Yale Department of Psychiatry Grand Rounds, November 8, 2019

November 11, 2019

Information

Cenk Tek, MD, Associate Professor of Psychiatry, Yale School of Medicine; Director, Psychosis Program, Connecticut Mental Health Center

ID4604

To CiteDCA Citation Guide

00:00Before we get started I would just want to tell you the next weeks. Grand rounds is hosted by Michael Stern yak in the division of public psychiatry and the speaker is going to be Gary Belk Belk in from the billion Minds Institute at Harvard and he's going to be talking bout thrive NYC an community mental health.
00:20And uh with that I hope you all will be, he ran the.
00:26Following week, we will just announced that next week. It's on the flip side OK.
00:32OK.
00:34Oh, in the next one is going to be at the Cohen Auditorium. So keep that in mind, so you don't show up at the wrong place, and that's going to be A to Gregory and it's going to be bystander intervention addressing harassment and bias at work.
00:49She's from Duke University.
00:52So with this, I'd like to introduce Doctor Genk Tech, who probably needs no introduction's. But he trained in Turkey before coming to the USS and he's been at Yale for quite a while. He's an associate professor in the Department of psychiatry. He's an expert in the management of treatment refractory schizophrenia with a specific special expertise in the issue of weight management. And here he's also directing the psychosis program of clinical research at CHC.
01:24We're looking forward to his talk today, which is a simple guide to counteracting antipsychotic induced weight gain. Thank you.
01:34Alright thank you for all coming in in the.
01:40And then
01:41I'm going to start with a confession that I decieved all of you with this title.
01:47It's clickbait as the young ones would say these days because there is.
01:57Nothing simple about weight management. It's it's not simple I used to think that when I first started.
02:06I used to think that, like those pool problems that we had in high school right there is a container and then you know, Cal is coming in that you're eating from this tab and this is the work calories. You spend whatever doesn't flow out.
02:22Uh is stored as energy.
02:26Fat.
02:27And but you know if you ever tried to lose a pound or 2 and maintain it off, you know that it can be further than truth.
02:37Uh the human body had several 100,000 years to prepare for the.
02:44A possibility that you have the silly notion of.
02:48Giving away those precious enerji stores, so there are multiple mechanisms in the body.
02:54That keeps the step.
02:58On and there's almost nothing that keeps this off so the second thing in the title is it's not a guide. I got nothing for you.
03:12I'll give you tips and tricks that I use in my clinical work, but I don't have any magical solutions. However, I am going to tell a story of trials and tribulations for the last closing 2, decades now in this very building.
03:33Uh with our patience an I'm sort of I wanted to tell a story because I expected. This to be a family affair and it is so far that you know how I did. And why I did what I did, and there must be some lessons there for for younger generations.
03:52And the finally when I think about.
03:56Antipsychotic induced weight gain, counteracting it is this.
04:02Uh.
04:05It this possible.
04:08However, it would be so much better if those things never got out of their basis. I want to. I want to Disabuse. You too, after notion that there are weight. Neutral Anti Psychotics. There are not an anti psychotics are prescribed but 10 times more than what would be justified with the incidence of psychosis, so these medications are being overused.
04:36Uh so the main message of this whole talk is that if you can get away with not prescribing an antipsychotic do not and.
04:47Uh if you'd have to prescribe an antipsychotic choose wisely.
04:54And also try to use lower doses.
05:00Uh because it deviates effect is quite those related now how it all started is this.
05:09Our patients die about 2530 years earlier and they die mostly of cardiovascular disease right. This is 86,000 deaths in that period. This is a relatively new study, but this was our clinical reality. We were losing a patient.
05:26Every other month to cardiovascular disease in this very building. I had a clinic about a little less than 500 patients 480 or so 420 of them were confirmed schizophrenia schizoaffective disorder.
05:43An hour patients were actually dying and more has been done in this very building by its CMHC by well partly myself by other colleagues. Some people in this very room to combat against this.
06:04And I can assure you that we were also very active in the changing state and federal policies and guidelines that many things that are standard. Now, Indiana care of psychosis. We were very early. Or maybe we started some of them, but as I was dealing with this.
06:29I found out what every physician dealing with chronic diseases do learn.
06:35And that was it so much more difficult to treat a disease once it occur.
