Psychiatry & Psychotherapy Podcast - How Psychiatric Medications Work with Dr. Cummings

Episode Date: June 12, 2018

In the latest episode of the Psychiatry and Psychotherapy Podcast, Dr. Puder interviews Dr. Cummings, a psychopharmacologist. They discuss the way medicine works in our bodies, and if medicine or therapy is more effective for treating different disorders. They also talk about the different factors that affect absorption rates, such as gastrointestinal surgeries, liver health and actual dosage. By listening to this episode, you can earn 0.75 Psychiatry CME Credits. Link to blog. Link to YouTube video. Join David on Instagram: dr.davidpuder Twitter: @DavidPuder Facebook: DrDavidPuder

Welcome to the Psychiatry and Psychotherapy Podcast, the podcast to help you in your journey towards becoming a wise, empathic, genuine, and connected mental health professional. I'm your host, Dr. David Puter, a psychiatrist who splits his time practicing psychopharmacology, individual and group psychotherapy, medical director of a day treatment program, medical education research, and teaching, residents, and medical students. So I'm back here with Dr. Cummings and an excellent psychopharmacologist, is looked at in the community as someone to ask the difficult questions of, and we're actually going to be going back into some of the basics of psychopharmacology and doing a little bit of a

series together over the next couple months. And today we're going to be going over how psychiatric medications bind to receptors and some of the basic pharmacology stuff that you need to know to understand how psychiatric medications work. So welcome to the podcast. Well, thank you. I'm glad to be back. Indeed, we're going to go over some of the core concepts in both pharmacology and psychopharmacology. These are often materials that either people weren't introduced to thoroughly, or it's been so long since they sat through a pharmacology class that some of the ideas have kind of gone away. Probably the place to begin is with just defining what psychopharmacology and psychopharmacology medications are.

Psychopharmacology is a sub-branch of psychiatry that deals with medications and substances that affect the way the brain works, both positively and negatively. And then psychopharmacology agents or medications are essentially any medications that's used to treat an illness or condition whose primary signs and symptoms are disturbances in things like mood, cognitive processes, behavioral control, all of the major mental disorders pretty much are typically addressed via a combination of medication and psychotherapy.

It's unusual for severe mental illnesses to be able to be able to. benefit adequately from psychotherapy alone in the sense that the medications often help make the person more available for other treatment modalities. One of the important things in defining what is a psychotherapeutic drug has to do with intent. Some medications serve, of course, more than one purpose. The molecules actually don't know anything about what the FDA labeled them for. For example, if you were treating somebody with a seizure disorder that was primarily expressed as motor symptoms and you were treating them with valproic acid, well, that would not be considered a psychotherapeutic agent.

On the other hand, if you were treating somebody with bipolar mood disorder with the same molecule, then it would be a psychotherapeutic agent. So a lot depends on the purpose for which the medication is being used. And again, the molecules don't know anything about their labeling. Yeah, that's, when I think about this, I think about just even like coffee or caffeine, you know, could be considered, you know, a psychiatric medication in that it binds to things, changes the brain, how the brain works. Yeah, indeed. Caffeine is an adenosine. receptor antagonist, adenosine serves as a minor sedating or relaxing neurotransmitter in the brain,

and by blocking its effects, people become more aroused, more awake. And indeed, when people switched from having wine or beer for breakfast to having coffee, it would be fair to say that the world's productivity increased substantially. In what time period are you reflecting to with the wine and the beer? Prior to the arrival of Europeans in North America, coffee and chocolate were largely confined to North America. At that time, because water was not entirely safe in much of Europe. You could die of dysentery. it was far safer to drink a fermented breakfast beverage, either beer or wine.

