Psychiatry & Psychotherapy Podcast - The History, Mechanism and Use of Antidepressants

Episode Date: July 24, 2018

In this week's episode of the podcast, Dr. Michael Cummings and I talk about the history of antidepressants, and their use in overcoming depression and anxiety disorders. By listening to this episode, you can earn 1 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. Welcome back to the podcast. I am here once again with Dr. Michael Cummings, a group. psychopharmacology resource. He's been on us in prior talks on schizophrenia, the basics of psychopharm, antipsychotics, and psychopathy. Dr. Cummings, welcome back. Thank you very much. I'm glad to be back. As I understand, today we're going to talk about the antidepressants, particularly in relation to treating depression and anxiety disorders. Yeah. So do you want to start again with a little bit of the history of the antidepressants?

Sure. If you may recall from our previous podcast on the antipsychotics, the investigation of anihistamines led to the discovery of promethethazine and then to chlorpromazine, and then the antipsychotics sort of took off, and there was a period of about a decade of intensive discovery and investigation of different antipsychotic compounds. As you might guess, though, as people made variants of the antipsychotics or what they thought might be antipsychotics, some of the molecules that were produced turned out not to be dopamine antagonists, but had other properties. One of the first in which that happened was the tricyclic antidepressant imipramine, originally clinically discovered by Dr. Kuhn in Switzerland.

He was working in a psychiatric hospital, and at the time, research was not nearly as regularized or as systematic as it currently has become. And he was largely experimenting with a molecule he had been given amypramine, which he discovered was not effective in treating psychosis, but appeared to improve mood and anxiety symptoms. and indeed that led to the discovery of the tricyclic antidepressants, which grew to include a fairly large number of drugs, both tertiary amines and secondary amines, things like amatryptylene, nortryptylene, amyprimine, and subsequently desmethyl amyprimine or desipramine. And somewhat in parallel with the discovery of the tricyclic antidepressants,

in large part because from World War II there was a great amount of hydrazine missile fuel left over. People began experimenting with that as a base compound for development of drugs. One of the first drugs to come out of that was isocarboxazid, which was not used in psychiatry initially. It was used to treat tuberculosis. Turned out, though, that a few of the people who were being treated for tuberculosis, happened to be bipolar and became manic while taking isocerboxid, which gave people pause. They sort of sat up and said, hmm, well, that's interesting.

And that led to the discovery of the monoamine oxidase inhibitors. Isocerboxid itself was eventually removed as a medication because it is fairly hepatotoxic. So before tricyclics, before monomine oxidase inhibitors, how are people treated for depression? By and large, people were treated for depression by sending them to restful places in the country, the asylum movement of the late 19th century. There weren't really any, they were also treated, of course, by psychotherapy.

Psychoanalysis had been in place since introduction by Freud in the late 19th century. there were, however, no effective pharmacological treatments for depression. The other modality that was in use was convulsive therapy, discovered originally by Meduna in Hungary. It was not originally electroconvulsive therapy. It was a convulsive therapy that was chemically induced, somewhat harder to control, but was effective. In the 1940s, the drug-induced seizures got replaced by electrically induced seizures, and it was frankly very widely used in both mood disorders and psychosis. Then as now, it was a highly effective treatment,

but in its original form was also quite a brutal treatment because if you induce a grand mal seizure to dismal seizure, two to three times a week. The persons are going to be pretty physically beat up by having that many seizures, even with precautions like bite blocks for the tongue, etc.

People wound up with broken bones and muscle damage. The other problem, of course, was that because there weren't many pharmacological treatments in psychiatry, frankly, ECT got overused and consequently developed a terrible public reputation.

It was reformed later on in terms of paralyzing people and using anesthesia prior to treatment, which has made it a much more humane treatment. It still remains the most effective treatment there is for severe melancholic depression. Yeah, I think it's important for those who may not be familiar with this, that they used to induce the seizure and the person's whole body would shake. But at this point, they use a paralyzing agent and also a sedating agent. So they're basically not experiencing the seizure. And their body is not shaking, except for they put a blood pressure cuff on,

I think the right calf, which allows you to see some contraction in the right foot. Yeah, exactly right. That's just to indeed confirm that the electric. activity is going on in the brain that you're looking for. When I was reading about Winston Churchill, interestingly, he had pretty significant depression, which it was thought allowed him to possibly see with concern some of the events that were developing with Hitler's rise. And so with his depression came maybe a realism that other leaders didn't have.

