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CME

Research Directions in Schizophrenia Treatment: Mechanisms of Action for Next-Generation Agents

  • Authors: Stefan Leucht, MD; Christoph U. Correll, MD; Rene S. Kahn, MD
  • CME Released: 10/13/2011
  • THIS ACTIVITY HAS EXPIRED
  • Valid for credit through: 10/13/2012
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Target Audience and Goal Statement

This activity is intended for psychiatrists.

The goal of this activity is to teach physicians about the mechanisms of action of current and future treatments for schizophrenia and the relationship between those mechanisms and efficacy and side effects.

Upon completion of this activity, participants will be able to:

  1. Describe the mechanisms of action of current antipsychotic agents
  2. Explain the rationale behind the development of new treatments in terms of receptor binding, targeted symptoms, and side effects


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Medscape, LLC, encourages Authors to identify investigational products or off-label uses of products regulated by the US Food and Drug Administration, at first mention and where appropriate in the content.


Author(s)

  • Stefan Leucht, MD

    Professor, Technische Universität München; Vice Chairman, Rechts der Isar, Munich, Germany

    Disclosures

    Disclosure: Stefan Leucht, MD, has disclosed the following relevant financial relationships:
    Served as an advisor or consultant for: Alkermes, Inc.; Johnson & Johnson Pharmaceutical Research & Development, L.L.C.; Eli Lilly and Company
    Served as a speaker or a member of a speakers bureau for: Janssen; Johnson & Johnson Pharmaceutical Research & Development, L.L.C.; Bristol-Myers Squibb Company; Eli Lilly and Company; Lundbeck Research USA, Inc.; AstraZeneca Pharmaceuticals LP
    Received grants for clinical research from: Eli Lilly and Company

    Dr. Leucht does intend to discuss off-label uses of drugs, mechanical devices, biologics, or diagnostics approved by the FDA for use in the United States.

    Dr. Leucht does intend to discuss investigational drugs, mechanical devices, biologics, or diagnostics not approved by the FDA for use in the United States.

  • Christoph U. Correll, MD

    Associate Professor of Psychiatry and Behavioral Sciences, Albert Einstein College of Medicine, Bronx, New York; Medical Director, Recognition and Prevention (RAP) Program, The Zucker Hillside Hospital, Glen Oaks, New York

    Disclosures

    Disclosure: Christoph U. Correll, MD, has disclosed the following relevant financial relationships:
    Served as an advisor or consultant for: AstraZeneca Pharmaceuticals LP; Bristol-Myers Squibb Company; Desitin; Eli Lilly and Company; Intracellular Therapies, Inc.; Pfizer Inc.; Otsuka Pharmaceutical Co., Ltd.; Actelion Pharmaceuticals, Ltd; Alexza Pharmaceuticals, Inc.; Merck & Co., Inc.; Novartis Pharmaceuticals Corporation; Sepracor Inc.; Sunovian Pharmaceuticals, Inc
    Served as a speaker or a member of a speakers bureau for: Biotis; Bristol-Myers Squibb Company; GlaxoSmithKline; Merck & Co., Inc.; Otsuka Pharmaceutical Co., Ltd.; Pfizer Inc.
    Received grants for clinical research from: Bristol-Myers Squibb Company; Otsuka Pharmaceutical Co., Ltd.; Janssen Pharmaceutica Products, L.P.; Johnson & Johnson Pharmaceutical Research & Development, L.L.C. Served on the Data Safety Monitoring Board for: Bristol-Myers Squibb Company; Cephalon, Inc.; Otsuka Pharmaceutical Co., Ltd.

    Dr. Correll does intend to discuss off-label uses of drugs, mechanical devices, biologics, or diagnostics approved by the FDA for use in the United States.

    Dr. Correll does intend to discuss investigational drugs, mechanical devices, biologics, or diagnostics not approved by the FDA for use in the United States.

