end of the optimal plasma

concentration range for that drug. If the patient fails to respond adequately to an optimal single agent, then the next step is to look for an agent that offers complementary mechanisms of action. For example, combining haloperidol and flu-finazine would make very little sense because they offer essentially very potent D2 receptor antagonism, but not much else. An example of something that would be a more rational combination would be haloperidol and olanzapine. In particular, olanzapine at its higher plasma concentration range, 120 to 150 nanograms per milliliter, begins to give you modest glutamate modulation in addition to dopamine blockade.

So combining that with haloperidol could give you robust. Just D2 blockade plus at least a weaker version of glutamate modulation, that is weaker than Clozapine's glutamate modulation. Such a combination in oral form has indeed been demonstrated to provide modestly superior antipsychotic effects. One would expect that giving both drugs in long-acting injectable form, would produce the same results, although that has not been specifically tested. One thing you would not want to do would be to combine a dopamine antagonist like haloperidol

with a partial agonist such as aeropipyproprozole, and that's because the erypiprozole has a much higher binding affinity for the D2 receptor, and will essentially displace the haloperidol, so that the heliparidol becomes an inactive drug if the aeroproprozole is occupying the vast majority of the D2 receptors. Excellent. And of course, if they're willing to do clozapine, that would be...

Even better. That would be even better. Okay, anonymous listener from Manitoba, who says, I've listened to all episodes with Dr. Cummings, and they are my favorite, and I'm very grateful for his wisdom and deep knowledge he shares.

By the way, if Dr. Cummins is your favorite, my ego is totally okay with that. He's one of my favorites too. Yeah, on the other hand, I'm blushing as I sit here. Okay, so this person asks, I would like to ask if there are any relative

or absolute contraindications to try and Clozapine for treatment-resistant schizophrenia, and whether there are specific factors that would make it unlikely that Clozapine would be effective. The reason I'm asking is that I see a lot of reluctance by psychiatrists to consider Clozapine even for the most treatment-resistant patients.

First, Clozapine is the gold standard for treatment-resistant psychotic. illness, the likelihood of a person with treatment resistance because Vrenia responding to Clozapine is typically in the 40 to 60 percent range. The likelihood that they will respond to a dopamine antagonist or dopamine partial agonist is somewhere south of 7 percent, so fairly bad response rates for everything except clozapine. Closopine does start to lose

efficacy after the person has been treatment resistant for more than 2.8 years. That's from a Japanese study by Yamashiro in which they looked at, well, what happens long term if you don't give chlozapine? There are other articles that have been published about the effects of delaying

Clozapine treatment. There are no absolute contraindications. People can be rechallenged after things like myocarditis and even after things like severe neutropenia, albeit it calls for a great deal of careful monitoring and a very, very slow titration in both of those clinical contexts. because chlozapine for many patients is their only viable option, the FDA removed severe neutropenia as an absolute contraindication. Basically said, well, if the clinician believes that the benefit is more likely than harm,

then yes, but with, obvious, with caution, obviously with caution given that, severe neutropinia or myocarditis can both be life-threatening. Yeah, excellent. So, in summary, more providers should have less reluctance to using clozapine. And remember that constipation kills more people than neutropenia, right? Yes. By a factor of almost 10, people don't appreciate that after someone has been on chlozapine for two years, The risk of death due to severe neutropenia is down in the less than one per 10,000 range.

So it's statistically tiny. With respect to the constipation issue, one thing to be sure of for anybody that you treat with closed apine is be sure they're on a good bowel regimen, which can be starting with an osmotic laxatives such as polyethylene glycol, if that's not sufficient, add a stimulant laxative such as synocides. If that combination isn't sufficient, then replace the cynicides with a secretagogue like linnaclitide or platonotide. That will avoid the issue of constipation or bowel obstruction in the vast majority of patients. also be sure that you don't load the person with other drugs that are anticholinergic.