But he was treated with his depression. I think with amphetamines at the time. Yes. And certainly the amphetamines were helpful in terms of energy, lack of energy. But the amphetamines turned out not to be an effective overall antidepressant treatment. We still occasionally use amphetamines or methylfinidate in anergic depression, such as in HIV or in the elderly depressed person who has a severe lack.

of energy as part of their depressive illness. But that's essentially in combination with antidepressants. So historically, if someone did not receive treatment, how did a melancholic depressed person progress in their years? It was a fairly negative development. The average length of an episode of major depression, if you don't treat it, is around 11 months, so almost a year. People often had an average of four to eight episodes during their lifetime.

One of the major issues with major depression then, as now, is that each episode of major depression appears to make the next episode more likely. The annual prevalence rate for major depression estimated in the U.S. and in Europe ranges from 2 to 7%. but if somebody has an episode of major depression, the odds that they will have a second episode at some point in their life rises to almost 50%. And then for each episode they have after that, the probability of the next one becomes more likely.

And certainly in people who had recurrent episodes of major depression, by the time they were in their 50s, 60, 70s, they had often become chronically depressed, withdrawn, apathetic. Their life had deteriorated significantly. One thing that I think is important to sort of understand, and maybe you can put more details to, is what physiologically may be going on in the brain that would cause a subsequent episode of depression to be more likely?

One of the effects of major depression, aside from changes in neurotransmitter signaling, is an actual reduction in the metabolic rate in neurons in the brain. There's a 30 to 40 percent decline in the rate of metabolic activity among neurons. There is a steep decline in the production of neurotrophic factors that is protein. that promote neuron activity and cell growth in the brain. And as a consequence, there is actually a thinning of the cortex, a loss of the dendritic spines on neurons. And there is evidence that although the recovery after major depression

is nearly back to original baseline, particularly in recurrent depression or in people who alternate between major depression and a more minor form of depression called dyshthymia, their brain may undergo gradually increasing anatomical damage in terms of the cortex and the dendritic spines. And that accumulating pathology appears to set them up for the next episode to be more vulnerable to stress diathesis and the occurrence of the next episode. of depression. Anything going on with cortisol, the hypothalic pituitary access in this?

One of the chief characteristics of major depression is a rise in the release of corticotropin releasing hormone, which in turn produces an increase in the release of adrenocorticootropin hormone from the pituitary that stimulates. the adrenals to produce more cortisol. Cortisol essentially functions in humans as a stress hormone. The intent is to help counterbalance stress and return us to a baseline state, but in major depression, that positive benefit fails, and essentially the person's brain winds up being exposed to chronically elevated levels of cortisol, which has an involutionary. effect on DNA transcription in cells in the brain,

particularly in the limbic system. And that may be, in some people's research, suggested as the source of treatment resistance as people develop more episodes of depression. So there's these brain changes going on, and there's, you know, cortisol, Cortisol is increasing, which is causing things in the brain to change. And what would you say is different about melancholic depression from other depressions?

Melancholic depression is at the severe end of the depressive spectrum. These people have a severe loss of enjoyment. They're anhydonic. They lack energy. They often develop mood-congruent psychotic symptoms that are, you know, delusions that they're guilty for everything in the world, very pronounced negative rumination, they lose interest in food, and in fact, if they're not treated, they just sort of curl up and die. It also tends to be the most resistant form of depression. These people often wind up requiring electroconvulsive therapy to get them out of that depressive state. Depression comes in, of course, a range of severity.

You have dyshthymic disorder, which is a milder form of depression. Major depression, which starts just above dysthymia and progresses to melancholic depression. The DSM-5 describes the criteria. Nine in criteria, either anhedonia or depressed mood daily for at least two weeks. And then it gives a host of additional symptoms the person needs mostly neurovegetative signs of symptoms like disturbance of sleep, disturbance of appetite, weight gain, weight loss, agitation or hypoactivity, early morning awakening. basically the person has to have nine criteria in order to be diagnosed as suffering for major depression. Dyshthymia is very much the same illness, but with fewer criteria having to be met. So severity I think matters, and I'd be curious what your thoughts are on,

like how severe someone needs to be to be put on, you know, an antidepressant? Certainly, if somebody's having an initial episode of depression that is not severe to the point that it's inducing suicidal ideation or impairing their ability to engage in activities of daily living, then certainly often a place to start is with psychotherapy. Several psychotherapies have been demonstrated to be effective in treating depression, including cognitive behavioral therapy, interpersonal therapy, brief analytic psychotherapies. Certainly exercise also can be of benefit in milder depressions. And that's often a place to begin. If, however, the person doesn't respond to those treatments or the depression is becoming more severe, or in particular, If this is somebody whose family is somewhat genetically loaded for depression, then treatment with an antidepressant medication becomes a larger consideration.

