I'm George Grossberg, I'm very happy to be chairing this symposium on the clinical effects and indications for testosterone therapy in men with depression. I want to welcome all of you. This is really a record turnout. I was at some of the sessions earlier this morning and there were no sessions that had as many people as we have here. So obviously there's a tremendous amount of interest in this topic. Couple of housekeeping kinds of things before we talk about introducing our speakers. As you can see, there are microphones in the aisle. Everything is being recorded, including questions and answers. So if you have a question at the end of the program, please step up to one of the microphones and make sure that it's recorded. I'll probably repeat the questions just to make sure that everybody can also hear. So again, welcome to all of you. This is somewhat of a new topic. There isn't a lot at this symposium about testosterone and mood. I do want to recognize one of our speakers, Dr. Amanatkar. It was really his idea to do this symposium that there was a need for us to really be updated on the role of testosterone and mood in both middle-aged as well as older men. His idea started during his residency, which he did with us at St. Louis University. He and I had a chance to work together on this topic as well as to look at the impact of testosterone on cognition in older men. We were just talking among us that maybe that's another topic that we can approach next year at the APA. In my program at St. Louis University, I can tell you that in the geriatric division, up until the arrival of one of our recent fellows, Matt Gibfried, who is here in the audience, who came from being a board-certified internist and now training in geriatric psychiatry as well, we hardly ever looked at testosterone levels in our depressed older patients. But we are now starting to look much more actively and finding that often they're low and it's something that can be replaced and may be helpful. So today in our symposium, as you see there, we'll have four speakers. Our first speaker will be Dr. Sarah Almey, who's at the Ontario Shore Centre for Mental Health Sciences at the University of Toronto in Canada. Our second speaker will be Dr. Mitra Kashgar-Jarovi, who's assistant professor of psychiatry at the University of Maryland in Baltimore. I will be the third speaker at St. Louis University. And our originator of this symposium and the one that should get the bulk of the credit for developing it, Dr. Hamid Reza Amanatkar, who's assistant professor of psychiatry at the Kaiser Permanente Bernard J. Tyson School of Medicine. So without further ado, I'm going to call up our first speaker, Dr. Almey. Please join us. I'll let you set that up. Thank you, Dr. Grasper. Hi, my name is Dr. Almi. I'm going to be talking about the introduction of this symposium about depression and testosterone. So I'm just talking about the basics of what is testosterone and what do we know about testosterone and depression. So testosterone level declines progressively in aging men at a rate of almost 1%, 0.8% per year. So hypogonadism is a quite common condition with aging. This is one of the data and literature I found. 12% of men in their 50s, 19% in their 60s, 28% in their 70s, and 49% in their 80s are hypogonadic. Testosterone is a neuroactive steroid and influences mood and behavior. There are animal models of depression that show administration of testosterone is increasing serotonin and it increases neuroplasticity and neuroconnectivity. And there has been a study showing that with exogenous testosterone, HRV increase, heart rate variability increase, which means it increases parasympathetic tone and it can improve mood. So there are lots of systemic causes of hypogonadism, including renal failure, cirrhosis, diabetes, COPD, different endocrine conditions, cirrhosis, psychosomalemia, malnutrition, AIDS, different cancers, metabolic syndrome, and obesity, lots of drugs such as steroids, also drugs of abuse, opioids, opioids and statins, alcohol abuse causes low testosterone level. Schizophrenia and depression have been shown to correlate with lower levels of testosterone level and neurodegenerative diseases such as Parkinson's also usually patients have lower level of testosterone, as well as Parkinson's plus syndromes. So what's the definition of symptomatic androgen deficiency? So one of the definition I found is testosterone level less than 300 nanograms per deciliter or free testosterone less than 5 nanograms per deciliter, presence of low libido, erectile dysfunction, osteoporosis, and or fracture, or two of the following symptoms, sleep disturbances, mood, depressed mood, lethargy, diminished physical performance. And in men younger than 70, the prevalence of symptomatic androgen deficiency is somewhere between 3 to 7% and in older than 70, it's 18%. So somatic presentation of low testosterone level is the variable. Usually it's quite slow in progression in CDS onset, so gradually individuals lose their sexual desire and their erectile quality gets worse, decreased muscle mass, increased body fat, decreased bone marrow density, which can cause osteoporosis and worsening bone density, weakness, fatigue, depressed mood, lack of motivation, low energy, lower psychological vitality, decreased work and sport performances. And there is a significant overlap, as you see with somatic presentation of low testosterone, there's a huge overlap with depressive symptoms, as you see. So, in the other hand, depression is more common in hypogonadic men, 21% of patients who were over 45 and had depression were hypogonadic, compared to 7% of patients, people who didn't have depression were hypogonadic, and in this study, hypogonadism was said to define as testosterone level less than 200 nanogram per deciliter. So it seems to be crucial to assess testosterone level in men, especially older men with depressive symptoms. There are multiple studies, but lots of controversies that my colleagues here will talk about them. So I mentioned a few of them here. For example, Lackner studied over 600 men between 45 and 60, and didn't find a depression specific testosterone threshold. This man reported that in men that had loss of libido and vigor, their testosterone concentration, they found that the threshold of 432, but at the same time, when they looked at depressive symptoms, the testosterone threshold was 288 nanogram per deciliter. And then one of the big questions here is that, who's the best candidate for this treatment of exogenous testosterone? At this point, none of our official depression guidelines is really talking about testosterone. So we'll talk about who's going to benefit with exogenous testosterone. There are different RCTs with different results. There has been two big meta-analyses, 2014 with Dr. Amanatkar and a newer one, 2019. And there has been subgroup analysis showing that overall, it seems middle-aged men, hypogonadal men, HIV positive, or people with milder depression have been benefiting from exogenous testosterone more. But this is a very important topic to decide who's going to benefit, because it's not like exogenous testosterone is very benign, because there are side effects to it. It can increase risk of prostate cancer, can cause edema, and some other side effects. So I'm going to... This is my presentation, I'm going to ask Mitra to... Thank you very much. Good morning, everybody. Thanks, Dr. Grosbeck, for introduction. I'm Dr. Mitra Keshkar, and I'm going to talk about clinical effect of testosterone trophy in men with depression, and also comparing the effect of testosterone trophy in hypogonadal versus yogonadal men. My disclosure, I have no financial relationship with any companies whose products are mentioned in this presentation, or with