06:41Uh then preventing it and most of these deaths are risk factors that are very modifiable.
06:51And so I start thinking about like? How do I prevent this thing and I remember this is not my specialty area? I came to Yale is a schizophrenia expert cognition.
07:04Uh so it was obvious that the first things that needs to be done and to decrease.
07:14These diseases is actually smoking cessation.
07:19And.
07:22We I was lucky enough we were lucky enough to have Tony George working in the building at the time he was running schizophrenia. An address my smoking cessation studies. So I started meeting with him and we we, we had a nice arrangement that he had a very good clinical team.
07:44Who was doing the research so we had an arrangement that we would send our patients to him and he would treat them his team would treat them regardless if they were eligible for his studies or not, that worked out fine and like you know, I said Oh I can outsource this stuff my first biggest headache is gone. Then I moved on to the second biggest risk factor. I started playing with cardiovascular risk calculators, etc and it was obvious that.
08:14The problem the second biggest risk factor for preventing you know for cardiovascular disease is an also diabetes and some cancers here is was excess weight right so I wanted to see you know what's going on in my clinic.
08:31And at the time.
08:35This is about. I think 400 schizophrenia patients. We don't have a first step shot connect and so there must be about 7 or 8 first episode patients an the graphic showed us that.
08:50Uh that we were seeing with our eyes were not meraj. We had about 3 times the.
08:59Oh, basically incidents compared to the New Haven population. We had about 5 times severe obesity.
09:06Uh you know incidence in our clinic.
09:10And the diabetes rates were about 3 times, which is a good bellwether for cardiovascular disease coming in.
09:17So the of course, the question is, I'm still pretty sure that it's smoking. That's causing it because our patients smoke so much more than everybody else, we looked at cardiovascular risk.
09:31And it's fairly easy to do, if you obtain the necessary components an well it turned out that.
09:40Uh our particular patience had higher cardiovascular risk than the rest of the population, but not only from the rest of the population from rest of the obese population.
09:54So we got to address this issue an at the time they all the rage was Atkins diet. So I was £40 less. I didn't know anything about weight and but the Denver suggestion that Oh they're eating more carbohydrates maybe.
10:13And so we looked at what they what people are eating.
10:17We did the nutrition analysis and they were eating about like exactly the same things that everybody else was eating. They were just eating more of it. About 500 calories per day more of it.
10:30So then there was a suggestion that well our patients. Maybe don't move as much. We looked at it an there was nothing there.
10:40That was like you know they didn't think that they were moving a little bit more than others. So there was an insight problem or self assessment problem there. But they were pretty much the same as as their peers and this particular.
10:55City all the healthy numbers are actually drawn from New Haven City of New Haven.
11:02So I started looking for I know basically person just like Tony George so I can.
11:10Uh.
11:11Outsource that issue too.
11:14Uh and so that I can you know, do what I'm?
11:18Trained to do.
11:20Uh an at the time we had a big obesity expert in at Yale. His name is was Kelly Brownell. He's at Duke. Now Kelly Brownell was a very important obesity researcher and he had moved onto.
11:36A population studies then.
11:39Uh.
11:42But in his earlier years, he had developed is a very successful commercialized weight management program.
11:51He was very busy it was extremely difficult to get an appointment from him, I think we
11:59Put some people you know.
12:03And either Bruce fixture or the other professor vexed and helped us to get an appointment. We went to downtown campus to his building. He had a building at Yale.
12:13And I can still remember the long walk from its office door to his desk little bit down thing. He was a larger than life figure. He is still is, and so that was a very defining meeting. I went there with my accomplice. Michelle John Baptist for those of you who don't remember him. He was the medical director of the 4th floor and Michelle having worked as a hat administrator.
12:43And surgeon in Haiti for many years before he became a psychiatrist had a really great sense of preventive Madison.
12:51So Michelle and I went there and uh.
12:54There are a couple of things that Kelly Kelly did for us or told us the First things first. He told us that well. There is obesity epidemic going on in the country and there are not enough. Obesity researchers so if you don't do it yourselves. Nobody else will do it for you.
13:11Uh.
13:12Crushed my dreams.
13:17Then he should some emails to the company that was managing his weight management program and gave us permission to use his weight management program.