Overall, it's thought that about 40% of the probability of becoming depressed is genetically determined the other 60% arising from the environment. There are also important gender differences. Women during their reproductive years have about twice the rate of major depression compared to men. Now, pre-menarchy and post-menopausally, men and women have the same rate of depression, suggesting that hormonal cycling during the reproductive years may add an additional burden in terms of vulnerability to depression and women. And certainly if somebody's had recurrent episodes of depression,

the thinking is very much along the lines of they should be on an antidepressant and it should be continued indefinitely. It used to be that if somebody recovered from depression, then after a year, everyone would be tapered off and discontinued. That changed when people began to recognize the progressive nature of major depression, that is that, as we said, each episode makes the next one more likely, and the more episodes people have, the more resistant it tends to become to treatment. Yeah, and I think I may vary a little bit on that point just because I think if someone

has followed closely outpatient and has been, let's say they've had a couple episodes, but they're not severe. Now, I have several patients whose episodes are severe and they have significant family history of depression as well. if they have that significant family history and they have this pretty severe episodes of depression, I would say absolutely they need to be on antidepressants. But if the patient has really engaged psychotherapy for a couple years or six months and they're doing lifestyle stuff that they weren't doing before, then I may try them off of, I may slowly bring them off of antidepressants and then watch them closely.

Yeah, certainly. Along with that, though, I would, add the educational point for them that, you know, if you've made these changes and you've benefited from psychotherapy and we take you off medication and the depression comes back, then next time we won't be nearly as ready to take you off of medication simply because of the risk of increasing probability. Sure. Sure. Yeah. Absolutely. because one of the things that's true with all of the antidepressant treatments we have is the more episodes the person has, the more resistant the depression becomes, which renders our treatments less and less effective,

such that thinking about the person's overall lifespan, we should be working to avoid the circumstance in which we now have an elderly depressed person who has lost the capacity to respond to most of the tools we have to work with. That's a very difficult position to be in. And that's often cases where we wind up with ECT as the treatment. In some cases, the only treatment that works. There's a couple thoughts on this, but I think the main sort of thrust of what I wanted to

look at and what I think we've really detailed well is a little bit of the history of what happened before, before the antidepressants came out, and a little bit of history of what happens if depression goes on untreated and sequentially how things develop in the brain. So with that, why don't we jump into what happened with the SSRI and the advent of the serotonin re-uptake inhibitors? Yes. Well, indeed, the first antidepressants, the tricyclic antidepressants were never a comfortable medication class, largely because these are drugs that are cardiotoxic at relatively low concentration, six to eight times the therapeutic concentration is a potentially lethal concentration. So taking

a week's worth at one time stood a pretty good chance of killing somebody. Well, in a population prone to suicidal thoughts, that's not a very comfortable position to be in. The monoamine oxidase inhibitors can, if the person is exposed to tyramine from food or to sympathomymedic agents, cold medications in many cases, can produce hypertensive crisis with blood pressures that can cause vascular damage or death. The SSRIs were almost instantly popular after the introduction of fluoxetine in large part, not because they were more effective than the older antidepressants, but because they were much safer.

As the name suggests, these drugs selectively inhibit the re-uptake transporter for serotonin, thereby increasing the amount of serotonin available in the brain. But by and large, they don't do a great deal else that is toxic or likely to produce problems. So that, frankly, if somebody overdoses on an SSRI antidepressant alone, it's almost impossible to kill the person with an SSRI. If you mix it with an agent that has other means for increasing serotonin, you can produce serotonin syndrome, which can cause death. But that's a relatively rare negative outcome. The SSRIs became very widely used very quickly for treatment of both major depression, dyslymia,