manufacturers of competing products. And I'm going to talk about clinical effect of testosterone trophy in men with depression, and then I'm going to talk about two categories of hypogonadal and yogonadal men, and finally we're going to conclude which group testosterone is more effective for treatment of depression. So we're going to review the multiple meta-analysis of literature, and all of them says that the positive impact of testosterone on the mood of men with depression. One of their meta-analysis is Walter, at 2018, they reported 27 randomized control trials, and they included about 1,890 men, and they mentioned a significant reduction in depressive symptoms compared with placebo. And in this study, the odds ratio was 2.3. And we have another meta-analysis of Amanatkar, at 2014, they also showed a significant positive impact of testosterone on mood, with a large effect size of 4.5. So in this meta-analysis, we see that testosterone is effective in treatment of depression in men. So right now, we're going to talk about effect comparison between hypogonadal and yogonadal men. And all of the meta-analysis we have so far, they revealed a positive impact of testosterone therapy on the mood of hypogonadal men, and also with the improvement of their sexual performance. And we have one meta-analysis of Elliot, at 2017, they included 87 randomized control trials, and 51 non-randomized studies, and they showed that testosterone replacement therapy improved quality of life, libido, depression, and rectal function in hypogonadal men. So so far, we see that in these meta-analysis, testosterone treatment therapy is effective in men who are hypogonadal. So the challenging part of this study is the effect of testosterone therapy on the mood of men who has a normal range of testosterone, and we call them yogonadal. This part is a kind of controversial, and we have different reports from different studies. So meta-analysis of Walter, at 2018, they showed that testosterone has a positive impact on the mood of men with normal range of testosterone level, but the effect was less than men with low testosterone level. And you can see we compared the size effect, it was 0.2 in yogonadal men versus 0.4 in hypogonadal men. However, the meta-analysis of Amanatkara, 2014, they showed that the effect of testosterone therapy in yogonadal men with depression was not statistically significant. And also, you can see the effect size of 4.1 in hypogonadal versus negative 1.02 in yogonadal. So in this meta-analysis, you see that testosterone is not as effective as in hypogonadal. And we have another kind of national federal database, NACURON at 2020, they included many, many people with using testosterone and also about 17 million men who didn't use testosterone. And they reported that testosterone use was independently associated with both major depressive disorders, suicidal thoughts, suicidal attempts, and self-injury behaviors. So they were thinking that there might be a relationship with use of testosterone and also new onset of mental health disorders in men. And they recommended that they needed future studies just to elucidate the role of androgens as a causal relationship for mental health disorders. So what should we do? We just need a conclusion, but due to the controversial efficacy and potential adverse effects of testosterone, like increased risk of prostate cancer, increased level of hematocrit, and many, many other side effects of testosterone, we recommend against the use of testosterone therapy in yogonadal depressed men. But again, as we mentioned, we can use testosterone in depressed men with hypogonadal for sure. So I'm going to ask Dr. Amanatkar to continue, or Dr. Grosbeck, sorry. Yeah. No problem. Thank you very much. All right. All right. Thank you. So it's my pleasure to be the third speaker, and we're leaving the best for last with Dr. Amanatkar. So my job in this symposium was to really look at the impact of testosterone deficiency and testosterone therapy or supplementation in older men. As you all know, I do geriatric psychiatry. I think I've got the new generation more technologically savvy than us older folks. So I'm going to be talking about the impact of testosterone replacement therapy in geriatric patients or geriatric depression. Most of the literature focuses on people who are over the age of 60. Some of it, a little bit that there is over the age of 65. Those of us that do geriatrics usually start at 80 or 85 plus as the true geriatric population, and there is no data, no data in that population at all, just so that we're aware of that. No disclosures for this presentation. So a little bit about the history of testosterone therapy and depression and the relationship between testosterone and depression. Some of you maybe recognize this gentleman, Dr. Charles Edward Brown-Saccard, you know the Brown-Saccard syndrome, lived many years ago. He basically, in 1889, he's a Mauritian physiologist and neurologist. So in 1889, he injected himself with testosterone, which he derived from the testicles of various animal models, and he noted on his own that his mood was better. So this is how it all started. Thereafter, we're looking at now, Kerrion et al. and his group, they reported that castrated male rats who were given testosterone showed decreased symptoms of depression. So that was important. That was in 2015. And then more recently, just a couple of years ago, there were reports that levels of testosterone were found to be lower in depressed versus non-depressed patients, but it was a relatively small study, and it wasn't kind of a placebo-controlled prospective trial, but more of a retrospective study. So these are some of the questions that I had that have been unanswered historically that relate to this older adult population. First, are symptoms of depression triggered by low testosterone in men? We all are, by the way, barraged by all these commercials, low-T commercials on radio, on television, on the internet. You would think that everyone has testosterone deficiency, but it's not true. But even those that do, can symptoms of depression be triggered by that? Is testosterone treatment effective in treating men with depression versus just treating some of the symptoms, major depression versus symptoms of depression? I think that's also very important. If testosterone is useful as a treatment, could it be used in treating major depression in older men, particularly who are hypogonadal, alone? Or is it most useful as an augmentation strategy in that patient population combined with traditional antidepressants? Do older men, in this case defined as 60 or older, benefit from testosterone treatment for depression? Or is the risk-benefit ratio not very favorable in the older adult population? So is this primarily a treatment for middle-aged men, or is it also useful for older men? And the literature is really conflicting and often quite inadequate, but there have been some meta-analyses. We'll go over those in a moment. A recent review that I think gives us some beginnings of answers to these important questions, particularly in older adults. So I think you've already seen a reference to the first of the meta-analyses that was done by Dr. Amanatkar in 2014. Hard to believe it's been almost a decade since you finished training with us, but nonetheless, looked at 16 randomized, double-blind placebo-controlled trials, close to over 900 subjects, found that testosterone had a positive effect on mood, highly statistically significant, but that didn't hold true for older men, men over the age of 60. It was mostly in younger or middle-aged men. Subgroup analyses really looked at those over the age of 60 was negative, but there were very few subjects that were looked at over the age of 60. Only four of the 16 studies