13:29But the other thing he did is that he introduced us to the concept of foot deserts and food deserts. If you're not familiar with the concept is the areas of the country where even if you have the means you don't have.
13:45Places to buy healthier food stuff.
13:48OK, most of the countries served by non Supercenter Walmarts or Family Dollar type of stores which focus on non perishable food stuff, which is usually chock full of calories and salt and all those kind of stuff.
14:07And this is our fair state and we are living right in the middle of a photo that turns out OK.
14:16And this is not of course for denizens of E Rock, who can drive to Costco and get their stuff.
14:22But most of the people in our town.
14:26Are you sure this is a map of poverty in Connecticut? So so people did not do not have money?
14:35And do not have the means to go buy the stuff that they need to buy.
14:41So Kelly said if you don't address this issue your patients are poor. They're they're living in the middle of.
14:47Foot desert there are no supermarkets in such that they can go buy their stuff if you don't address this issue.
14:57You're not going to be able to get any results.
15:01So.
15:03We started talking about you know about this and Michelle and I decided to give people healthy foods. That doesn't work. That's not such an easy thing because there's a lot of logistical problems with it. Healthy foods are very perishable and I think we got an astounding now from the people who would facilitate that we had a cook named Mark.
15:33I think if we didn't let us use his phrases, etc. So that that was not going to fly at the time I engaged clinical nutritionist in the Yale New Haven Hospital Nutrition Clinic. Her name is Alan Lisco, who told us there is no point in giving people the foot. They're just going to eat it and they go back to to do whatever they do. She had extensive experience with another special population developmentally disabled adults.
16:03And.
16:05So she said that we need to do teach them half to show how are we going to do it so we came up with the idea of guided supermarket tours this is like museum tours. You take people to the supermarket you go around because Ellen assured us that it is possible to eat healthy with a limited budget.
16:23Uh.
16:24Then we change the idea of giving people foot we need to address the poverty problem.
16:32Because you know, I'm very also I'm reading the literature in other fields and contingency management was all the rage at the time so I like you know, we came up with the idea that will actually do a contingency management for behavior change. So we were going to reimburse people first teach them how to shop. Becaus supermarkets are very cluttered environments and they're highly curated by marketing gurus. You're not going to go in a supermarket.
17:00An see frozen green beans when you get in what you're going to see is like you know, mostly junk because there is more profits in there for about the companies and the supermarkets, so.
17:16We thought we were going to teach people have to shop and then reimburse them.
17:22Uh when they buy the good stuff.
17:25OK, we identified some good stuff, so Michelle wet and got up service grant from CMHC Foundation. Thank you for that I think it was $1000.
17:37Uh I don't remember well and so we did the first program 24. I engaged 24 of my patients 18 of them, actually out of the 24 who signed up did it for $1000. We did the first pilot study.
17:55I think the most simplest foundation gives away these days is $50.00, so that was good money and so we did the first study.
18:06Which worked is like I chose particularly heavy patients the average BMI was 37?
18:15And.
18:18So almost everybody in that group was eligible for bariatric surgery right and it worked. But you know to our surprise. It didn't only work but it continued working 6 months after.
18:33So at this point we have something that works, but I wasn't really happy with the learn program because it was you know it really belonged to a company at that time you had like I felt like we had to pay for this each time or ask permission for it.
18:50Uh so I decided to do something better for my patients are patients have subtle cognitive impairment and.
19:04Uh.
19:05I also wanted the words were too big you know, I I had little kids I was watching a lot of Mister Rogers. I thought that you know well the I. It was boring. But I was enamored with the guys style, the words were simple concepts first simple message was clear that's what I wanted. I wanted to intervention that Mister Rogers would be proud of.
19:32Uh.
19:33So.
19:36Uh.
19:38That was one thing the other thing is that well. Morris is here. I was helping them out with their cognitive rehabilitation studies and I learned something there that you know you have to start very simple.
19:52And then increase difficulty slowly.
19:55And then repeat repeat repeat repeat repeat repeat repeat repeat as much as possible to go beyond the cognitive impairment.
20:05So.
20:07We already got down the supermarket with it. I I really like that. That was very popular. We usually started those visits with 8 people and it with 20 and then you know, people from the community joined and they applaud that was fun. So I was already familiar with diabetes prevention program. And if you don't know what time it is prevention program? Is I think this is this is the one of the best studies and I HM refunded.