and also for a host of anxiety disorders, increased serotonin input to the limbic system, particularly the anterior temporal lobe in the amygdala decreases the amount of anxiety and vigilance that the person has. They've been found to be useful in, for example, post-traumatic stress disorder, obsessive compulsive disorder, generalized anxiety disorder, social phobias, and even in orders that are more impulse-based like binge eating. The SSRIs have shown benefits. So they've become widely used. altogether the SSRI antidepressants account for about 70% of the antidepressant prescriptions in the United States each year, being used for both anxiety and major depression and dyshthymia. They are as effective as the mixed serotoninorean antidepressants in mild to moderate levels of depression. they tend to become less effective than mixed mechanism agents

once you get into the more severe, more melancholic depressions. Yeah, what do you make of that? Why do you think in the more melancholic depressions that noraphenephrin re-uptake inhibition is helpful? Well, I think basically one thing that has changed is our model of depression has gone from, oh, well, you're depressed simply because you don't have enough norapenepine, or serotonin, which was kind of a simplistic catacolamine model to now looking at it more as

things have gone wrong in the limbic system. And these molecules, serotonin and noraphenephrin that are supposed to modulate the limbic system have gotten overwhelmed. The limbic system has gotten beyond their ability to modulate. And what we're doing is essentially artificially increasing the modulatory range of these molecules. Well, with an SSRI, we're largely increasing one of them, whereas, of course, with a mixed antidepressant, we're increasing serotonin and norapherine. And it may be that in more severe depression, using a single lever to try to push the limbic system back into operating normally just isn't as effective as using more than one lever. Okay. Okay, so it sounds like when you have a severe depression, a

melancholic depression, having two of those levers at once can be helpful. What else would you say in terms of like if the antidepressants aren't enough in that melancholic depression, where else would you go with the patient? In many cases, I think you're then looking at considering electroconvulsive of therapy, particularly if it's a severe melancholic depression. The person's not eating, not drinking. They're literally going to curl up and die if you don't do something. There are other adjuncts available that have been looked at that show promise, certainly transcranial magnetic stimulation, has shown positive benefit in terms of augmenting

antidepressants, as has vagus nerve stimulation in some chronic recurrent. depressions. Certainly combining the antidepressant with an effective psychotherapy has been shown to have additive benefits. So in many cases of depression, it calls for a multimodal intervention. One of the caveats with the antidepressants is that their efficacy is more limited than we would like it to be. If you look at most antidepressant studies, they report effectiveness in around 60 to 65% of samples.

Well, they're defining responses of 50% reduction in depressive symptoms. Well, if you're severely depressed, it's great to have a 50% reduction, but that doesn't mean that you're well. If you look at how many people go into remission in those studies, you're now talking about numbers down in the range of about a 30%. Well, that's not a very satisfactory outcome if you're the depressed patient. So our antidepressant treatments indeed do have limits. We've looked at ways of augmenting that, including the methods we've already talked about, use of combined antidepressants that have different mechanisms of action, augmentation with mood stabilizers like lithium.

in women in particular supplementation with thyroid hormone, specifically tri-iodothyronine is effective in some patients. One of the caveats in this as well is that many people who are depressed and receive treatment don't really receive adequate treatment. a number of years ago, the APA American Psychiatric Association did a survey in both primary care and psychiatric offices looking at dose and duration of treatment for major depression. They found that depressed people in primary care offices got what they judged to be adequate treatment about 41% of the time, and in psychiatric office is about 61% of the time. So certainly one of the things we can do is psychiatrists is be sure that our patients receive an adequate dose of antidepressant for an adequate duration. Duration in this case means at least six to eight weeks to see if the person will respond and in many cases pushing the dose to the upper end of the therapeutic range. I think it's worth going through some of the side effects of the SSRIs. One of the complaints I get quite frequently from parents of the adolescents I treat is the black box warning, increased suicidality.

And it seems very counterintuitive to the patients. Here you have a medication that's being used to treat depression, and yet it causes suicidality. Yes. And in part that's, you know, frankly, I've been around long enough that the SSRIs aren't the first antidepressants in which this has occurred. it frankly occurred with the older drugs as well. One of the truisms about depression is that when you start treating somebody with an antidepressant, not all of the features of the depression respond at the same rate. People who are anergic, anhydonic, apathetic, and have a depressed mood,

often don't do much about it. When you start treating somebody with an antidepressant, the energy level and their thinking and their neurovegetative signs often respond before their mood does, which means that you now have a more energetic depressed person, and indeed studies going back decades suggest that that exposes the person to a period of vulnerability to suicidal ideation and suicide impulse. Now, the warning that the FDA issued was correct, that is, giving somebody an antidepressant, SSRI, will increase their risk of suicidal ideation early in the course of treatment, meaning the first few weeks.