with very small numbers looked at older men. He looked at, in the literature, hypogonadism versus eugonadism, showing that the positive effect was only in hypogonadal men, only in the subgroup that were hypogonadal. Other things that have been found were that the levels of depression, some studies have looked at major depression, others at sub-threshold depression. Many have looked at testosterone as an augmentation therapy. It seems like, in the bulk of the studies, the effect size was greater in sub-threshold depression, but even in major depression, in some of the studies, there seemed to be a clinically significant response. Other studies have looked at duration of therapy, and there have been statistically significant benefits seen in both 6-, 8-, 12-, and 24-week trials, but it seems like after six months, after 24 weeks, that the effect size declines as well beyond 30 weeks of treatment. One of the issues, and we had a little discussion about this before the symposium this morning, was route of administration. Whether you give it intramuscularly or maybe use a testosterone gel, which can be applied underneath in the armpit area. There's also an oral version. I think most agree that you don't want to use the oral version. You have unreliable levels. So the best would be to give the intramuscular injections or to use the testosterone gel if you're gonna be using testosterone supplementation or therapy. Other pieces of evidence. A study in 2017 looked at testosterone therapy in hypoclinical men. It was kind of a review and meta-analysis. What they found was, was that, this is very important, that testosterone replacement therapy improved a lot of things. Improved quality of life, some measures of mood, erectile function, libido, but was not effective for clinically major depressive disorders. So the degree of improvement was relatively mild and would not be recommended as a sole therapy for major depression. They didn't find any significant AEs. Again, they found that most of the studies were fairly short. We need longer term studies. And this is a repeated kind of message from all the studies in the literature is that we don't have enough older men, particularly those over 65. I'd love to see some people in their 70s and their 80s to evaluate testosterone replacement therapy in the true older adult kind of population. A more recent study in 2018 looked at the efficacy in adverse events of testosterone replacement therapy in hypogonadal men. Again, a systematic review, meta-analysis, particularly focusing on randomized placebo-controlled trials. Now interestingly, though there were a number of randomized placebo-controlled studies in the literature, they only found four, about close to 1,800 patients, that were at low risk of bias, which would mean generally that they were not funded by one of the manufacturers or what have you. But they found four large studies, almost 1,800 patients. Only one of them had any patients over the age of 65 and they were quite few. When they looked at these randomized controlled studies, they found, again, similar to what we heard earlier, testosterone replacement therapy improved sexual drive, erectile function, but did not have a statistically significant effect on mood, energy, or cognition in hypogonadal men, keeping in mind that these were middle-aged individuals. Very few were even over the age of 65. They also cautioned that replacement therapy can increase the risk of erythrocytosis in hypogonadal men, but did not seem to have any significant effect on lower prostate, lower urinary tract kind of symptoms. This is, again, one of the more recent kind of meta-analyses which looked at the association of testosterone treatment with alleviation of depressive symptoms in men. Again, it was done in 2019, so more current. Looked at 27 studies. Again, over 1,800 men were looked at. They found that there was a moderate reduction of depressive symptoms, especially at higher doses of replacement therapy, 500 milligrams a week versus 200 milligrams a week, even in eugonadal men. However, for major depression, it did not seem to be effective. So their suggestion was that, again, the studies that they looked at seemed to hint toward using testosterone as an augmentation strategy. They also found that, again, the few men that were over the age of 60 seeing the testosterone treatment was also efficacious for them. But again, the conclusion that they reached, which is a real need in the literature and in our data, is we need large, randomized, double-blind, placebo-controlled studies looking at testosterone treatment effects in men, particularly older men, with depression or major depression as a primary outcome. This is the most recent study looking at testosterone replacement therapy and the treatment of depression last year. Most recent review of all the literature, and their bottom line was, basically, we need more research. There's no doubt that declining testosterone levels in adult men, as far as whether and how they impact development of depression, we know that that's there, but there's mixed evidence that testosterone replacement therapy is effective for the treatment, particularly of major depression. So my reading of the tea leaves, as they call it, shows that, basically, what we know currently is that testosterone treatment of depression in older men, and we're gonna define it as 60 and above because there's no data on the true geriatric older male population, may be useful, particularly as an augmentation strategy, especially in men that have low testosterone levels. So there may be a need, and this is something Dr. Almey and I were talking about earlier, is that we sometimes use, basically, estrogen and antiandrogens in our older males with dementias who have sexually aggressive and inappropriate behaviors. And we never, I mean, at least in the United States, in our program, never check testosterone levels before we do that. Probably wouldn't be a bad idea in that subpopulation before we treat with antiandrogens, like medroxyprogesterone or estrogen, to maybe check their testosterone levels. But even in older men that present with a particularly, present with, let's say, decreased libido, things that are suggestive of low testosterone and depression, probably not a bad idea as part of our depression workup to check their testosterone levels. Also, a greater need to monitor for side effects in older men, especially if they have a history of cardiovascular disease, they're on anticoagulants. We don't have sufficient evidence to suggest that testosterone therapy alone is efficacious in treating major depression in men, in older men in particular. And of course, we do need more long-term, randomized, double-blind, placebo-controlled trials to look at both safety and efficacy, whether we're looking at testosterone treatment for augmentation of a antidepressant that's already on board or alone in treating depression in older men. Thank you. Dr. Amanatkar is gonna put it all together, will all hopefully make sense. Thank you all for being here. Thank you, Dr. Gersberg. Good morning, everybody. It's kind of now after all of these numbers, I think you should be very confused now. That's my understanding. So we gave you lots of numbers, and now we are going to review everything who we can really consider at least testosterone therapy for. I know for lots of psychiatrists talking about testosterone is like walking in a dark room. So they are not sure when they should get a testosterone level. They don't know how to treat it. Should I refer it, or can I treat it or not? So this is a very complex scenario if you have a patient and you're thinking you need to get a testosterone level. What should I go with the low number? So let's talk about more of the clinical aspects of the treatment