20:39Thousands of people got randomized to lifestyling intervention.
20:44Uh to metformin and placebo and there is quite a bit of weight loss and the.
20:54And that weight loss remains.
20:56Uh and this is metformin remember that I'll come back to that. It's about 4 pounds and then it Peters off towards the end, so the this study had to be stopped midway because it would be unethical to continue the difference between lifestyle and placebo was so big.
21:16OK, they had the different sensors use different modules of the life of a lifestyle information or their own lifestyle intervention. I think but they put all of those behavioral interventions into a zip file that I downloaded from from NIH after asking permissions. It was free to use free to download in public domain. It was a little chaotic, but we went into it and we chose what we wanted.
21:48And we created our own program, with you know with followed.
21:55Which followed you know all the principles that I mentioned to you with my colleagues?
22:00And it is.
22:03This one and the deception continues. I always warn people that it's not simple it's simplified towards are simple and I don't know if the Spanish version is if the words are simple, too because that's a courtesy of Upper Manhattan. Mental Health Center. If you know, New York City. They have a large Spanish speaking population. This is not translated to. I don't know 67 languages used.
22:35Around the world, I'm most proud of Icelandic because Icelandic.
22:40So and the funniest email, I got was from colleagues from UK. They translated to English.
22:53Well, they didn't really translate it. That's not what they said. But they had to adapt it to British eating patterns like so we had to.
23:05Obviously test this and.
23:09So.
23:12I found out that clinical trials, especially behavior that can cut trails are super expensive the largest grant, I over garden with my cognitive studies was below $100,000.
23:24And this thing was going to cost millions of dollars.
23:28Uh so.
23:31I called the program officer and I said, Don't worry people know if you write another one, and like you know, I never written that NIH grant, let alone another one.
23:40So I collected.
23:43Our own applications from friends and family and if you're in the audience and gave me your aldara. One applications now. I know that people don't give away their old our own applications and I didn't know that, but some of you in the audience. did I had. I had a sense of structure of habanera. One is written an you know it didn't have nice page limits that we have now if they were long things to read.
24:10So I wrote another one.
24:13And like you know, I have to give a shout out to I made everybody who would be willing to read it read it and edit it.
24:24And I'm going to give a shout out to many of those people here. I mean, like the Co investigators. Of course, did read it and editeded like Bruce Vextor Carlos Grillo, who graciously decided to join Lydia Swastik, Florida. Pietro was at exercise physiologist at pier slap who designed the lifestyle activity program for that study.
24:51And people who are not Co investigators.
24:55Who?
24:57Did review it and critiqued it out of either out of the goodness of their hearts out of their kindness or maybe to get me off their back.
25:07Oh, God, so many people Bruce Rounsaville May, he rest in peace spend a lot of time on that I presented it to Psychotherapy Development Center, Katy Carol was there, she made helpful commands. Sushi track Krishna insulin. Stephanie O'Malley because I buy it in her office and asked her to please help and people.
25:34Outside the Department cereal, D'souza introduced me to wrong, Ganguli that spit who had a competing study at the time.
25:45Uh but you know, he liked the grant, so he decided to join in as a Co. Investigators this one. Two John newcomer at wash U kid, not to line at UCLA. Several other names. This this grant has been critiqued much more than any NIH review committee could do so by the time it went to it went to review it got.
26:09Find it.
26:11OK, there were 2 critics there, I mean, there are 2 lessons. If anyone of you are junior investigators. There are 2 lessons here, one get help.
26:212 don't overdo it becaus several people who would be friendly. Rivers told me that they had to recuse themselves from the Review Committee. So we got the grant, there were 2 critic Swan recruitment goals were too ambitious.
26:37Which I knew was not true because I know my clinical population the second critique was that I wasn't asking for enough money, which turned out to be true, although the money. We got was more than my lifetime income. So so we went ahead and did this study. It took what 6 years. We randomized 190 patients and it did work it did work wonderfully.
27:07The the if you notice the control group stop gaining weight too. And that's the common finding actually in weight management. Studies in the general population. The nice thing is that the actually the number of people who lost clinically significant weight increased after the intervention ended and the treatment as usual group remained the same and I wanted. I wanted to know if really like you know, signing up for a weight loss study is doing anything because all they get is.