Their intent in issuing the warning was to try to get clinicians to not do what clinicians often do is say, start this and come back and see me in a month, because that's after the person begins to become vulnerable. it would be more appropriate to say, here, start taking this and make contact with me in a week. Unfortunately, what happened because of the warning was that many prescribers stopped prescribing SSRIs for children

and adolescents and young adults, and the actual suicide rates went up because now they were suffering from a depression that wasn't receiving appropriate treatment. and it was a great example of unintended consequences. I think it was something like 2% in the placebo group and 4% in the, correct me if I'm wrong on that, 4% in the SSRI group had just suicidal thoughts,

but no more suicide attempts. Yes, yeah. Is that around the numbers? And in fact, what tends to occur is that, right, the group receiving the medication had more suicidal thoughts, more episodes of thinking about suicide. Their rate of completed suicide, however, did not differ from the placebo group. And indeed, over time, as you might expect, as their depression improved, their risk of

suicide declined. Are there any studies that show that antidepressants decrease suicidality? There are a number of studies that there are a number of studies that that they're that demonstrate that antidepressants decrease completed suicides or suicide attempts. I think that's one thing that was lost in that initial message was that the increase was limited to suicidal ideation. But when they compared actual completed suicides or rates of suicide attempts, the antidepressants initially don't differ from untreated people, but then the antidepressants begin to improve the depression and suicidality declines,

meaning suicide completers and suicide attempts. I wonder, because the suicidal thoughts had a very, very slight increase, I wonder if it's tied to acesia at all or tied to, sometimes patients will get a little bit increased anxiety as they get on the medication before the anxiety decreases. Do you have any thoughts on that? It may well be. acothesia is a possible but relatively rare outcome with the SSRI's serotonin decreases dopamine release

and that may cause acethesia in some patients particularly elderly patients who may not have a lot of dopamine reserves to begin with certainly increased anxiety initially is a possibility and in fact when these drugs are used to treat anxiety disorders it's very, very important to educate the patient that initially their intensity of anxiety is likely to increase before it decreases. Because these drugs essentially increase the amount of serotonin available within a few hours, whereas the improvement is dependent on more downstream processes, like downregulation of post-synaptic receptors and changes in second messenger populations inside the neurons,

those processes take weeks, whereas the increase in neurotransmitter takes hours. So initially the person is going to have an increase in anxiety, and if you don't educate them, they're not going to be very happy when they go from two panic attacks a week to three panic attacks. attacks a day. But if you warn them in advance of the increase, they at least will be forewarned. And in many cases, you may need to use an anxiolytic transiently at the beginning of treatment

to dampen that effect of the antidepressant. Yeah, I had one patient in particular that comes to my mind, and I'll change a couple of variables, as I always do, to hide their identity. But this person was a, let's say, female respiratory therapist who had to stop working because she had severe panic attacks. And she ended up in the county system because she had lost insurance and lost her home and was essentially very, very poor at this point, estranged marriage and just huge consequences from the panic attacks. And the only thing that she wanted was Xanax. And she came in and that's all she wanted and she had tried Selexa for two weeks and she had tried Zoloft for I think three weeks

and she said that it worsened her anxiety horribly. And she's likely right, it probably did. Yeah, yeah. And I think she had tried even a couple more. And I told her I would give her Xanax only under the condition that she worked with me and took an antidepressant at the same time. And I think we started off at like, like, an eighth of a dose of the smallest dose possible of, like, Lexapro. So she was, like, cutting it multiple times. And that was the only thing that she would, like, tolerate. And, like, slowly, I held, I held her hand. And by holding her hand, I mean, like, you know, frequent calls to remind her to, you know, I told her, before you quit, just give me a call here. And I'll talk, we'll talk and see if it's a good time to

it or not. And she, it took about six months to get her to a dose that was a small dose that she could tolerate and she was on it for six weeks and the panic attacks went away completely. And

once those receptors begin to down regulate, then things improve dramatically, but it may be quite a steep climb for some patients to reach that point. That's where indeed, as you did with this patient, repeated support and education about what to expect is very important.