of the low T. So I have no financial interest or any relationship to disclose. I'm glad that we brought a decade of working in testosterone to this crash seminar so you can really have more of the idea for your patients if you want to really consider a testosterone therapy. So why I'm saying it's super confusing, because major depression and any depression can lower the testosterone level in men. And also low T can cause depression. So it's super confusing. The incidence of depression in hypogonadal men is almost three times compared to general population. So it means 21% of hypogonadal men have some form of depression compared to 7% of the men with no low T. Another aspect of the confusion is any physical issues, chronic physical issues from CKD to cirrhosis to diabetes to COPD, HIV, cancers, malnutrition, everything and even simple obesity can lower the testosterone level. So we have the epidemic of obesity in the U.S. One out of five men has some level of obesity and it can really lower the testosterone level. So this is another dilemma that in many mental illnesses like schizophrenia, we have low T. Even in MDD we have low T. So where should I treat my patient with low T? So it's very confusing. So first we need to really distinguish between what patient is originally came with low T and what patient came with originally depression. And it's like we are going after which one is first. Is it the chicken or the egg? So how we can distinguish is very interesting to really see how we can really make this distinguish. So first I want to say the development of low T in man is very gradual. So as Dr. Elmi said, it's like 0.8% per year. So man's testosterone diminishes by 0.8% per year. If you have a patient who has a depression for several years, this might really have the first thoughts of maybe this is just low T. It's not major depression. So maybe it's simple low T. So that's very important to pay attention to the duration of depression. So basically low T can cause a pattern of like dysthymia or persistent depressive disorder than MDD. So MDD patient comes with a few weeks, two weeks or a few months of like depression, but low T patient comes with years of low mood. And that's very important to pay attention. So this is the first. So it's very interesting in our meta-analysis, when we have a distinguish between subthreshold depression, so we define dysthymia and minor depression as subthreshold depression. When we distinguish between subthreshold depression and MDD, we had a huge difference, even double size in the effect size. You will see double effect size in subthreshold depression, the efficacy of exogenous testosterone on a man with dysthymia is much higher. Another thing is although it's very interesting. So one of the main question is lots of psychiatrists might ask, should I use the testosterone as a monotherapy or I can just rely on it on just augmentation therapy? So it's very interesting. So when I reviewed all of the randomized control trials in our meta-analysis, there is no any randomized control trials with MDD who use testosterone as a monotherapy and has a statistic response or even it might be a various statistic response, but it's a very slight significance. So I won't really use testosterone as a monotherapy in my patient for MDD. So I think this is not really going to help you. So this is the first. Consider it in more of dysthymic patient, we can consider it as an augmentation for MDD patients. The second thing is, it's very important to ask about the sexual performance of your patient. So low libido can be happening in both low T and MDD. Even is more reported with MDD patients, but I think erectile dysfunction is the one that you are looking for because patients with low T, they have more low libido. So that's very important to really get a very full history of sexual performance of your patient who comes with depression. So is the chance of erectile dysfunction in hypogonadal man is almost 70%, but the chance in MDD patient is 40%. So it's almost double in the patients with the low T. So there are two things I think I will really pay attention in my patients. How long they have been depressed, and the second, the sexual performance. Is it the sexual performance and sexual dysfunction is more ED or is just low libido? So the next thing is for all of us, I think we always have the question of when should I get the testosterone level? Tell me exactly when I should get the testosterone level. We get the TSH for all of our patients for major depression, but it's not a general approach to get a testosterone level in our patients with depression. So where should I get it? Where should I get bothered with low T? So I think my suggestion is to get a testosterone level in any middle-aged man with depression, specifically with these four criteria. You know, I put down these four criteria based on the review of the literature. So one is if the pattern of depression is more dysthymia than major depression. The second is if you have an MDD patient who comes with erectile dysfunction, get a testosterone level. If the patient comes with MDD superimposed on top of dysthymia, somebody with the low mood for several years and now we have MDD, superimposed MDD, get a testosterone level in this patient. And also I will get testosterone level for MDD patients who has a low libido after sufficient treatment of the depression. So MDD comes, you treat enough with antidepressant and patient is still complaining of ED or low libido. This is the time you need to really get a low T. You might really, you might be missing something here. Okay. So we know where we should get a testosterone level now. So what should I do with the testosterone level? So first of all, if you get a testosterone level, one number is not enough. So all of the endocrine societies that are suggesting getting true testosterone level should be morning before 10. You know, in my practice, I noticed when my patient goes during the day after 10 in the morning, the testosterone drops and it's like showing, you might really be confused with low T. So if you get a testosterone level, you need to say to your patient, you need to get the testosterone level in the morning before 10. This is very important. And it needs to be fasting. I know it needs to be fasting. All of the endocrine societies saying it needs to be fasting because eating can have an effect on the testosterone level. So you need true testosterone level, true morning testosterone levels, which is fasting. And if the number is less than 300, you go to treatment. So let's talk more about the different guidelines here. So what is the latest endocrine society guidelines. They are saying consider testosterone therapy in any age less than the age of 65 with two morning total testosterone level less than 300 plus your patient needs to be symptomatic. So most of us having patients with depression so that's why you have you already have this symptomatic criteria. So basically this is the guideline. So when you have a patient less than 65 you have two testosterone two morning fasting testosterone levels less than 300 you need to really treat it. So it's very interesting most of the endocrine society guidelines are against routinely prescribing testosterone for men age 65 and older. So we'll talk about the controversies. We'll talk more about the controversies here. So what should I do with low T? I think this is I suggest this guideline. It's a very simple thing. So first is look at the pattern of depression. If it's dysthymia first get two testosterone two morning testosterone levels. If there are less than 300 no need antidepressant. If you are starting SSRI on this patient they will come and complain of more of sexual dysfunction. So make sure you start with monotherapy with testosterone