Of course, that somewhat slowed you down just a bit for the rest of the day. Kind of a, you know, get up and have a sedative. So basically, because there was bacteria in the beverage, it was happy bacteria and not the way. ones that would hurt you? Yes. Well, actually, you know, alcohol content in the beverage actually helped kill off many of the pathologic organisms, whereas the, if you will, the village well water might have been

contaminated with a variety of bacteria that could cause illness. Interesting. In terms of psychopharmacology, there are several concepts that apply. to everything in general. All medications undergo, at least orally taken medications, undergo the same series of steps in terms of how they get to their target. If you swallow something, it has to be hydrolyzed, liquefied, basically. Before you can absorb it, there are limits for some molecules on how well they're absorbed. It then goes through the liver, and of course some drugs are highly metabolized on their first pass through the livers, others not so much.

It then gets distributed in the blood supply and via the blood supply it reaches its target organ. There are things that can alter absorption and distribution and metabolism quite a bit. Yeah. One thing in that I see a lot is like gastric bypass ruin-wise or gastric banding. Mm-hmm. and the influence on that in getting it absorbed? Yeah, gastric banding luckily does not do much to inhibit absorption. It mostly limits the volume of food people can eat at one time.

The people who've actually had a bypass surgery that takes away a portion of their small bowel, which is where we absorb most of the medications, reducing the surface area, It can absorb medications. That tends to limit those medications that have a longer absorption time. For example, if someone takes oral olanzapine, zyprexa, the time between when they swallow it and when it reaches its peak in the plasma is six to nine hours. If somebody's had bypass surgery, the odds are they won't absorb as much of the drug because it's a very slow absorption.

On the other hand, if they were taking a very well-absorbed medication like lorazepam orally, its absorption is very rapid and having a shortened bowel essentially would not have any effect on the total area under the curve or the total amount that was absorbed. Yeah, one of the things I see in regards to that, just a clinical pearl, is often get a patient with depression who had, a ruin wire or whatnot, then their depression came back. And simply by telling

them, hey, start grinding up your pills, it can increase the dose that gets through. Yes. Basically,

the steps people go through is, obviously, we swallow most pills whole, except for a very few chewable varieties or

rapidly dissolving varieties. And until those pills dissolve in the GI tract, and undergo hydrolysis become liquid, they can't be absorbed.

So, indeed, grinding them up and offering a bigger surface area for hydrolysis will speed the rate at which they get absorbed. Once a drug is absorbed, it, of course, enters the portal circulation and goes up to the liver. There are several things that can alter how much of the drug gets through there. Some drugs require active transport for absorption. Others are good substrates for a protein called P-glycoprotein, which basically pumps things back out into the gut lumen. So if it's a good substrate for that, like risperidone, then some of the drug will have a difficult time getting in.

Once it reaches the liver, we have an entire array of enzymes that are designed to break toxins down. essentially we and plants have been locked in an evolutionary war for, well, longer than we've been a species, which is why we have a lot of cytochrome P450 isoenzymes. There are five major families, and each of those have multiple subcomponents. And basically those are there, not because of medications, but essentially to break down plant toxins. and basically the war goes like this. The plants generate toxins to try to discourage animals like us from eating them,

and we develop enzymes to get rid of the toxins so that we can go ahead and eat the plants. Those same enzymes, though, do break down medications. There are several that apply specifically and frequently to psychiatric medications. 2D6, 1A2, 3A4 are the most prevalent. ones for psychiatric medications. They're named basically the first number is the big family that they belong to. The second, the letter is a subgroup within that family, and then the last number is sort of that individual enzymes identifier.

2D6 seems to be the one I would tell people to start learning first. I don't know if you would think differently. Yeah, 2D6 is the most common for. psychiatric medications, both in terms of if it is elevated, they will be a rapid metabolizer. If they lack an adequate number of copies of the gene for 2D6, then they will be a slow metabolizer. After that, 3A4 is the most universal in terms of things that it breaks down. And then 1A2 is important if people prescribe things like chlozapine or olanzapine that depend

very heavily on that particular enzyme for their metabolism. In terms of drug-drug interactions, pharmacologists spend a great deal of time looking at is the person taking something that's going to induce metabolism of the drugs, or are they taking something that will inhibit the metabolism of a specific drug? Because that will vary how much of the drug is present. and may either make other drugs ineffective or may make them toxic if it raises or lowers the plasma concentration too greatly. Yeah, so let me break this down a little bit simpler and tell me if you would add anything.