You know, patients are much more likely to adhere to treatment if they know what's coming. It doesn't come as a surprise. Yeah, and this patient, just to give the good news, she was able to get back to work, she was able to get remarried, and she's doing well. And once in a while she shoots me an email and says, hey, Dr. Peter, me anymore, but I'm doing great. Just want to let you know. Thank you so much. Well, I think the other thing people don't appreciate with panic disorder is just how severe the initial panic attacks can be. These people do literally feel as if they are dying.

This is a, I think as we may have touched on before, a false triggering of our fight-flight response. essentially having a panic attack would be a normal response to a life-threatening event of some kind. You're suddenly faced with something that's likely to have you for lunch. That system is largely the located in the non-dominant temporal lobe and involves the amygdala, the anterior temporal lobe, and the parahippocampal complex. That part of the brain is sort of there to chronically monitor. monitor the environment for threats and hopefully allow you to either fight or run away before something bad happens to you. In some people, though, it appears that that system is a little

too hair triggered, and in panic disorder, it goes off when there is no threat. And of course, it's a horrible experience, and then people develop all sorts of anticipatory anxieties, depending on what their environment is at the time of the panic happens. Yeah, and it's interesting as I look at a panic episode, like a severe one compared to a traumatic event. And it is on the same level in my sort of experience as like them going through a near-death experience. The same type of PTSD symptoms I think can develop. And sometimes I think after people get the treatment and don't have the panic attacks, they still need to get like some therapy for those panic attacks in the sense that they were like felt as if they were traumatic events.

And sometimes I've sent patients to like EMDR, for example, to kind of work through those discrete episodes. And it's really helped, it's really been helpful for them. Yeah, they often need, you know, after they've accumulated the anticipatory anxieties, they often then indeed need help with behavioral exposure therapies to, make them less sensitive to those environments. In fact, that's thought to be how people with panic disorder, if it goes untreated, eventually become agoraphobic. They can't go out of their own house or in some cases their own room

because they've become phobic of essentially the entire world. Because if something horrible like that happens to you, you then tend to associate whatever your environment was with that horrible experience and obviously if it happens in enough places, well, the entire world becomes provocative. There was another story that I think is a good one to relay of OCD. And I think the tricyclic clomeropramine is one that uniquely has a high effectiveness for OCD compared to the SSRIs.

I don't know if you agree. with that completely or if you... Yes. There have been a number of studies that have demonstrated clomipramine anaphrinil is the trade name, is more effective for OCD than the SSRIs. Now, the SSRIs can be highly effective. People often, if they're using antidepressant doses, don't push the SSRIs far enough. For example, if you were using cert Rolene to treat major depression, the dose range is typically 50 to 200 milligrams a day. with OCD, you may not uncommonly have to increase that dose up to around 300 milligrams a day or more.

And instead of taking four to six weeks to get a response, it may take 8 to 12. So it's a slower response. Even in those cases, though, an aphronil is more effective. It's thought to be more effective in some ways because it is a somewhat dirtier drug. it's a tricyclic antidepressant. It is a very robust increaser of serotonin by blocking re-uptake.

It also does, however, have some affinity for noraphenephyrine, so it increases norapheneph. It's antihistaminic, so it tends to produce some anxiolytic effects by blocking histamine receptors. And it may be indeed

the combination of effects that make it overall more effective. It's a somewhat difficult drug to tolerate because it also is a good alpha adrenergic blocker so it lowers blood pressure. People can get dizzy or can faint if they are taking too much. And it's very anticholinergic, which gives people blurred near vision, dry mouth, constipation, urinary retention.

So it's side effect profile like most of the tricyclic antidepressants is a little bit harder to tolerate. One thing I wanted to pick your brain about is the common side effect of sexual dysfunction that occurs with antidepressants. One of the sort of difficulties as an outpatient psychiatrist that I see is, you know, you may be treating a patient. I have a number of really severely depressed male patients, a couple of female patients as well, but specifically some male patients that it's like they weren't thinking about having sex that much when they were severely depressed.