50 milligrams of clozapine is roughly equivalent and anticholinergic effects to one milligram of benzrapein. That's a lot. That's a lot of anti-collargic power. Okay. Anonymous listener asks, What do you have to look forward to in the world of new antipsychotics? Are there any new classes of medication

that work differently than those other D2 meds, any hope of long-acting injectables for clozabine, anything to help with negative symptoms and cognition. Okay. Should we take an episode on that or should we like? I started saying that's about an episode and a half sort there. We'll do the Cliff Note version. Let's go.

The Cliff Note version is, yes, The main area that's currently of interest in research for a new mechanism to control schizophrenic symptoms is modulation of M4 muscarinic receptors. The first drug likely to be available in that area is xenolamine. It's an M4 agonist. By the way, chlozapine is also an M4 agonist. basically this is a way of presynaptically modulating the release of dopamine in the ventral tegmental area. So rather than trying to block dopamine post-synaptically, this would be an attempt to modulate the release of dopamine in this specific circuit presynaptically. There are also allisteric receptors involved in that pathway,

and there's some research looking at tracamine-associated receptor molecules to modulate the same circuit. Those are a little further away as potential drugs. Will there be a long-acting injectable version of chlozapine? it will be difficult because of the doses of clozapine required and consequently the volume involved, but I know there are a couple of people interested in that area. I'm not sure how far along they've gotten with the physical chemistry aspects of looking at, for example, subcutaneous gels that could contain an adequate amount of

Clozapine, not in the United States, but in other countries there is an immediate release injectable form of Clozapine. It's available. I know in the UK and Australia, may be available in other Commonwealth countries as well. Doses are not high enough for maintenance treatment, but are large enough to permit initiation of Clozapine. Interesting. Okay, Caden Page, long-time listener and someone who's helped with the podcast, who has successfully entered his first year of medical school. Congratulations. Yes, congratulations. Page. And he says that Cummings is the Yoda of psychiatry.

You're going to hear more of these compliments as we go, Dr. Cummins. Well, can I say, honored I am. Yeah, honored I am. Can you speak more to the mechanism in which CYP inducers and inhibitors work? For example, how the interaction between flu voxamine and clozapine works, what it does in the body and what the effects are? Okay. Let me briefly start back in the beginning. We have CYP enzymes, five large families of them.

the first number in the name represents the family. The second is a group within that family, and then the last number is the specific enzyme in that group. So, for example, 1A2 is family number one, group A, enzyme number two in that group. Fluvoxamine inhibits 1A2, which is the principal metabolic pathway for chlozapine, and can consequently increase clozapine by as much as 500 to 1,000%, which is why if you're going to do that to inhibit chlozapin's metabolism, you need to be very careful about dosing in effect

because you can make somebody very toxic very quickly. The way inhibition works is that the molecule you're giving, which is an inhibitor, directly binds to the enzyme and blocks its activity. You know, the enzyme has to attach to its substrate, alter the substrate, and then release the substrate. If you have a molecule present that binds to the enzyme and then basically, like a bad houseguest, refuses to go away, that enzyme can't move on to do anything else. And that's what Vluvoxamine does to 1A2. So basically, fluvoxamine, the bad house guest,

comes in and then doesn't let 1A2 break down chlizapine. And because clozapine is so dependent on 1A2, clozapine jumps up 500 to 1,000 percent. Yes. Is that what you're saying? It can. If somebody gives a, what would be a fully antidepressant dose of fluvoxamine,

you can use fluvoxamine at tiny doses to increase clozepine plasma concentrations. for example, in a rapid metabolizer, but you need to be very careful about that because somebody else might come along and go, oh, that's not enough antidepressant and give the person a dose that will get them into toxic territory with the clozapine.