So for example, let's say you have a medication that's broken down by 2D6. So a lot of the tricyclics like amyptylene, nortryptylene, are broken down by 2D6. So you have 2D6, it's a liver enzyme that breaks this medication down. And if you don't have this, then the medication levels rise. Like if you don't have this P450, this way to break down the medication. So you can either have a gene that has a mutation, so you don't have this gene that works as well, breaking it down. Or you can have another medication on board that is blocking.

the P450 from working. And that would also cause this medication to increase. Yes. For example, if you were taking the anti-depressant amatryptylene, Ellaville, and somebody started you on a drug like ketoconazole, a very potent antifungal medication, you could easily increase the blood level of the amyptylene by five to tenfold.

Which I've seen actually a couple times, a couple, I've had maybe five to ten patients in the last five years with this issue. So they come in on amatryptylene, and they also come in on a 2D6 blocker. For example, Prozac. Yes. And what's happened is, you know,

you had some primary care physician or some neurologist stuck them on amyotryptylene for pain issues or for headaches or migraines. And then they've been, they got a 2D6 blocker on board, and all of a sudden they got confused. And, you know, they're going to work and they can't focus, they can't concentrate, and they end up in your office saying, I just don't feel like myself. I just feel confused. I feel, you know, I can't remember things anymore.

Yeah, that's a very potential outcome with that. Because, you know, for pain with amatryptylene, people often prescribe 25 milligrams. but if they take a drug like fluoxetine prozac or peroxitine paxil or buproprion, they can easily increase their plasma concentration tenfold. Well, that's, that equivalent would be they went from a dose of 25 milligrams to a dose of 250, which can be toxic and make them confused also can be very dangerous. The lethal dose for tricyclic antidepressants is only about six to eight times the antidepressant dose for tricyclics. So it's very easy to push somebody into dangerous territory in terms of plasma concentration,

which is one of the reasons that people pay attention to drugs that either induce or inhibit the liver. Inducers, of course, can do the opposite. They can easily drop a drug right out of being therapeutic. For example, the anti-epileptic drug phenotene, dilatin, is a really good hepatic inducer. And for antidepressants and antipsychotics can reduce the plasma concentration by a lot of, anywhere from 30 to 80%. So your patient who may have been doing just fine has a seizure, they get put on dilatin,

and then their psychosis or their depression comes back. And what's happened is that their antidepressant or their antipsychotic is no longer present in amounts that's effective. Yeah, so this begs the question, one, should we be genetically testing our patients to look at their P4.50? 50s, or two, should we be looking at the level of the medication?

Or three, should we just know enough about, you know, how these drugs are interacting and, you know, all the different combinations to kind of judge like, okay, this might be an issue or it might not be an issue. Well, the good news with drugs is there now a variety of resources available in terms of drug-drug interaction software programs that if you enter a drug list, it will point out if there are any important known interactions. So that's one approach, so that people don't have to remember thousands of potential drugs interactions.

My one criticism of most of those programs is they don't do a very good job distinguishing between those interactions that are truly clinically important and those that there may be an interaction, but it's a minor, not very relevant interaction. And I get called by the pharmacist often on the ones that are of not as important significance to myself, and it's kind of like, you know, it can be frustrating.

Yes, it can be. Probably the most accurate method of approaching, whether the person has got too much or too little of a drug is to actually measure the plasma concentration of the drug. For any patient, if you start them on a medication and you titrate them up to what you expect, to be an effective dose and you see nothing, you know, no benefit, no side effects, a plasma concentration may tell you that this person is inherently a rapid metabolizer of that drug.