27:38Getting weight measurements every other month right so I looked at you know randomly chosen selected group among my patients. An I found out that they are actually gaining weight in that form Mount period of time.
27:56So this is the story of the behavioral intervention development. I also was curious about if this contingency thing is working for behavior change. So we did. Another pilot study for one thing. Let me tell you this intervention has been used in this building by our behavioral health home team directed by Nancy Watsky without the contingency part and they got the same results.
28:27You know, people stop gaining Wayne half of them lost weight, which looks great. But I was still curious about the contingency part so I did another study where we paid people just to attend.
28:43We paid people per pounds, they lost.
28:46And we paid you know, we did our contingency behavior and it seems like contingency for behavior change is work, a little bit better. This is a short term version of the same program because I did it with bipolar so now. I'm moving away from schizophrenia little bit. I'm going to tell you why in a moment but before I move onto I'm going to move on to the pharmacological part of this story.
29:11But before I move on to that. Let me share you some tips and tricks that I have learned along the way.
29:19Very quickly so that you know you can use your in your clinical practice.
29:25And the
29:28First thing is there is nothing special.
29:31And right management with any serious mental illness. They gain the weight for the same reasons. Everybody else gains weight OK with a little help from the medications.
29:42And they lose the weight, the exact same way that everybody else loses weight.
29:47OK, it's extremely important to be non judgmental.
29:52Our patients complain a lot about weight stigma. They complain about weight stigma actually more than mental illness stigma. How do I know we actually did the research is in the literature you can go take a look?
30:05Always way people don't take their word to how much they weigh people underestimate their weight. Part 10 to 20% and the general population and so is our patients. We did the research. We showed that as correct. There is no reason to do any waist measurement or nothing like that. BMI is a perfectly good.
30:26A proxy for Adapa City and the body. We did research that actually because I wanted to have practical ways of following people.
30:37And.
30:40It's always good to have a scale in the office.
30:44Because it's a prompt for this discussion. I mean, remember that, you know the reason for that visit is not right management. The patients are there for their mental health problems your primary job is to do with mental health.
31:00And maybe you have 2 three minutes.
31:03To address the weight issue.
31:06So don't try to change people's lifestyle in those 23 minutes choose one thing that they can give away.
31:14It's usually a bag of chips or a full calorie soda and that strategy worked very well for us.
31:23An we advocate frequent self monitoring I have bought.
31:30With my own money and distributed 400 scales in this building.
31:34Uh a patient called me Johnny Appleseed of scales and I did not know who Johnny Apple speak to her so I went home. Ask my kids sounds like a stand up guy, so.
31:53Uh.
31:54I I have one actually I lied I distributed 399 scales. I still have one in my office. So if you don't have one. I give it away to any resident stuff for patients who want one.
32:09So the last thing is like you know refer to weight management programs if they're available. Obesity is now a disease. Some insurances do pay lifestyle programs work in our patients can do anything that other people do.
32:26Uh you use different types of programs over the years and it works, so coming down to the pharmacological part. This is a story that you know now. The new medications came on this is stolen slight must have stolen it from either microcell.
32:44Uh and this meta analysis started all and prove to us that what we were seeing in the clinic is happening to everybody else.
32:55OK, this is the initial meta analysis, but of course, like I have an updated one for you and you can clearly see the anti psychotics right here work pretty much the same with the exception of close Appin. Of course, all right, but their weight gain liability is different greatly.
33:15And.
33:18But how I'm looking at this as a well. You know researcher clinical. Researchers is that these medications on this ad are mostly anti histamine can anti cholinergic.
33:34All right and these ones in the middle are not really anti Semitic, but they do. Black 552 C Receptor. Certain 2C Receptor, which is probably not needed for antipsychotic action, but comes in the package with 5H T 2A.
33:50And Well, you know they all black the D2 receptors.
33:56And but the Pure D2 receptors look, you know coming out of Roses.
34:04The my problem with this was when I started Hello Paradol, too.
34:11Patients who did not use anti psychotics before they gained a lot of weight.
34:15So I I thought that well these are studies that are actually done with chronic patients they must have been on Anti Psychotics before.