for these patients. And then it's very interesting the effect of testosterone is very slow. So if we get a response with SSRI within four to six weeks you need to give testosterone therapy eight weeks of time to have response. So we don't have any six weeks of randomized control trial with the positive response basically. Our meta-analysis didn't show a strong response within six weeks. So you need to give eight weeks. So I will wait. I will treat. I will wait for eight weeks and then I will get the patient back and see how they are doing. If they are doing fine, fine. We don't do anything. If they are not doing fine after eight weeks you might really up the dose to 500 a week of testosterone. So it's basically the last meta-analysis of Walter showed that the dose has a huge impact on your response. So I think the dose more than a hundred milligram a week is much more effective. So I will consider from the beginning a good dose of the testosterone. More than 100 milligram a week if you are using. More than 500 milligram a week. So if you are using gel so use the more of 100 milligram form than the 50 milligram. And then you will do if it's not responding to testosterone treatment. Okay I will do my patient. I will put my patient on antidepressant. What about patient on MDD? Okay so for MDD do whatever you do on your day-to-day practice. So if the patient is less than 65 don't bother the testosterone level. Treat your patient the medications. And then see how what kind of response you get. If you have a resistant depression after sufficient like with the medication it still is not resistant and it's not really going anywhere. And specifically patient is complaining of loss of ED or low libido. Now this is the time to get the low T. To get the testosterone level and see it is low T or not. To rule out low T. So then if you have true testosterone level less than 300 morning fasting. So start testosterone treatment on top of your psychotropic medication as an augmentation. As an augmentation and make sure that when you are treating a patient with testosterone the range of the testosterone level comes to the mid range of normal like above 600. So that's exactly all of the endocrine societies are recommending the numbers above 600. So make sure you sufficiently treat the low T above 600. So I think this is basically the summary of everything. So I want to really go back to some some of the patients who are getting more benefit and how to treat. So when you're treating the testosterone hypogonadism or low T make sure you your patient using a form of a route of treatment that is effective. In our meta-analysis we found oral testosterone has no effect on depression. So basically because of the first pass effects in the liver. So they go to the liver. So you need to either use the patch or the gel or the IM form. So you won't go anywhere with the oral testosterone therapy. So most of my patients are on IM. I have a more of the response on gel. So either IM or gel is the best form of treatment. And this is another point here that is very tricky because it's based on just only one study. I'm not sure you are familiar with the DHEA. It's a supplement, over-the-counter supplement. It's a 50 milligram of DHEA. You can get it over-the-counter from any pharmacist. And there was just only one study in 2006 show that the DHEA with the raising dose from 100 to 400 per day has a positive effect on the HIV patient with depression. But the type of depression here was not major depression. That was like a soft threshold depression. You might really consider DHEA as over-the-counter supplemental supplements that you can really use it sometimes. When you are using the R in 50 milligram and you raise it by 400 milligrams. So don't stay on 50. You won't go anywhere with the 50. So raise it every week to 400. This is another thing is not expensive even. So when we can get the response? Usually we get the response within eight weeks when you treat the low T with testosterone. So you need to be patient basically. It's very interesting. In one meta-analysis of Walter in 2018, they found the testosterone dosage of above 500 is effective. So you want to make sure that either testosterone level comes in the mid-range or above 600 when you're treating testosterone. Or you're giving at least 500 milligram per week of testosterone. So one of the sub-population in our meta-analysis had a much more effect size. It's a larger effect size. And that's the population of HIV patients. So I might really use testosterone for this group of the patients more because it's not only helping with the depression. It helps the energy level, helps the sexual performance and specifically in the population of HIV patient with wasting serum. So it can raise the muscle mass in one of the study shows like 2.2 kilogram within three months. So I will specifically think about testosterone in my AIDS patient with wasting serum. So I think we have some idea of where should I get the testosterone level, how should I treat it. The next thing is I want to really step into Dr. Grasberg's theory. So it's very controversial. We have more studies as Dr. Grasberg said. We don't have much of like a huge studies that's supporting the efficacy of testosterone treatment with depression. Even the endocrine societies I'm seeing they have a different kind of a stance. Like Australian endocrine society saying don't treat low T after the age of 65. Don't treat a patient with obesity with testosterone. First you need to really rectify obesity. So let them lose weight and see what numbers you get in the testosterone level. So basically this is a very much of strong stance came lately but the US guideline saying make sure you help the obesity with weight loss and after the weight loss you can consider testosterone therapy on an individual basis, not as a routine. So routine approach is like they are against routine treatment of low T in geriatric field but on an individual basis they say you might really want to try. So what about the side effects? What kind of the testing I need to really do for the follow-up? So when you are getting that you're too low morning testosterone you need to really get a PSA and hematocrit level. Why? Because PSA of above four in somebody who doesn't have a family history of prostate cancer and above three in somebody who has a family history of prostate cancer. And in men, African-American men, above three is contraindication for starting a man with testosterone. So you need to be aware of the PSA level. So if it's above four or three in patient with first-degree relative of the prostate cancer, don't go with this route. This can cause more issues. And if the hematocrit level is above 50% don't go there. I think this is an absolute contraindication in any endocrine societies everywhere in the world. So if your patient has an untreated severe sleep apnea that lots of our patients might have, so don't treat. Make sure you first get the treatment for a sleep apnea and then consider the testosterone therapy. So if it's severe formal OSA and untreated, so there's no go there. And another one is a severe form of uncontrolled heart failure or somebody who has an MI or a stroke within the last six months. So this is an absolute contraindication. Or somebody who has a more history of blood clots, no. So no to testosterone therapy for these patients. So you will get a PSA and hematocrit level and then you will get every like six months, three to six months. And if the number goes above 50 or goes above four on PSA, so you will stop it and you will get a consult. So this is how to follow the patient. So overall I think sexual function, functioning and sexual performance is an essential part of our patient with MDD. So if you miss a patient who come with depression, like very