And consequently, you're going to have to use a larger than average dose in order to achieve a therapeutic benefit. Conversely, you can have a patient who comes in, you put them on your drug, you start to tritrate it, but they come back the following week, tell you. oh my god I feel awful I'm having this list of side effects and sure enough there are side effects that the drug can cause when the level is too high you measure a level and find out oh you're a very slow metabolizer of this drug genetic testing can give you a less specific

warning basically that that may happen a lot depends on whether the testing can give you an accurate idea of how slow or how fast this person is going to be. The plasma concentration always will tell you how much of the drug is actually present. Yeah, one thing I would sort of just reflect on about that is if someone's having issues with the medication and side effects, I don't know if I'd always wait to get a plasma level. I think I sometimes would say, okay, let's decrease this in half. for? Depends on the nature of the side effect.

Certainly if it's an intolerable side effect or a truly problematic side effect, then certainly reducing the doses worthwhile. The other thing that frankly happens, and one of the major reasons people develop side effects with many of the medications used in psychiatry is that the titration was too rapid. Many of these medications are better tolerated if they're titrated gently. There are a lot of forces that mitigate against that. Clinics are under pressure to move faster. Certainly hospitals are under pressure to discharge people sooner, and that can lead to

basically people being ramped up on their medications more quickly than would be desirable. A lot of these side effects actually go away if the person's receptors have a chance to adapt to the presence of the medication. For example, many of the medications used in psychiatry block histamine receptors. That makes people sleepy. If you go up too quickly, it can make them very sleepy. Many of the drugs we use are good alpha blockers. They block norapinephrine and epinephrine receptors.

And if you go up too quickly on that, you can make people orthostatic, make them dizzy, and can even make them faint if you really push hard. Interestingly, if you give those receptors time to adapt to the medications, often you don't see any side effects at all. A number of years ago, UCLA did a study with a tricyclic antidepressant where they took amypremine, which is a good alpha blocker, good antihistaminic drug, anticholinergic drug as well. They followed a standard titration to 150 milligrams, 25 milligram dose increments once a week and

got about the same level of adverse effects as in the package insert for the drug. They made people sleepy. They gave them dry mouth. They dropped their blood pressure in some cases. They took a second group and put them on a titration of 10 milligrams a week, much slower, and they had zero side effects. And they got to the same blood level eventually. They got to the same blood level eventually. It just took longer. Wow. So sometimes being in a hurry is not necessarily the best way to avoid side effects.

Since we've talked about receptors, that kind of leads us into, well, how do these drugs work anyway? Most of the drugs we use work by binding to a receptor site. A receptor site is a protein that typically sits on the surface of a cell. And for psychiatrists, usually it's on the surface of a neuron, a nerve cell in the brain. And the drug can do a number of things there. It can be an antagonist, meaning it binds to that receptor, and it basically blocks it. It does not activate the receptor. It gets in the way of whatever the normal neurotransmitter would be, just like caffeine gets in the way.

Or I should say caffeine gets in the way of adenosine. Drugs that do that, for example, are the first-generation antipsychotics, block D2 and D3 dopamine receptors. Or a drug can be an agonist. It can actually go in the same direction as the naturally occurring neurotransmitter. We don't have very many of those that we use in psychiatry. It can be a partial agonist, a drug that activates the receptor and goes in the same direction as the naturally occurring neurotransmitter. transmitter, but does not do so as robustly or as powerfully. Drugs like that are things like aeropiprozole or Brexpiprosol, which bind to dopamine receptors

go in the same direction, but produce activation that's only about 25% of what you would get out of a maximum amount or concentration of dopamine at that same receptor. The other area where many psychiatric drugs work is by blocking the re-uptake of certain neurotransmitters. This is the means by which many of the antidepressants work, many of the neurotransmitters we have in the brain, rather than nerve cells having to synthesize new transmitter as much, they actually depend for their store of about 90% on re-uptake. That is, they actually have a transporter molecule that vacuums up the neurotransmitter back into the pre-synaptic neuron where it gets repackaged and then reused.