34:27And it
34:30Maybe the the two effect is dopamine 2 receptor effect as mask, so we went ahead and did our own meta analysis.
34:40And as you can see, there in the long run haloperidol in medication, naive patients.
34:48Actually goes 20 pounds of weight on average.
34:53Uh.
34:54And the first year so obviously I have 3 receptors. Now the actually 4. If you count the Anti Cholinergic Anti Semitic Anti cholinergic concept.
35:06The complex and 552 C.
35:11Which is an appetite related receptor and probably depression antidepressant activities there?
35:19And the D2 Receptor all our medications, Black T2. We don't have an antipsychotic which doesn't blocked it.
35:27And if you can cause people. It's more, with a chemical maybe you can call them. It less with another one.
35:35And the 2nd question was that is this is kind of linear problem then.
35:40Uh because people cited blur and crap linen that they talked about weight fluctuations. They would talk about weight fluctuations. They paid a lot of attention to body shape head shape all kinds of things and however they never talked about obesity.
36:00So we hit the historical literature and found out actually studies that were done before anti psychotics.
36:08And.
36:10This was presented in 1942, the second one, the first one was presented 8 years before that.
36:16And the patients with schizophrenia.
36:20Uh we're actually.
36:22Undernourished.
36:24And the second slide is after 8 years of specialized nutrition programs. They fail to gain weight so obesity is not a feature of schizophrenia.
36:35So.
36:36Other evidence comes from group of patients that were tracked in India. There were 6 for about 30 years. Never received the medication. They did not have an obesity problem and then of course, the antipsychotic native people who don't have psychosis who have things like borderline personality disorder. PTSD the anti psychotics cause similar weight gain OK.
37:02So now how I try to so now I'm moving beyond schizophrenia. We are in the anti firmly in the antipsychotic induced weight gain territory.
37:13Um.
37:14I had to start with histamine because he study more receptor blockade. Obviously was the biggest problem but I'm I also have.
37:26Other than
37:28Other than 30 or so patients on closer pin.
37:31OK remember that I specialize in treating refractors 'cause of rain, yeah, I'm obviously the biggest prescriber of close up in between. New York and Boston. I've been told so actually. I know the guy who prescribe most in Boston, too. It's all over.
37:51So uh.
37:53Now we are uh.
37:57I have to do something about this, though I mean, I don't know anything about this to me and I had to hit the pre clinical literature again, and see what worked what didn't work for you know what? What's active. The histamine receptors. There were there was a study at least that showed that the histamine receptor induced weight is due to the to the action in a specific area of the brain on a specific enzyme system. I'm not going to go into details there.
38:24And and the anti cholinergic activity comes with it an it is meaningful. But I'm not going to talk about that I can answer your questions after.
38:36Uh at this point of course, the question is a lot of people use anti histamine X for their allergies in this country and around the world right. It's allergy medication. Anti is Dominick's.
38:47And so the idea was like let's take a look at the population numbers.
38:54To see if
38:58People who use allergy medications gain weight. Two we did that my claim to fame. I got on a local TV station in Cleveland and blurbs in New York Times in Boston Globe and yes, people who were an antihistamine ICS after the allergies are controlled not everybody with allergies.
39:25Uh.
39:26I use anti Semitic's.
39:28And are heavier than the rest of the population.
39:33And there is an obligatory slide after this, because there's always people in the audience. We use anti histamines and that question is going to come. So I learned to put that slide in the most commonly used allergy medications and they are the.
39:51Green one purple one and the blue one.
39:54Do not cross blood brain barrier for most people, most of the time OK, the pink one.
40:00Play my drill does and I'm telling you the colors because obviously they come with different names. But those colors are pretty standard in on the shelves.
40:13And you know you don't have to stop your anti histamine. There is a simple trick to figure out if it's crossing to your brain.
40:22If it makes you sleepy it's in your brain. It makes you eat OK if it doesn't make you sleepy and then switch to switch your anti histamine to another one if it doesn't make you sleepy it's you eating and not your anti histamine.
40:37So so let's move on. I looked at the of course, like in after examining the pre clinical literature. There are several medications that are available for humans that can work on this particular system. The first one came out to be met foreman, but I was using metformin already because of the diabetes prevention program city.