CYP inducers are substances that are metabolized by the target enzyme, but also cause the liver to go, oh, we need to work harder to get rid of that, and therefore the hepatocytes ramp up the synthesis of that particular enzyme so that you simply physically have more of the enzyme, and that, in other words, the synthesis has been induced, and more of whatever that enzyme metabolizes will be done away with more quickly,

because there are more copies of the enzyme present to attach to and metabolize that particular substrate. Very cool. Well, I think, shout out to Caden Page. I think his first couple emails to me where he was listening to your episodes, and he was taking notes, and he figured out that one of his, he was on an inpatient unit as like a helper. You know, he wasn't in medical school yet. And so he was catching some side effects in patients, and he was emailing me about it. And I was like, wow, this is a bright kid. So shout out to him. Yes, indeed. Okay, a listener asks, I work on an impatient psychiatric unit. Sometimes we have patients who still have pretty significant psychotic symptoms,

despite up titration of a single antipsychotic, usually risperol or zyprexa. I know that technically response could be up to six weeks. weeks, but we never have that much time to wait for improvement. In these sort of cases, do you recommend combining antipsychotics during their hospital stay to try to get better symptom control? If so, what combinations would you recommend? This question is assuming that we can't do clozapine for practical reasons, such as homelessness, noncompliance, etc. Again, this brings us back to the polypharmacy issue. There is data out there suggesting that polypharmine, pharmacy is modestly more effective than monotherapy provided, as we said before, that you choose

drugs that offer complementary mechanisms of action. Again, for example, it would make no sense to combine two drugs like heliparadol and flufenazine that have essentially identical activity profiles, the one mentioned here, Heloparadol and olanzapine is a very common combination because the olanzapine offers a second mechanism of action that heloperidol does not, so you may get essentially a better antipsychotic effect. One important issue with time of response, if you're giving a drug and you're titrating it, the effect you're going to see from that drug, you'll see about 80% of the response in the first two weeks.

So you don't need to wait six weeks to titrate again. If you give somebody what you think is a therapeutic amount of the drug, you're above the minimum response threshold, and you wait two weeks, what you see is about 80% of what you're going to get. So if it's not adequate, you can go ahead and hydrate further. That will shorten the amount of time that you're waiting. I know in a lot of inpatient, acute inpatient settings, even that time frame is too long. I was talking with the local county hospital here where I work.

Their average length of stay these days is 3.5 days. So just barely enough time to initiate treatment, certainly not enough time to complete treatment, which speaks to the importance of step-down and day hospital programs after acute hospitalization. I'd be curious, what do you think about, like, let's say someone was on Abilify-Maintaino, so air-per-zole injection, what augmenting strategies would you give if like 400 wasn't completely bringing them out of psychosis? If 400 milligrams of Maintena a month is roughly equivalent to 20 milligrams of oral aeropropyzole, frankly, no one has demonstrated much of a difference between 15 milligrams of aeroproprozole a day and any higher dose.

and that's because it has such a high binding affinity. Augmenting the partial agonist is very difficult because of the very high receptor affinity. I certainly would not choose, for example, a dopamine antagonist because it won't ever see the D2 receptor for the most part. If there's any evidence, for example, of bipolar diathesis, then I would certainly be looking at addition of a mood stabilizer,

most likely lithium or valproic acid, unless the patient is female and at risk of pregnancy. I would also consider other drugs such as SSRIs for negative symptoms. Beyond that, there's not a lot. One of the things I always encourage people to do if they're thinking about starting a long-acting injectable partial act, antagonist, either Maintena or Aristotta, be really, really, really sure that that person is a responder to Arapersol before making that commitment, because the washout time for the long-acting injectables is incredibly long. Excellent.

Okay. Here's a question from an anonymous New York psychiatrist who calls Dr. Cummings, that John Oliver of of psychiatry. There seems to be a rise in popular media, TikTok YouTube, of psychiatric professionals critical of psychopharmacology and intervening in mental health care with medications. For example, a TikTok doctor making rounds on the four-you pages with videos critical

of SSRIs and benzodiazepines. His TikTok and YouTube channels have recently featured a prominent English psychiatrist and research expert on deprescribing. what do you make of these criticisms? Are they new, newly revisited? Does popular media attention to deprescribing and the overuse of mental health medications do more harm than good? Put another way, is it on balance better for patients to observe these psychiatrists debating these issues online or more harmful to the overall goals of the field profession?