It's kind of a biological version of recycling. And what we do with the antidepressants most frequently is, slow down that re-uptake transporter and leave the neurotransmitter out in the synaptic cleft between nerve cells for a longer period of time, making it more available to the post-synaptic cell. Yeah, one thing that is sort of an underlying question, and maybe this is a little bit off topic, but, okay, so you have a build-up of the serotonin there, but the medication takes, you know, two to four weeks to work, and for anxiety, it takes about six weeks to work. Well, and indeed that brings about the issue of how do these drugs in general work.

They fall into two broad categories. There are drugs like barbiturates or benzodiazepines that change ion flow that is electrically charged particle flow into and out of nerve cells. The effect of those drugs is immediate. You know, if you give somebody medazalam, for example, IV, as soon as the drug is present in the brain, that person will get sleepy and go to sleep, and you can then, you know, that drugs are used most often for procedures like cardiac catheterization and things that are uncomfortable, essentially a form of anesthesia.

The effect of the drug, though, is present as soon as it alters the, the ion flow into or out of nerve cells. All of the benzodiazepines, for example, do that by causing chloride channels to open more frequently, allowing more negatively charged chloride ions into the nerve cell and moving it away from firing threshold. Alcohol works similar. Alcohol works by altering the fluidity of the membrane right around the benzodiazepine receptor, which because receptors get activated by physically changing shape, changing confirmation,

that activates the benzodiazepine receptor and indeed produces an effect just like a benzodiazepine. In fact, if you make somebody intoxicated on a benzodiazepine, it looks exactly like alcohol intoxication because we have GABA and benzodiazepine receptors are most plentiful. In the frontal cortex, people get a little disinhibited at the beginning. Then they start to get motor effects. They get ataxic. And then once it gets to a high enough concentration that it inhibits the brainstem, they go to sleep. And it doesn't matter whether you're talking about a benzodiazepine molecule or molecules of alcohol.

You'll see the same effects, different time course because of the different conditions. genetics of the two substances. In contrast to those immediate kinds of effects with drugs, most of the drugs used in psychiatry functioned via a process called initiation and adaptation. Basically, we're perturbing the way a particular nerve circuit works by increasing, as you pointed out serotonin with an SSRI antidepressant. That by itself, if that's all that happened, not much would result. But repeatedly increasing the serotonin causes a downregulation, a decrease in the actual number of post-synaptic serotonin receptors. That in turn produces changes in what are called second messengers, molecules inside the nerve cells,

and some of those go all the way on to alter DNA transcription in the nucleus of those neurons. The reason that it takes so long is that we're setting in motion a whole cascade of events that takes both time and repetition in order to alter the way that person's brain is functioning. Interestingly, this is the area where psychopharmacology and psychotherapy overlap. If you think about psychotherapy, psychotherapy essentially is a repetitive perturbation of brain circuits, looked at from a biological standpoint.

And that's not inherently different than perturbing those same circuits with a molecule. The best illustration of that was done by Lou Baxter while he was a neuroimaging specialist at UCLA. He operated a PET scanner. The experiment he did was to take a group of people with obsessive-compulsive disorder and anxiety disorder. He specifically chose people who had contamination obsessions. they responded by feeling an urgent need to wash their hands repetitively. He divided them into two groups randomly. One group he had to behavior response prevention.