41:00An I wasn't that impressed with it and Tryna Baptist from Venezuela was doing early studies than he published maybe 10 of them. I hope he's doing all right there that place really went down to chaos. So he wasn't very impressed with it, either, so I didn't pursue met foreman.
41:23Others did.
41:27And what they found is like this is with the lifestyle program what they got is about 4 pounds in 1216 weeks write an if you look at the diabetes prevention program.
41:44At 4 that's what you get with people who are not on Anti Psychotics. So metformin gives you an obligatory 4 pounds of weight loss. It is definitely not a medication that will work against.
41:59Antipsychotic induced weight gain.
42:02Uh I always get consultations that you know, I started olanzapine with Metformin. Why did my patient gain weight when they probably gained 4 pounds less?
42:12But you know whoever is teaching that.
42:16As is doing a disservice. It is not a medication for weight loss, preventing antipsychotic in this way can at least.
42:25It's a good Medison I use it still to prevent or pre treat diabetes, I would say.
42:33So the next group of medications that might have worked on the system where carbonic anhydrase inhibitors and asceticism might as well? Is Semite and Top pyramid to pyramids of medication. We know very well, we use. It sometimes and it's well studied in.
42:54And none smi obese populations. It does cause significant weight loss. I was of course, aware of that and I was using it with close up in patients and this, this slide is from 2008 and.
43:14Or, 9, so I had a group of patients that I was following with this medication that extremely difficult to use medication because so frania. Of course causes a little cognitive impairment that usually patients are not aware of it set up.
43:31To pyramid causes the cognitive impairment that people are acutely aware of painfully aware of and when you stop the medication. It goes away. So it's very difficult to keep the patience on this and.
43:46Also, it has other problems.
43:50Kidney stones gallstones increased risk of pancreatitis, and we use it with medications that have increased risk of pancreatitis, so it's difficult to keep patients on this, but I still wanted to try it.
44:03OK, so I wrote the grant, and now at this point my all my grants are automatically reviewed by obesity committee. I'm aware of and I image.
44:14Uh.
44:16And you know they?
44:19They accused me for trying to prove the obvious.
44:25And they gave me an excellent score, but excellent scores don't pay salaries. So I we didn't get that grant funded. But other people did that study. This is with olanzapine and this is from Korea.
44:42And 100 milligram actually is the sweet spot between 75 and 125 that patients can tolerate and after 200. Usually, it doesn't have any effect, so it still can be used as a medication.
44:57Is only Samantha has been tried to it's a migraine medison? Which was approved and that works as well?
45:04Uh so the last one was Alpha lipoic acid.
45:08It went from the pre clinical literature and so I went ahead and did a meta analysis with like smoke from small studies that are used in general population for weight at times and I wasn't very impressed with it look exactly like metformin, but after the per cassette was an anti oxidant an anybody who knows how I think about you know research. I do a lot of anti oxidants studies to improve cognition, etc.
45:37So it has this really nice double suffer bound, which scavenges free radicals. So I wanted to try that I thought like you know two birds with one stone.
45:51I did what any reasonable.
45:55Expert clinical scientist would do I went to Amazon and read the customer reviews. and I bought a bunch of bottles of it from a brand that had five stars and was cheapest because I have a family budget. Thank you very much just like the rest of you and it was $4.35 a bottle.
46:20We did this study.
46:23And very cheap study.
46:26And it didn't do anything for cognition or symptoms, but Jack pot.
46:34It didn't work only on people who are enclosed opinion olanzapine.
46:40OK, it's very nice now we are on track the problem was the supplement.
46:48It was impossible to blind because part of it is thrown away with from the kidneys. It gives the urine specific smell and color.
47:00Good for monitoring compliance, but it's not that good for.
47:05Blended.
47:08And this is this was another grant, which was received an excellent score, but did not get funded. So I'm going to pursue this probably as a combination with something else, OK, so this, this part is the H1.
47:22Part of the of the story theater to see receptors to make a very Long story short. I had to deal with a company that was developing a serotonin to see agonist as an obesity medication. They said they were going to give the medicines after it got FDA approval. They got FDA approval and they got sold immediately so I didn't get my medicines, but that same group that studied the.
47:53Metformin are now studying doing a study with.
47:56Combination of metformin and Locus Air and it is a medication, which actually.