How would you recommend talking to patients who have been de-influenced after consuming this media. This is not new. The use of medications has been debated since the introduction of chlorpromising and to some extent before that with the use of the barbiturates. I think the criticism in one sense is founded and that sometimes people get carried away with expecting things from medications that medications cannot deliver. I'm very careful to educate both the people I consult with and patients that medications are tools. They are there to improve certain symptoms and symptom complexes. They are in psychiatry generally not curative.

That is, they don't change the person's underlying genetics or epigenetic. sufficiently to make them, you know, a completely different person. I also caution people not to expect pharmacology to address complex issues in the person's life, either past or present, and to adopt a more balanced view of medication versus psychotherapy, in fact, more often it should be medication plus psychotherapy. You know, someone was critical of the podcast recently and said, why is there so much psychotherapy stuff on here? This is not a good podcast for us prescribers.

That's wrong. It's like to call yourself a prescriber, first of all, like, can we talk about that? Are we just prescribers, really? I certainly hope not. You know, I am a psychopharmacologist, as people can tell, I think spend a lot of time thinking about molecules and neural circuits. I can tell you that there is no pill that is going to cure or fix any complex issue in your life. The pill may help you, but there is still work to be done beyond that.

And I think that when people forget that, that's where a lot of the criticism arises from, oh, here, take this pill and everything will be 100% okay. Well, that's nonsense. You know, life is complicated. Life is often difficult. And calls for responses beyond symptom reduction. Yep. So I think I would say, you know, to any psychiatrists who are venturing to make TikTok videos and put out stuff on social media, you have to think through how we can present ourselves in an accurate, nuanced way.

And it's difficult. And I think fear-mongering medication side effects, without a sort of a buttressing of why we're using them or how we're using them or when they're helpful or not helpful, I would say is probably not helpful for the field. I don't know. Any thoughts on that? Yeah, I would say, you know, the approach always has to be balanced and nuanced. Again, medications are tools. They always have both benefits and risks. Those need to be explored with the patient, discussed, and choices made carefully. Okay, let's move on.

Jacob, who owns his own practice in Wyoming, says, Dr. Cummings is magical. I wish that even a minority of clinicians in the field of mental health were able to study and learn from Dr. Cummings on a regular basis as we are. His knowledge base is more godly than its standard, and that is both terrifying and enlightening. Okay, so he uses the information to support his treatment teams. Let me move on to his question.

What is your opinion of when a patient qualifies for the need for brain imaging or formative and summative evaluations in treatment using a type of brain imaging in mental health? For most patients with at least severe mental disorders, major depressive disorder, schizophrenia, bipolar illness. Certainly, I'm very much one in favor of the patient at the outset of treatment receiving a fairly thorough workup.

You know, a good physical neurologic exam, lab profile. And if they've never had a brain image done, then an MRI without contrast is not out of being reasonable. And I say this because there are a whole host of both medical and neurological illnesses that can present initially with psychiatric symptoms, and we need not to be missing those.

I'm very much not one of those psychiatrists who was of the opinion that, oh, psychiatrists should never touch their patient. I do a physical exam and at least focused neurologic exam on almost every patient I see. Just to be sure nothing is being missed. And I'm also a firm believer that psychiatric offices should own things like scales, given that we give drugs that cause people to gain weight and so forth. In other words, we need to be physicians first. So I have a fairly low threshold for ordering an MRI, even if I'm perfectly aware that the overall yield is likely to be low.

But every now and then you find something that you weren't expecting or the patient wasn't expecting. And occasionally it's helpful in terms of directing their treatment. Do you think that there's ever a role for a spec scan, a single photon emission computed tomography scan of the brain? There can be in cases where you suspect, for example, something that's fairly rare like non-convulsive status, epilepticus. I actually had such a patient when I worked for the VA. frankly, all of us had thought he was schizophrenic, except that every time you gave him an antipsychotic, he got substantially worse.