That is, they would touch something they perceived to be contaminated, then they would be prevented from washing their hands, and that would be done over and over again by a behavior therapist. and indeed they got incredibly anxious the first time they did that but with each repetition they got less anxiety because nothing horrible happened to them he took a second group and put them on fluoxetine SSRI antidepressant increased their serotonin both groups got treated for six weeks at the end of six weeks he scanned them and found that the circuit involved in obsessive

compulsive disorder had essentially changed in the same direction in both groups. It didn't matter whether they got the behavior therapy or the Prozac. The activation of that circuit decreased and the strength of the negative feedback loop that's supposed to turn the circuit off had improved in both groups. a good example of how in this case a molecule and a psychotherapy had essentially the same biological effect that that is amazing um one one thought on that is how permanent is the behavior therapy versus the medication i know if you stop the medication the oCD comes back and my indeed that was one advantage of the um behavioral therapy because people actually learn to

take the behavior therapy home with them. They did a six-month-out follow-up, and those people who got the behavior therapy had some worsening of symptoms the further they got from the therapy, but they maintained benefit much longer than the people who had been on the medication, and then the medication was withdrawn. Essentially, once the medication washed out, its effect went away. I've treated some OCD patients, though, that they really need the medications to help them get over that hump of being able to do the behavioral therapy. Well, indeed, one of the interesting other findings they did, because as you might guess, this turned into a series of studies, was they later did a group where they combined behavior therapy and fluoxetine and found that the treatments actually had additive effects. that is they got greater benefit from the combination than they did from either treatment alone okay so with the depression so you're changing um epigenetically things going on which helps

treat the depression is that that's correct is that correct and what would you say um like so you're treating an episode of depression how long does someone need to be on this medication and have this change. And when you take them off of the medication a year later, is that the same thing like the OCD where it goes back? It depends on the individual. Some people do indeed have a single episode of depression in their life. And if you treat them to remission,

keep them in remission for a year, and then gradually taper and discontinue the antidepressant. They may never have another episode of depression. One of the things we learned, though, because it used to be indeed the recommendation in APA treatment guidelines and elsewhere that once somebody went into remission from depression, you always tapered the medication. We quickly learned, though, that if somebody's had two or three episodes of depression, they need to stay on antidepressant essentially permanently. because while we have corrected their epigenetic or phenotypic presentation, we haven't altered their underlying vulnerability to depression. And one of the unfortunate things about recurrent major depression

is that each episode the person has makes the next episode more likely. Yeah, and we're talking about pretty severe depression. I have one patient in particular that comes to mind that even has gone through ECT, electroconvulsive therapy. And although he wants to get off of his medication, it's, you know, talking to him and working through kind of the dissonance he has on being on medication at all, he has been stable for a couple of years with no significant depressive episodes, which has allowed him to continue his life and work and, you know, connect with his life.

family. So, yeah, I don't know. Well, I think the correct clinical framework for looking at that, for people with recurrent major depression, they have an underlying genetic abnormality that is going to make them prone to depression. And basically, their history has demonstrated that the framework is very much like treating somebody, for example, with type 1 diabetes melitus. If you put them on insulin, yes, you can normalize. their blood sugar, but we don't go, oh, your blood sugar is normal now, we can discontinue treatment because this is a chronic relapsing disease. Many of the psychiatric illnesses, we treat things like major depression, recurrent subtype, bipolar mood disorder, obsessive compulsive disorder,

psychotic disorders. Those are all chronic relapsing illnesses. Unfortunately, none of the medications we have, are at the present time curative. Instead, they ameliorate or control symptoms, but they don't really get rid of the underlying pathophysiology. I often talk to my patients, like once I get them out of a severe episode of depression, and if they want to try to get off the medications, I often talk to them about introducing a lot of lifestyle stuff, about getting therapy,

and making decreases in the medication very, very slowly. So let's say they're on like Lexipro 20, we'll go down five milligrams, have them come back in two months, see how they're doing. If they're feeling worse, we'll consider like, okay, what's the best course of action next?