48:04Was associated with a little bit more depression than placebo in the registration trials and of course, the best study is that study. Other people do with their own patients with new stuff. So I'm waiting for the results of that. Now let's get to the D2 receptors. I'm not going to like you know, even talk about why they do receptors would cause weight. There are 2 world class experts in this very Department rough deleon studies in animals.
48:34Dana small studies in humans, we listen to both of them here. This is from a review that Dana recently published which shows what obesity does 2D2 system.
48:50Anne what I'm thinking is that?
48:53This arrows go both ways.
48:56Because when you increase dopamine here.
49:00Which I'm going to show in a moment people eat less?
49:05And actually if you follow this authored reward the food reward is.
49:11Uh it is true partly through endorphin system. If you saturate that system and downstream with let's say medications like methadone.
49:25People eat more?
49:27Uh.
49:29So, but of course, the obvious thing is to increase the.
49:33Dopamine here and it's been done.
49:37Uh.
49:39For decades in this country amphetamines have been used.
49:44As weight loss medications this is methamphetamine.
49:51Which I as far as I know The New Yorker ads by the way which as far as I know still in the books for obesity medication. But I'm not aware of any drug company that produces it is still being produced in small labs.
50:06Uh the back alleys. This is Bronx, so obviously people stopped using it because it causes psychosis and highly addictive.
50:22So I put that aside I didn't discard it.
50:26You know, I didn't discard it, but I put it aside because there are other things that we could try to do that. But what happened is that I was introduced to a group of scientists who formed the company and they were they were developing a combination of not Rick Stone and book pro prion as a as a obesity medication. I don't know if Carlos you didn't introduce me or.
50:57Uh and Dale data looked really great at the time, but you know. Just you know, said. Let's wait for them to get approval and see like you know, do the bigger studies.
51:10And but what happened is that?
51:14Uh.
51:15One of the times, I crashed into Stephanie O'malley's office again and this distract her from her work.
51:21Uh she showed me some at that time, unpublished data that when people received not friction during stop smoking trials and stop smoking they gained less weight.
51:36And there is a relationship you have to take my work. I'm not going to go into details why but essentially you're blocking the food reward downstream and I had some food reward studies with so failure patients showed that actually food reward is blunted, so that was a good thing so in collaboration with Stephanie. We did a pilot. We got my I got money from.
52:00Vielles woman research you know, I'm really grateful to Carolyn measure. Our faculty member who created that center and give away those pilot fonts it was a pretty dramatic study.
52:16People lost weight, there was only one person jinx of randomization in the in the diabetes group, so that was not significant for non diabetics. We had a pretty significant result just medications. There is no other intervention here and as a proof of concept if we were really blocking the full reward the This is.
52:43Measure of food reward. And yes, we were black in the food reward compared to placebo. So we did sit down and write. This study, the collaborators were the usual suspects. Carrasquillo Stephanie O'Malley and Carol Napoleon, who is a fairly important obesity researcher up in BU and we did a one year long placebo controlled randomized double blind.
53:15Trial as an add on medication. That's a very difficult study to do with serious mental ill patients.
53:24And the result was.
53:28Negative.
53:29Such is the fate of critical research 6 year long and.
53:39There is nothing demoralizing as your to find out that you're working hypothesis doesn't really work.
53:45So.
53:49I have of course, some future directions. There are a lot of threads to follow as.
53:56Some of you may know I'm a full-time condition and spare time researcher so.
54:03Tieman resources, allowing
54:07Uh I'm going to continue chugging on on that railroad.
54:12And see if we can find a solution to this problem.
54:16And if I'm lucky someone else will so I can declare victory and go home.
54:21At now at the risk of being cheesy. I'm going to. I'm going to remind you that the best things in life are not things. This lady is now medical school. This is a year after I came to Yale. This guy is about to go to college time flies and.
54:43Uh I am truly grateful. This has been a wonderful home for me for 17 years. The I'm I'm really grateful to all the CMHC patients.
54:56CMH stuff some of them departed, but not forgotten. So all the L faculty L trainees. Everybody who helped me along the way I learned a thing or 2 from everyone of you.
55:10And.
55:11I hope it all ends. I live a good echo around here, so that is my presentation, I can take some questions.