And when we got a spec scanner, this speaks to how far back this goes, we did a spec scan, and sure enough, he had a hot focus, hot metabolically, deep in the frontal lobe, we put him on valproic acid, and suddenly his psychosis,

went away. So yes, can have used these days. Positron emission tomography has replaced spec scans in many settings simply because it provides a more accurate, detailed three-dimensional image of the brain. Okay, so there are certain types of clinics, we won't name names, that use this type of thing often. Do you, just for routine evaluation, is that what we're talking about? Are you saying? No, no.

Spec scan would not be for routine evaluation. Spex scan would be if you suspect that there is an underlying organic cause going on, usually something like non-convulsive status or an average. What do you get, what, do you just get an EMG for, like, if you thought a seizure was going on, though? Non-convulsive deep epileptiform fosy may not show up on a surface EEG. And that's because the focus is very deep-seated. In this guy's case, it was in the anterior basal ganglia. Well, there's a lot of tissue between that and the cortex.

And what you're seeing in a standard EEG is primarily the electrical activity of the cortex. and if the cortex is fully active, it may mask more subtle underlying metabolic hotspots. I appreciate your nuance here on like the very rare use of it. Okay, so what would be the symptoms of this deep seizure that's ongoing? Usually, in this case, the presentation was of cognitive disorganization. occasionally visual hallucinosis. The tip-off in this particular case, though,

was the worsening whenever exposed to a drug that would lower seizure threshold, like an antipsychotic. Oh. Which was the tip-off in this guy's case is that it was not a case of, oh, he didn't respond to the antipsychotic. Even minor doses of antipsychotic would make him

substantially worse, which was, of course, not the expected outcome. And got people saying, well, this may not be what we think it is. You know, it's like that old saying when you hear hoofbeats go look for horses. But every now and then you find a zebra. Okay. Awesome. This is great. Okay.

That's like, so no one can say that they didn't learn anything from this episode after learning that. I'm pretty sure everyone learned something there. Okay, Ryan states, he's probably the most brilliant and articulate man I've ever heard speak. I often revisit with Dr. Cummings episode list because I know everything with him will be a gem. Okay, so here's this question. Do dopamine partial agonists overcompete dopamine antagonists at the D2? Would air prepyzole, for example, preclude further D2 blockade from other antipsychotics? If so, if a patient is on a long-acting, abilify by apropyzole and experience breakthrough psychosis,

what would be the best strategy to manage their condition? Usually in those cases where the partial agonist is not proving to be an adequate medication, it's often the case that you're forced to discontinue the long-acting injectable partial agonist, because if you're truly giving the partial agonist at a therapeutic dose, the odds are you're occupying well more than 80% of the D2 receptors with the partial agonist. So your antagonist is not going to have much of a target. You can go ahead and initiate an antagonist, stop the partial agonist, and of course it will then gradually wash out.

With Main Tena, for example, however, the half-life is on average 46.5 days. If you do the math, that means complete washouts going to be 232.5 days, so long time. But it will be going away the entire time, and every time the aeropiprosol falls off a D2 receptor, that means that receptor is now available for your dopamine antagonist. Just be aware that the antagonist may not have much of an effect initially. And of course,

we can always come to the gold standard of antipsychotic treatment, Clozapine, which can be used with the partial agonists because it does not provide its antipsychotic benefit by blocking dopamine. The two, known mechanisms so far are glutamate modulation at NMDA receptors and likely

stimulation of M4 muscarinic receptors in the ventral tegmentum, neither of which is directly affected by a dopamine partial agonist. Yeah, I did a polypharm episode without you, Dr. Cummings, and one thing we looked at was the combination of clozapine and ariaprizo actually makes sense and there's some good data to support that as a good combo yes indeed there have been some articles studies published that demonstrate that clozapine plus eripipiprozole is has a more robust augmentation effect than many other combinations all right we're going to move on to some questions about depression dr saverin han from hamburg Germany in his second year of psychiatry training, who really appreciates you.