Yeah, and that's very prudent because, and many of these patients will find that if they attempt to get off the medication, the illness is going to come back. And I think educating them about that and about the fact that for many of the illnesses we treat that are chronic and relapsing, these are really based on underlying genetic abnormalities

that at present we don't have the ability to fix. And consequently, their probability of having a relapse in many cases, particularly if they've had a number of episodes, is going to be quite high if they discontinue the medication. Probably the other important element in that is when people have a relapse of major mental illnesses, things like major depression or psychosis, schizophrenia spectrum disorder,

there is no guarantee that the next time the treatment will work. We gradually tend to lose capture in terms of being able to put the person into remission. You know, that is, many psychiatric illnesses that are chronic and relapsing tend to become, more and more and more resistant to treatment over time. I've had a number of patients in my career who, when they were young, their illness responded pretty promptly to fairly modest treatments.

By the time they were older and had a number of relapses, they were reaching the point where medications didn't really put them in remission anymore. They got improvement, but they didn't really remit. And basically their illness was getting beyond the effectiveness of the medication. I'd be curious, how do you differentiate, you know, this person needs medications, let's say they're early on, you know, they haven't had a lot of episodes, versus this person would benefit more from like lifestyle changes in psychotherapy? A lot of it depends, I think, on their presentation.

If somebody is dysphoric, that is, they're unhappy with some aspects of themselves or with their life, then certainly making lifestyle changes and pursuing things like greater exercise are certainly a good place to begin. I think medications get introduced either when the illness is more severe, they have neurovegetative signs and symptoms, or when they've tried the life. lifestyle changes and they just aren't adequate. Describe like the neurovegetative symptoms of depression. Neurovegetative signs and symptoms are things like typically loss of appetite or increased appetite associated with weight loss or weight gain respectively.

Severe energy. The person just doesn't have the wherewithal to get out of bed. severe sleep disturbance, often with early morning awakening, either psychomotor retardation, they are physically slowed down. They look like they're embedded in molasses or psychomotor agitation. They can't sit still. Those people are suffering from central nervous system or brain disturbances that are so severe that lifestyle changes aren't likely to benefit them adequately.

that doesn't mean they can't benefit from lifestyle changes once the illness is under better control. In fact, I tend to see the role of medication is often improving the person's illness to the point that they can then take advantage of things like psychotherapy or lifestyle changes. Yeah, I think it's harder in this day and age to get good psychotherapy. I had even at like Kaiser had a couple of patients recently tell me it's really, hard to get in and consistently see someone or you know if you're a county patient it's really hard to often get into a weekly therapist yeah it is unfortunately there is a huge deficit in terms of the number of therapists available out there what do you think like in terms of depression do you think all depression is a serotonin issue or how would you do you think that there's variance on

that what do you think and what do you think about inflammation as like a component of depression? Well, I think picking any single neurotransmitter and saying this is the cause of depression is probably overly simplistic. Psychiatry's gotten fallen into that trap. Previously, depression appears to be a core dysfunction of the limbic system.

And that has several components because that system is modulated by a number of neurotransmitters Certainly serotonin is a major one, but norophenephrin and GABA and other protein neurotransmitters all play a role in that system. It's likely that in many depressions, the reason that we don't get an adequate response to a single agent is because fixing that particular neurodiscences, transmitter pathway is just not adequate. And you can see that in some of the data of comparing selective serotonin re-uptake inhibitor antidepressants to other antidepressants in major depression in mild to moderate illness,

meaning severity. The SSRIs do just as well as things like tricyclics and mixed mechanism antidepressants. But once you start getting into severe depression, more melanom. oncolic depression, worse neurovegetative signs and symptoms, all of a sudden, the SSRIs don't do so well. And that may essentially speak to the issue that nudging or perturbing a single neurotransmitter in severe illness may just not be adequate. You may have to go after several therapeutic targets at the same time. What do you think about the inflammation as like a component of depression? Certainly it is true that cytokines in general do have a depressant effect on people.