But now that they've been brought out of depression, and all of a sudden, you know, the side effect of, you know, difficulty with ejaculation or difficulty with decreased libido comes into, like, focus with some of the SSRIs. Yes. Increasing serotonin dramatically does tend to impair sexual function in males that can. result in erectile dysfunction, delayed orgasm, or anorgasmia. And in women, it can result in vaginal dryness or anorgasmia, delayed orgasm as well. Basically, arousal is based on activity by the parasympathetic nervous system using acetylcholine, and orgasm is based on triggering by the sympathetic system using norapinephrine, increasing serotonin in the spinal cord

basically can interfere with both of those processes. In the original, if you look at most of the original package inserts for the SSRIs, they quoted sexual dysfunction figures of 5 to 7%. Those were frankly falsely low because they only were, reported those cases where people stated this spontaneously. They didn't ask. When you actually went out and asked people how many were having sexual difficulties, it's more like 50 to 70 percent, have some degree of sexual dysfunction.

It can be mild or it can be, as you say, severe with loss of sexual functioning altogether. Moving to a mixed mechanism agent will help fix that. use of drugs like buproprion that are mostly noradrenergic can also reverse that effect of the SSRIs. And more recently, there are now what are essentially SSRI antidepressants that also have as part of their pharmacology's direct stimulation of 5HT1A receptors. This is vortyoxetine. and velazidone, their rate of sexual side effects is much lower because that stimulation of 5HT1A

receptors tends to mitigate against their partial agonists at that receptor, so they tend to protect the receptor from the overall increase in serotonin. The problem with both of them, of course, at present is they're both still proprietary drugs, which makes them more expensive than the SSRI antidepressants that have become generic. What do you think about, so my go-to with a male patient that comes in with depression, that complains of previously having pretty significant erectile dysfunction issues with an antidepressant, my go-to would be to try buproprion or metasapine first. Yes.

Bupropyron is excellent. It is almost purely noradrenergic and consequently it does not interfere with sexual functioning. In fact it may actually improve libido much more than

the SSRIs. Mertazapine is a unique drug in that at higher doses it increases norapinephrine release by inhibits. Inhinephinephinealase by inhibits inhibiting auto receptors for noropenephrine, alpha-2 receptors in the locus serulia,

so you get more norapinephrine output. And it also blocks 5HT2A receptors, so it acts as a serotonin antagonist, that particular receptor, which may provide some benefit with respect to sexual functioning, but it appears to be primarily the fact that it can include. increase norapinephrine substantially. What do you think about, okay, so if those don't work, you know,

phylazidone would be another option in my mind. But let's say they have to be on an antidepressant. Would it be helpful in your mind to, you know, check their testosterone levels, optimize their testosterone. Is there any studies on that? There are studies on that, and indeed it is particularly a thought in older male patients. Unlike women, men don't go through a tightly defined menopause

with a sharp drop-off in testosterone production. The peak of testosterone production, and most men, however, is around 18 or 19 years of age, and then there's kind of a gradual, steady decline thereafter. so that by the time somebody's in their fifth or sixth decade, erectile dysfunction becomes fairly common. It's estimated that about 40% of males over 50 have some degree of erectile dysfunction. And indeed, checking their testosterone is worthwhile doing because you may find out that they're in a subpopulation

that have had a more rapid decline than other people. And, of course, for erectile dysfunction per se, even if the person needs to be on an antidepressant, if it's not anorgasmia but is erectile dysfunction, the phosphodiasterase 5 inhibitors, Cialis, and cilinophil, Viagra, can be highly effective in treating that particular side effect of the antidepressants. And one of the inputs that you gave me, I think, was helpful,

and one of my patients was Sildenafil daily. Yes. And it made more of an effect than once in a while taking it. Or not Sidenafil, Cialis. Yeah. Cialis has an effect length of about 36 hours, and it can be effective if taken on a PRN or as needed basis, but it does become much more effective if it's taken routinely.

Cyldenafil has a much shorter effect time of around four hours, it works much better as a, as needed our PRN medication. So if the person's erectile dysfunction is chronic and they would like not necessarily to have to plan ahead carefully, or if their erectile dysfunction is more severe, then using Cialis chronically may be more effective for them then using sylidinifil as needed. What about tracidone as a use for kind of decreasing the erectile dysfunction?

Have you seen that? Can work in some people. It is less often effective than the phosphodasterase 5 inhibitors. Because it's an alpha antagonist, it can work. And indeed, as you know, one of the. the adverse effects of Trazodone and some people is to cause priapism, which is prolonged

painful erection. Usually in lower doses, it can be tried. The other caveat with Trazodone, though, is it's a very potent antihistaminic drug. So you can wind up with the unfortunate situation

of somebody who now is sexually functional, but too sleepy to be interested. So you couldn't take in the before you would have to take it before the sexual encounter? Pretty much, yes. You'd want to have the sexual encounter during the drug's onset of action. Onset of action is usually between one and two hours after the doses taken.