He said he has an entire note of little wisdoms from you that he uses, and he wishes you could be his personal mentor. He said, where do you see MAOIs in the treatment algorithm of depression? How would you treat depression in an algorithm, including more exotic options like MAOIs, primaprexol, S-Zo-Plydeclone, Sammy, T3, etc. Specifically, in what order

which specific antidepressant first and so on would you do including lithium atypical antipsychotics thyroid medications? Okay. This could indeed be another entire episode.

In brief, however, usually these days, antidepressant treatments starts with either an SSRI, an SSRI slash 5HT1A drugs such as vortoctine or velazadone, or an SNRI, meaning venalifaxine, duloxatine, in most of the world milnasopran, or levo milanacopran. or be approprion. Basically, if you have a person who does not respond to adequate trials of those medications at sometimes greater than the typical dose, then it may be time to think about,

would this person perhaps respond better to a tricyclic antidepressant, although there is data now suggesting that the tricyclic, Bicyclics are not necessarily superior to the SNRIs, if they're truly equivalently dosed. Beyond that, though, you do have the monoimmune oxidase inhibitors, and frankly, the MAAO inhibitors are likely somewhat better antidepressants than any of the drugs up to this point. And the reason for that is that most of our antidepressant drugs directly affect either serotonin or norapinephrine or both. The M-A-O inhibitors go a step beyond that

and affect norapinephrine, serotonin, and dopamine because the M-A-O-Is block the degradation of all the mono-amines. And we sometimes forget that dopamine also plays a role in depression. The reason, of course, that these never became widely popular drugs is because of the risk of hypertensive crisis known in the 1960s as the cheese reaction because it was triggered by aged cheese. Foods are not typically that much of a problem because tyramine levels are limited in food. The more dangerous interaction is between the M.A.O. inhibitors and direct sympathomimic stimulants, i.e. cold medications. Those can cause severe

hypertensive crisis and death. Consequently, these have become unpopular, but we should not forget them. In cases of very refractory major depressive disorder or severe anxiety disorders, the MAO inhibitors are a little more effective than all of the other antidepressants that we have. Of course, the other thing we can do these days that wasn't previously possible or, well, it was possible for ECT, is that people with refractory depressive illness ECT is still more effective than any of the pharmacological interventions. We also now have transcranial magnetic stimulation and vagus nerve stimulation as well for chronic recurrent depression. And I think we sometimes still forget that in addition to pharmacotherapy for depressive disorders, things like exercise, lifestyle, cognitive behavioral therapy, or related psychotherapies, are incredibly important.

Again, this is an area where you do not expect the medication to fix all of the problems in the person's life. Awesome. Dr. Hahn also asks, what do you make of measuring

antidepressant plasma levels? I think that can be useful in the sense that, well, the antidepressants don't, in most cases, have as well-defined plasma concentration ranges, for example, the antipsychotics or lithium do. There are some general indications.

For example, if you want to know if the person's actually taking the drug, a blood level can help you with that. If you want to identify whether they are a rapid metabolizer of the drug, blood levels can also be helpful with that so that you can at least figure out if you're getting the amount of antidepressant

that you're expecting in the person from the dose that you're prescribing a plasma concentration is an excellent way to know that. Okay. He also asks if you were treating a depression that also has some external stressor that's very large that likely cause the depression

or a personality disorder that's prevalent in the mix of things, would use the same algorithm as pure major depressive disorder? I would use the same algorithm. However, there would be a very large emphasis on use of psychotherapy. Okay. All right, let's move on.

Chris from Ohio says he loves learning from you, and he asks Vrelar, which is curriiprazine, is FDA approved for use with antidepressants to treat depression? He says, I believe they are now marketing more towards this market and would like to be viewed as a monotherapy for depression and more first in line than an SSRI. What are your thoughts on this? Cariprazine is an interesting drug. It, of course, is one of the partial agonist antipsychotics, and you're right. Drug companies like to market drugs for mood disorders, because frankly, that's a larger population, i.e. more potential customers.