prolonged depression and they have low T and you just start SSRI. So SSRI overall causes sexual dysfunction in one-third of the patients. You will add more into their sexual dysfunction. So that's why you need to be very, very cautious about this group of patients. Not to add more into their depression, which is more of sexual dysfunction. So we will open the floor for Q&A and then we will see how things will go. Thank you. I think we have plenty of time for questions and comments. Please go up to the microphones. Great symposium. Congratulations everyone. So I have two questions. First, have you seen a certain endophenotype depressive patients in men with hypogonadism? And the other one is related. Replacing testosterone levels in, for example, irritable endophenotype, maybe worsening the symptoms or not? Is there any specific phenotype we are looking at for low T? I think a man with more of like a low vigor, low level of depression, more of like a challenging sexual lifestyle with ED is exactly the phenotype. And the second question was... If testosterone replacement can be worsened in some depressive symptoms like irritability? Yes. So there are... So when we are talking about treating testosterone therapy, we are replacing testosterone low T, the normal range. But if you want to really use it as an argumentation in patient who has already normal range, definitely can cause more irritation. Sometimes it can cause more irritability, more of like even we have studies of higher violence, testosterone therapy. The person in the back will just alternate. Yes. Two related questions. One, is there any evidence of men with depression and low testosterone after their depression list is treated, does testosterone come back up? And I ask that in the context, I've had a number of male patients with depression who their primary care doctor or the urologist start them on testosterone. They love it and they're taking it. They do not want to stop it. And what are the long-term effects of testosterone? Because I see these men, I'm not sure they're ever coming off. And once you're on testosterone, is it like thyroid hormone that your levels are suppressed and you're pretty much destined to a lifetime of treatment? So it depends what we are treating. So there is one study... I saw one study in literature saying testosterone therapy for six months, they stopped it and they saw a persistent, really good response in the long run. It means even six months of testosterone therapy helped them to get the boost and then go away itself. But if we are treating the sexual dysfunction, I think they need to really stay with it for a long time. Do testosterone levels come up in depressed men who are treated with depressants, do well? Has it ever been looked at that their testosterone levels come back? I don't get... So a male has a low testosterone and is depressed. If the depression is well-treated, have you ever looked at their testosterone levels six months or a year later? Do testosterone levels come back to normal? This is very common. This is absolutely very common. So I see exactly it's happening for lots of the patients with MDT. That's why I'm against starting testosterone on somebody who is already in the MDT phase. So I think we need to really first treat the depression and get the testosterone level. Don't jump on testosterone on patients who come with a couple of months of depression. So it's very common. You have an MDT, you get the testosterone level, it is low, and you treat the depression enough and the testosterone level comes to the normal range. Very common. Very common. So that's why I'm against using of the testosterone therapy as a first line in MDT patients. That makes sense. The other comment to your question is that if you look at the literature, there's almost no data beyond six months of treatment as far as controlled studies in particular. So that's an area where we need more information. Yes. I have two questions. If the goal of treatment in patients that do get hormone replacement treatment is 600, what about men who present with sexual dysfunction and dysphoria and they're in the range of 300 to 600? In other words, not hypogonadal, but isn't there a role for correction, the low normal testosterone? So it's very interesting. When we review the literature, we didn't get very much of like positive response on patients with a higher than 300. So like normal range of the testosterone levels. So basically, if even the effect size in our study was negative, it means if you are giving testosterone to somebody who's above 300, they might be more irritable. They might be having more of the mood swings. So if you specifically want to target depression, I think 300 is a good number. I think one of the major studies that has done, as Dr. Elmi mentioned, so they found 288 for depression, the level of 288, but was not replicated at this level in other studies. But I would consider 300 as a level for depressed patients. In this study, they found patients who had more problems with libido and sexual vigor, the threshold was around 400 of testosterone, but for depressive symptoms was around 288. Any studies on the supplements that are very popular, like Toncat, Ali, and things that are thought to improve natural teeth? Not that I'm aware of. No. Thank you. Well, congratulations. And on the case of this persistent depressive disorder that you find with the, that you recommend testing for testosterone levels, how often does it actually happen that they are low? And once you do start the replacement therapy with all the prior prosthetic, hematocrit and prostate markers, do you actually find abnormalities induced by the testosterone? So, I think you know, when we are getting the PSA, we need to follow on that. But it's very interesting that the majority of our studies, our meta-analysis studies, there were like RCTs at the range of like three to six months of treatment for testosterone. So there is just only, there was just only 152 weeks, a year of it. And that was not very much positive because of all of the participants oral testosterone. So I think when you are looking at everything in a long range, I think you need to have a more collaborative approach with other specialties like endocrinologists or urologists to have a rectal exam for the prostate and also PSA won't be the only marker that just follow the patient. So what you're saying is that usually you're collaborating with someone else whenever you decide to start. I think for the sixth month you should be fine. If you are really going with this range. But in that six-month mark, how often did you find PSA that were altered? Not very often. Thank you very much. This is really interesting. Kind of going along with that question, looking at monitoring, I may have missed this, but how often do you recommend monitoring the level of testosterone and then also to what degree do you recommend coordination with primary care? So I think everything depends on how comfortable you are with the treatment. So if you're comfortable, you can like use it for six months and then refer it to a primary care physician for further evaluation for prostate and then go from there. If you want to really continue after six months, make sure that you get the patient into more of the next level. But if you are doing a very short treatment for six months, you should be fine. Basically, none of the studies or meta-analysis had any adverse effect for six months of treatment for testosterone. Yeah, just to comment on the coordination with primary care, in the few cases where I've attempted to do that, I've found that there's an even greater lack of knowledge about appropriate use of hormone replacement therapy, in this case testosterone replacement therapy, in older men among primary care physicians than