It's one of the reasons people have a feeling of dysphoria, malaise, and urgia when they come down with many viral illnesses. Essentially this is a response of the immune system producing cytokines, which in turn alter neuronal functioning. and it appears that in depression and in psychosis and perhaps in anxiety disorders, there is an element of dysregulated and inflammatory response as well. What do you think about people who would say that there is no such thing as a serotonin deficiency? Well, in a very strict sense, that is true. In fact, our model of looking at things like major depression has changed. because if you actually measure the amount of serotonin via magnetic resonant spectroscopy

in people who are depressed, the amount of serotonin is normal. What we may be looking at instead is much more analogous to something like congestive heart failure, where the limbic system in this case is failing, and its failure or its pathology has gotten beyond the ability of the person's serotonin and noraphenephrin and dopamine to adequately modulate. Essentially, they've gone over the psychiatric version, the top of the starling curve,

if you applied it to the brain as opposed to the heart. The systems are driving as hard as they can to try to correct limbic system functioning, but they've failed. We come along with our antidepresser. and we basically give those modulatory systems an artificial boost in much the same way that we give cardiac modulatory systems a boost with things like de jocin. I think it was Kirsch out of Harvard who looked at a meta-analysis of like antidepressant studies and he included the ones that were not published, the unpublished and the published. and he came out with like very low effect size for antidepressants and the use of them.

I was wondering if you had any thoughts on that study in particular. Well, indeed, that was an interesting study in that it looked at both published and published sources of data. Even in the published literature, though, the overall effectiveness of antidepressants is a lot lower than we would like it to be. If you define response as a 50% reduction in depressive signs and symptoms, then most of the antidepressant trials will cite you a figure of around 60 to 65% response rate. If you get more strict, though, and say, well, how many of these patients actually went into remission?

That is, they were free of depressive signs and symptoms. That number drops to somewhere around a third, which is, you know, if you go to somebody with a disease, and they tell you, well, we got a one-third chance of making you well. That's not as good as would be desirable. Yeah. So the other thing that I was thinking about when they look at effect sizes of antidepressant trials is that the placebo is often fairly powerful. Because when you look at psychotherapy and you compare psychotherapy treatment to no treatment

or you look at exercise, exercise to no treatment, the effect size is actually quite a bit larger. And I think it's because the placebos are not very good for those groupings of studies. Whereas for antidepressants, you know, if a doctor gives a patient a pill, like there's the belief that that is going to help. Well, you have a direct placebo effect from having received a pill that does not contain any active ingredients. But one of the problems for both psychotherapy studies and psychophromic,

of the pharmacology studies and in depression in terms of the effect size is that you're taking somebody who was previously getting no attention and in a research study even if they don't get the active treatment they're still getting brought in regularly they're getting talked to they're getting attention and time and for many people with depressive illness those are sometimes enough to push them toward being less depressed you know, social interaction itself has antidepressant properties. And even if you're in the placebo arm of a trial, you're still getting social attention and time. Which is why in many of the antidepressant trials, you'll often see a 25, 30, 35% placebo response rate.

Yeah. Plus, some of that may be they're spontaneously getting better. Yes. Well, that's the entire reason you have to have a control group because if you simply give somebody something that you suspect might be a treatment and they get better, you can't really say that what you gave them caused it because it could have been something completely different that caused the change for them. You have to have a group that is as much like them as possible but isn't getting the treatment so that you can ferret out what was caused by the treatment and what. wasn't. Well, I really appreciate you, Dr. Cummings, and coming on here and giving some of this information. And yeah, I don't know, do you have any final thoughts or shall we leave it there? I think that's probably a good place to stop. Okay, so next session, what will we be diving more into? Next session, we'll talk about the antipsychotics, both their history, how we think they work, and what kind of illnesses and conditions they've shown benefit for,

and we'll also talk about some of the risks of various medications. And I'll put some in the show notes. I'll put a link to some of the notes that Dr. Cummings has written on this, plus some notes from the episode. And I hope this was helpful for you, and until next time, have a good day.