Cariprazine does have significant antidepressant and anti-manic effects. It's one of the few drugs that, like lithium, can be effective for both the manic and depressive poles of bipolar illness. And it differs from the other partial agonists in that, in addition to being a fairly robust antagonist or partial agonist at D2 receptors, it also has a significant and even more robust interaction with D3 receptors, which alters dopamine activity. particularly in the frontal cortex. I'm not sure I'm willing to go as far as saying that caraprozin should be used as antidepressant monotherapy,

but it probably is one of the more robust augmenting agents currently for major depression or for bipolar illness. And it may prove itself as monotherapy, but I haven't seen a gap. could head-to-head comparison across groups, say, comparing standard antidepressant treatment with curieprazine monotherapy. All of the studies I've seen have seen it's been used as an augmenting agent. Same person further says, you know, he's never seen studies that look at the risk for this medication and TD. What's your educated guess as the risk given its mechanism of action. You're right.

There are not good studies regarding chryprazine and TD. In fact, there are not good studies looking at aeropiprozole or Brexpiprozole and TD. Since these do decrease dopamine signaling, it is

almost certain that in some patients, they will induce neurologic side effects, including things like acute dystonia or Parkinsonism, albeit at much lower rates than the first-generation antagonists. And my guess is you'll also see tardive dyskinesia arise in some patients. Again, it's very likely the most common patient will be elderly female patient with a mood disorder. Okay. An anonymous fan of Dr. Cummings says,

big fan, very big fan. And I've listened to his episodes with Dr. Puder many times. I even have his book on treatment resistant psychotic disorders. He is so knowledgeable, but more than that, I trust him. And this person's question is, the tardy trial has been re-examined and current controversy seems to lean towards the belief that SSRI medications are ineffective

or lacking more than before. SSRIs have been the go-to medications for many disorders and personality. I have seen them work well. How do you view the controversy and do we need to rethink SSRI use? Is the controversy warranted? I think the controversy has more to do with our understanding of things like major depression and anxiety disorders. early on people simplistically thought well depression is a lack of monoimmune neurotransmitter

and that turned out frankly not to be the case we've talked about before on this podcast that things like major depression and anxiety disorders are likely based on primary dysfunction in limbic circuits that get beyond the mind. modulatory ability of the monoamine neurotransmitters. And that sets them an inherent limit on how effective things like the SSRIs can be. If you look at trials of antidepressants, while the numbers don't match precisely, they are relatively uniform in that if you look at, well, how many people in a depressed sample or an anxious sample show a 50% reduction in symptom severity, it's about two-thirds,

meaning two-thirds get better, one-third don't get better by that much. How many of those people achieve full remission? Then you're talking about numbers down around one-third, and I think that's what people have recognized is that while these medications do have a positive benefit, you know, achieving remission only in one out of three cases is not as satisfying an outcome as people would like. And I think, again, this speaks to the issue that while the medications are effective and helpful and in many cases, life-saving, they should not be the entirety of treatment. Yeah, I think he's kind of hinting that Starditra has been re-examined. Is there anything that

you've seen on that? It's more a case that the Star D trial has been debated, which of course is not uncommon. Almost every major study that occurs then has subsequent smaller studies that examined various aspects of it, and there's typically in the literature an ongoing debate, and that certainly has been the case with the Star D trial. There was a somewhat provocatively titled study about a year ago that the title was, and I'm paraphrasing here, something along the lines of why aren't the SSRIs effective, which of course was an overstatement, but it was, I think it was phrased that way to essentially get attention. And they went through the same thing that I just noted that in the vast majority of people with major depressive disorder or with severe anxiety disorders,

the SSRIs are helpful. Two-thirds of people get a 50% reduction in symptoms and one-third to actually go into remission, but that's a less than completely satisfying outcome. You know, in the ideal world, of course, we'd like a medication that the person takes the medication once and they're cured. We don't have a lot that functions like that.