among all of us as specialists. I think the fact that we had such a big attendance today and we have so much interest and so many questions and comments shows that this is an area that's really ripe for further information and further research. So thank you again for bringing this to everybody, Dr. Amanatkar. In the back, please. Yes, I want to echo that. Thank you so much for doing this because I think I really needed this guidance, so thank you very much. I feel like the recommendation to tell an overweight man to lose weight before you prescribe him testosterone is really cruel, right? I mean, this is a guy who's coming to you saying, I have no vigor, I have no energy, I'm depressed, I don't want to do anything. How am I supposed to lose all my weight before you'll give me the prescription to help me have vigor and energy, right? So I think this is a very complex patient. When you are going with obesity and depression, there is loss of resistance. So I think I will consider my first choice as well-butrened in this patient. As which one? Well-butrened, like bupropion, not as... If I'm thinking about, like, if I'm getting a very comprehensive sexual history and are reporting low libido, ED, and are depressed, and I will definitely, my first choice, if it's an MDD patient, my first choice is well-butrened and then, hopefully with the medication, they have more energy and then have just a little bit of weight loss before they can go to the next level. So you're looking towards the stimulant angle. Exactly. My second question is about, so I have a guy who's hypogonadic by birth and can't get testosterone because he's also polycythemic. He has too many red blood cells. And I kind of feel stuck. I feel we've tried everything, TMS and lithium and 20 different antidepressants and it's just nothing. And I'm starting to feel hopeless that if I can't fix his testosterone, I can't fix his depression. Have you seen that effect? I think, you know, we are, we have many of medication and route of the treatment coming to psychiatry from TMS, ketamine, psychedelic, and everything. And we are at the burst of all of this new commerce. Maybe in the next five to 10 years, we define very strict indication for each of them. And testosterone is one of the treatments that we might really make a more of indications where you should get a testosterone level, where you should treat the test. Thank you so much. Thank you. And good to see you. I have a few questions. It's that about sexual dysfunction, majority of sexual dysfunction, I don't remember exactly the percentage. It's about delayed ejaculation, not necessarily. And your last slide sounded in a way that testosterone can help, but I'm not sure. Does it actually help with delayed ejaculation? First one. The second one actually a little bit on piggybacking on the previous question about people with higher weight, individual with higher weight, they don't necessarily, they might have had, this might have been the ideal body weight and not necessarily anything abnormal for them. And we know that people with higher BMIs, they're not necessarily, the data shows that they're not necessarily of anything abnormal. This is their actual body weight. But the language, unfortunately, progressively has been in medicine. People with higher BMI are sick and they have to lose weight. And in the process of weight, that's one piece. How do you actually integrate it into testosterone? The second one is that when people lose weight, especially if it's forced to lose weight, often there is a subsequent hypogonadism. That can be actually misleading treatment after weight loss, especially with a short-term weight loss. And the last question I have is actually about any study in transgender men, because these individuals are treated with testosterone. I personally have not seen the effect, like usually in terms of change of depression, but I'm wondering in sort of like a comparison, if we see anything like that or not. Three questions. So we will start, I think. I will answer the first one, okay? So the first one for premature ejaculation or delay organism under SSRIs, I think this is exactly what you're getting with SSRIs. But low T causing more ED. So it's like the chance of ED in low T patients is almost 70%. So I think I will give more of like a point ED patients compared to somebody who comes on SSRI with delay ejaculation. So this is one of the questions. I haven't seen any studies in transgender patients, so I cannot really comment on that. This is a very nice question. I think this is the future of research, we'll show more. I haven't seen any. And you asked the three people? Or higher weight, with a higher BMI. Oh, higher BMI. And in higher BMI weight? You know, personally... We don't have the BMI, so it's higher BMI. Right. Yeah, but the problem is we don't know if lower testosterone is really low testosterone or is just the result of the higher BMI, the metabolic syndrome. So that's why it's not really recommended to treat. It's very tricky because it's just only a number. We don't treat numbers, we treat our patients. So to my patients who are, whenever I see a patient with low T with morbid obesity, more than the BMI of 40, when I start testosterone, I don't get any response. Any response. So that's why I think you might really consider testosterone therapy, somebody who has a BMI of 26, 27, but I won't treat, I'm talking from my experience with the patient with morbid obesity, I won't consider testosterone therapy for morbid patients, morbidly obese patients. That sounds reasonable. I think the doctor in the back. Yes. Yeah, so one of my questions was on the obesity. So let's say, is there a target for, okay, this is, are we aiming for obesity, morbid obesity? And if they lose weight, is it a percentage that says, okay, well now we can consider testosterone or are we trying to lower a particular BMI? Is there a minimum age to start screening for testosterone? And my last question is, let's say we're talking about comorbid issues. So a patient with major depression and OCD or major depression and anxiety. Are there any considerations with testosterone? Maybe, I'm sorry, I'm just going to begin to answer that because I haven't had any questions about older adults. I think the issue of weight, you know, and weight loss is very different in 85-year-olds versus, you know, younger and middle-aged kind of men. And our older adults, sometimes it's protective to have a little extra weight on board and we don't want them to become, lose a lot of weight and become cachectic, even though that may benefit their testosterone levels. So you have to kind of weigh the pros and the cons. On the other hand, it may be different in the middle-aged or younger men. Maybe you can answer that as far as weight. So I think if the low T starts... Yeah, just speak into the mic, microphone. Very young age, if they have low T, start with a low testosterone at a very young age with like inclined patients, like very much of like a very young age, it is much more comorbid. Definitely, if we have the low T earlier patients, they have much more depression, years and years of depression. Okay, thank you. And for the comorbid? I haven't seen anything. Would it be reasonable to try anyway? Without data off-label, I probably would be reluctant. I haven't seen anything that shows a positive response, so I cannot really comment. Yeah. My name is Ingrid Havnes, and I'm a psychiatrist and researcher from Norway. And I treat patients who try to quit using anabolic steroids. And I think among your patients that in the studies that you've shown, that it's a substantial amount to have used anabolic steroids previously. And there has been studies looking at use of off-label flamifen, selective estrogen receptor modulator, for men with