Unfortunately, that's also the same period of time in which it tends to make people sleepy. Okay. Interestingly, as I think about this and I think about the cases that I've seen, a lot of the times you know, you give the sedentphil and they're able to get an erection and they're able to ejaculate. And then they realize like it's more of a marriage problem. Have you seen any stats on how often people don't subsequently fill the Viagra or like what the, even if it successfully helps them? I haven't seen any good statistics on that.

However, the problem you point out is a real one. Often people who've focused on sexual dysfunction as problematic in their relationship find out that there are other problems or that the sexual dysfunction was essentially the identified problem when there were other more core problems present. I've even seen a few cases in which the partner was not happy necessarily about return of sexual functioning. And that caused some degree of dispute. Yeah.

And sometimes I think if someone's been significantly ill for a while, the spouse takes on more of a mother role, either, you know, irregardless of the gender, sort of the parent role. And that can decrease sort of the sexual interactions. But once they sort of level out their roles again, maybe. maybe by taking back responsibilities that they gave up when they got severely ill or working it out in therapy. I think that's one of the big things that can increase. Yeah. Well, it's another point that helps underscore the importance of, as in many areas of psychiatry,

medications can be useful tools, but they are rarely the overall answer to the person's problems. and in fact one of my own favorite viewpoints about medications is the medications are there to make the person more available to broader psychosocial treatments. You know, if you give somebody a medication that improves their depressive symptoms or improves their erectile dysfunction, that's not going to fix all of their relationship problems for them. or all of their psychological issues based on past history. You know, we don't have medications that basically rewrite your life history for you. Yeah, that's really good. Any other further thoughts you wanted to get out before we sort of wrap up this section?

Maybe pointing to some further developments for, you know, treating depression that are coming up the pipeline, general thoughts on those? Well, I think as we alluded to earlier, if we learn how to better modulate cortisol, that may help us a lot with treating refractory depression. There also are continuing developments going on in terms of learning more about direct electrical stimulation of the brain, which may be helpful in treating depressive and anxiety disorders. and certainly I think once we evolve to the point where we have medications that can directly help increase some of the neurotrophic factors in the brain, that also may go a long way toward altering the long-term course of depressive illness. I don't think anyone is satisfied with the overall effectiveness of the antidepressants we currently have to work with.

a two-thirds response rate and a one-third remission rate is just not adequate by anyone's standards. And the effect size, I've read there was a really interesting meta-analysis where they looked at ham D scores and the effect size of the antidepressants versus placebo. And the effect size did go up as the severity of the depression went up. And especially in the super high realms when the ham D scores, it's like, it's like a physician-rated depression score. As that got into the very high numbers,

the effect size went way up compared to placebo. So that was, I think that's important to sort of conceptualize. Yeah, the more severe depressions, probably those that have gone from being, if you will, a more psychologically based depressed mood to severe disturbances in metabolism, in some ways the drugs are better at fixing the metabolic components of the depression because depression is not a simple illness. The other element in this, of course, is that in milder depressions,

one of the major problems with antidepressant studies has been that there's typically a fairly large placebo effect, in large part because although the person's taking a placebo medication, if they're engaged in a research study, they're still being seen. seen, they're being talked to, they're receiving support on an ongoing basis, and those elements of psychosocial interaction are not really inert, if you will. Absolutely, absolutely. And that's a really good sort of understanding for when you compare effect size of antidepressant studies versus psychotherapy studies and versus like exercise studies, because often the placebo

group, the control group for psychotherapy and for. or exercise is doing nothing and being on a wait list, which it's really hard to compare with being in an office with a doctor who's prescribing you something, who cares about you, seeing the people who are doing the different checkups on your scores of depression. And all of that stuff influences how someone is going to respond to treatment. Yes, very much so. So Dr. Cummings, thank you so much for coming on again.

Okay, great. I enjoyed it. Thank you very much. And I think our audience as well enjoys it. If you want in the show notes, I'm going to put a link to Dr. Cummings notes on this and my notes on it. And until next time, thank you, Dr. Cummings. Thank you.