Yep. And that's why I think in my actual clinical practice, it looks a lot like, okay, they got 50% reduction in their symptoms. That's probably what we're going to get from an antidepressant. Now we're going to highly encourage them to get out of bed and do some behavioral activation, get some exercise, start some therapy, you know, things that maybe when they were severely depressed, they couldn't do or had a high resistance to do. Okay, let's jump to the next question. Scott Kennedy, a senior policy advisor of the Virginia Medicaid program, says, do SSRIs, SNRIs, and other medications for depression lose their clinical effectiveness after years of use? They can.

And this is something that speaks not to necessarily a defect in the medication, but to, to, the fact that many psychiatric illnesses, such as bipolar illness, schizophrenia, major depression recurrent, are themselves progressive in nature. For example, with major depressive disorder, the overall risk in the population is around 6 to 8 percent, but if somebody's had one episode of major depressive disorder, their ongoing risk for a second episode. is up around 50% and keeps going up the more episodes they have. That speaks to, I think, an evolving underlying abnormality in the way their limbic system functions that can become increasingly resistant to medication. And certainly, if you look at the elderly depressed

population, those who've had a long, essentially a lifelong history of recurring major depression, they often reach a point where they become pharmacoreistant. That is, they reach a point where they don't respond to antidepressants at all. And indeed, they often wind up on things like maintenance ECT as a result. Okay. We're going to have to maybe have, we'll try to get through depression, and maybe we'll have to do a second recording for the next series on anxiety, bipolar, ADHD, and so on. Yeah, I was going to say, otherwise, this could be a marathon podcast.

Well, maybe we'll put them all together, you know, we'll just kind of glue them all together. It'll be like a six-hour, six-hour session with Dr. Cummings. When initiating an antidepressant for unipolar depression, does concomitant prescription of an antipsychotic accelerate response times? That has been looked at because people have been trying to accelerate the antidepressant, for as long as the antidepressants have been around. And indeed, there's now one product on the market that's a combination of buproprion and dextramothorfan for that very purpose.

In its pivotal trial, the dextramothorfan edition got a superior response at two weeks, but then by six weeks, the superiority had vanished because the buproprion monotherapy caught up. Adding an antipsychotic can accelerate antidepressant response, particularly for those antipsychotics that have proven themselves to be augmenting agents in terms of antidepressant effects, whether to routinely use an antipsychotic outside,

of psychotic depression, however, I think warrants careful consideration of potential adverse effects, you know, because you're adding a whole new class of medication that may involve adverse effects the person would not have from antidepressant monotherapy. Most of the acceleration study with antidepressants, frankly, have not been that impressive. We're talking about shortening the response time by two or three weeks. Awesome. Yeah. So, yeah, I think this is a good place to stop. Maybe what I'll do is we'll schedule a part two and we'll allow some people to add some questions. This could just go on forever. This may be like just an ongoing Q&A with Dr. Covey. So if you have a question, I'll put up a, I'll send out another email when this, when this episode leaves. And you can add your question to the Google form. And I'll try to put it together for the next episode. But Dr. Cummings, it has been a pleasure. I think you are well loved in this community here across the world. And I didn't, I didn't expect this to be as popular as it has been. But I think we're nearing or have reached 8 million downloads.

and that's more than I expected. Any final thoughts? I know one person said I was magical. I did like the Harry Potter series. However, I don't own a magic wand. Your magic wand is your brain. Someone asked you, I don't think we got to it. How do you study or how do you learn so much?

Or what's your process? basically I and we can discuss it at some point in greater detail but basically I look for new information two ways I have a number of the major journal table of content sent to me which I basically just scan those to see what's sort of new and upcoming what's the current focus of research so that's more or less a cross-sectional sample if you will and then in certain areas, if I get interested in a particular topic or something appears to be becoming important, I'll do a literature search on that, and then look at the research in one particular area vertically. So in short, that's how I look for information. Nice. All right. We will leave it there for today.

Thank you guys for listening. Thank you, Dr. Cummings, as always. Okay. Thank you. Bye-bye. Thank you.