hypogonadism, with really good results and less side effects than testosterone. And we have conducted a study among men who tried to quit steroid use, and it seems like it's just a small pilot study, but one-third have good effect, get normal testosterone level. One-third gets quite low levels of testosterone, lower normal range, and they have really severe symptoms of hypogonadism. And I think this is a group that self-initiate testosterone, non-prescribed, and use it. So my question is, one, what do you think about clonifen as treatment instead of testosterone for hypogonadism in general? And what do you think about exploring anabolic steroid use among patients with hypogonadism? I really haven't seen a study. So I think this is the first time I hear. So this is a very promising, as you mentioned, it's a small study. I will look at this study tonight. I guess this is a very interesting study. It will be published in not so long, so it's not published yet. Oh, it's not published yet. It sounds like if it's really can help, I think it's in the field of testosterone, I think testosterone is the big beast and is like all of the pharma companies are trying to make a different route of testosterone. But this is a very new study. That would be nice to really look at the data and see how strong it is. Thank you. Thank you for that. Gentleman in the back. Hi. Thank you very much for a timely talk. I think a much needed one. Just a small clarification. You mentioned about fasting testosterone levels to be done, at least two. What should be the time interval between the two? So a week should be fine. So because testosterone have a denormal variability and also has a day-to-day variability, at least a week. That's good. Yes, gentleman in the back. I really enjoyed your talk. I have a question, I guess, about the mechanism. So somebody mentioned that maybe testosterone is modulating serotonin. And so my question is, are there other mechanisms there that may link testosterone to mood? And related, a lot of these conditions that you mentioned, obesity, cirrhosis, they're associated with hyperestrogenic states. So I wonder, is the mechanism via testosterone or via estrogen? And how would you differentiate? There has been a study, not in human, because it's really hard to study human brain. But in Roden's model, in rats, they saw that with exogenous estrogen, testosterone, serotonin levels significantly increased. There is heart rate variability. So there are studies that patients who are on exogenous testosterone, their parasympathetic tone increases significantly, which means they become calmer and their mood improves. So those studies, neuroscientific studies have been shown. And overall, there are all of the chronic medical conditions. Oh, we can't hear. Yeah, all of the, yeah, all those systematic conditions that they will lower testosterone, unfortunately. And it doesn't mean that in those conditions, if you really substitute testosterone, they get better, because probably you need to first treat the underlying condition rather than trying to treat with exogenous testosterone. I didn't quite understand. For the 40 or 50-year-old male with low testosterone, complains of low libido, low energy, supplement the testosterone, they find it works very well. Are you recommending that they only stay in it for six months? Or can they, because what I'm finding again in practice is primary care and neurologists are prescribing this, and these guys are on them for years, never attempt to take them off. What is the recommendation if someone has low testosterone, it's successful, how long should they stay on it? And do you worry about people staying on it? I guess the issue of long-term treatment, yeah. So I think we discussed it and we mentioned that we can do the testosterone therapy for maximum of six months. And after that, we need to check the level of testosterone and also the clinical improvement of the patients. But more than six months, we have the side effects of testosterone. But if you take them off after six months, is it likely their level is going to drop down again? The levels should be dropped, right? I think the levels might really drop. The question is, should I treat it further or not? In six months, are we giving the patient a chance to come off of testosterone and see how the mood goes? Another thing is, if I want to continue testosterone treatment above six months, I will get much more monitoring. I will get a neurologist involved, I will get the primary care physician involved with more of checking of the... they need an examination they need a monitoring. It's very interesting, you know, the guideline of urologists are saying after one year of treatment, they would be even less of the monitoring. So it would be a yearly monitoring. So if you, on the first month, first year, we get all of this TSA and the hematopoietic level, every three to six months, after a year, it would be once a year. I'm just saying, what I'm seeing is these urologists and primary care doctors are not taking patients off of it. I have a couple of guys who are four or five years, they just continue to take their testosterone. Do we have to worry about that? Long-term effects of... So if they are doing all of the monitoring of the hematopoietic level TSA and the exam, so they need to get at least a yearly digital regular example. After the first year of treatment, they need to get the TSA level and they need to get the hematopoietic level. They can continue with definitely monitoring of the organs. Yeah, I agree with that. The older patients tend to be on it long term, whether through primary care or others. And I think as long as there is periodic safety monitoring or there are no new, either cardiovascular or other conditions that the patient has developed, I'm actually okay with that. But of course, if they've had an index MI or they have other, their PSA is up, what have you, then those patients, you want to stop treatment. But have you seen patients whose testosterone will come up to five, 600 on treatment after 16 months or a year, you stop it and it stays at five, 600. All my patients are worried about, they don't want to go off of it. I'm not prescribing it. So thank you all very much. I think, was it another question? Well, in our setting, we do. The question is, should psychiatrists prescribe? Again, working closely with the primary care physician, you can either have them prescribe or you can prescribe as long as you're working collaboratively. We sometimes do prescribe, yes. Yeah. We've never prescribed to our patients. That's a little bit of a double-edged sword. Yeah. You need specific, you can prescribe if you have the education. Yeah. About hormones. Yeah. Yeah. You have to have a comfort level. You have to have a comfort level. Yeah. Yeah. Yeah. Again, there's liability in everything that we prescribe, as long as I think, as you mentioned, you have a comfort level and feel you have a sufficient background and then working collaboratively is very, very important with the primary care. I mean, in Canada, there are lots of family doctors that are prescribing the hormones for transgenders. Yeah. And if you want to get the education to prescribe as a psychiatrist, yeah. That's a very specific population. My comments were not geared toward the transgender population. In my state, you can't even prescribe hormones anymore. I mean, the restrictive legislation is a huge problem, but we can talk about that privately. All right. Thank you all very much. A great amount of interest. Thank you for being here. Wow. Thank you to our panel.

testosterone therapy

depression

George Grossberg

mood disorders

hypogonadism

neuroactive steroid

serotonin

neuroplasticity

meta-analyses

prostate cancer

augmentation strategy

clinical guidelines