  • Rene S. Kahn, MD

    Professor of Psychiatry, Director of the Department of Psychiatry, University Medical Center, Utrecht, the Netherlands

    Disclosures

    Disclosure: Rene S. Kahn, MD, has disclosed the following relevant financial relationships:
    Served as an advisor or consultant for: EnVivo Pharmaceuticals; Eli Lilly and Company
    Served as a speaker or a member of a speakers bureau for: AstraZeneca Pharmaceuticals LP; Bristol-Myers Squibb Company; Eli Lilly and Company
    Received grants for clinical research from: Bristol-Myers Squibb Company

    Dr. Kahn does intend to discuss off-label uses of drugs, mechanical devices, biologics, or diagnostics approved by the FDA for use in the United States.

    Dr. Kahn does intend to discuss investigational drugs, mechanical devices, biologics, or diagnostics not approved by the FDA for use in the United States.

Editor(s)

  • Margaret McLaughlin, PhD

    Scientific Director, Medscape, LLC

    Disclosures

    Disclosure: Margaret McLaughlin, PhD, has disclosed no relevant financial relationships.

CME Reviewer(s)

  • Nafeez Zawahir, MD

    CME Clinical Director, Medscape, LLC

    Disclosures

    Disclosure: Nafeez Zawahir, MD, has disclosed no relevant financial relationships.


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CME

Research Directions in Schizophrenia Treatment: Mechanisms of Action for Next-Generation Agents

Authors: Stefan Leucht, MD; Christoph U. Correll, MD; Rene S. Kahn, MDFaculty and Disclosures
THIS ACTIVITY HAS EXPIRED

CME Released: 10/13/2011

Valid for credit through: 10/13/2012

processing....

 

  • Christoph U. Correll, MD: Welcome to today's program Research Directions in Schizophrenia Treatment: Mechanisms of Action for Next-Generation Agents. My name is Christoph Correll. I work at the Zucker Hillside Hospital in Queens, New York; and I am Associate Professor of Psychiatry at Albert Einstein College of Medicine.

  • Slide 1.

    Slide 1.

    (Enlarge Slide)
  • I have with me today, Professor René Kahn, who is Professor and Chair of the Department of Psychiatry and Head of the Division of Neuroscience at the University Medical Center, Utrecht, The Netherlands. I also have with me Professor Stefan Leucht at the Technische University in Munich, Rechts der Isar in Munich, Germany, and he is also vice chairman of the department there.

  • Slide 2.

    Slide 2.

    (Enlarge Slide)
  • When talking about schizophrenia, we are still somewhat hampered by the fact that the pathophysiology is not that well known, and that obviously influences our capability of developing agents that have a very targeted approach to remediating symptoms of this illness. Moreover, as Bleuler put it so aptly, when talking about schizophrenia, we have to talk about it in the plural. So there might be subgroups that only certain mechanisms of action are particularly useful for. When we talk about schizophrenia, usually dopamine comes to mind. René, is that the full story?

    René S. Kahn, MD: Definitely, I don't think it's the full story. Dopamine is important, but it's important in psychosis. But we all know and Bleuler was the one who indicated that, and Kraepelin as well, that schizophrenia is much more than psychosis. Psychosis is very nonspecific. You see it in many other illnesses. So what's much more important are the cognitive changes -- and that's obviously why Kraepelin called it dementia praecox because he thought the cognitive changes were central to the illness -- and the negative symptoms, the social interactions, which Bleuler indicated were so important. I think dopamine is part of the story, but certainly not the entire story.

    Dr. Correll: Right. In that sense then we're lacking a piece of the puzzle. But let's talk about what we know of those puzzle pieces. So, Stefan, what about the dopamine hypothesis, can you summarize this for us?

  • Slide 3.

    Slide 3.

    (Enlarge Slide)
  • Stefan Leucht, MD: Yes. I also think we should first summarize it quickly. As you all know, usually we need dopamine as a transmitter in the brain. On this slide, you see the normal situation where the dopamine is released and then you get a signal. The theory is that in schizophrenia, there is too much dopamine, and this then leads to hallucinations, delusions, and other positive symptoms.

  • Slide 4.

    Slide 4.

    (Enlarge Slide)
  • What all the antipsychotic agents that are currently available do is block these postsynaptic dopamine receptors. There's actually not a single one that does not share this common mechanism.

  • Slide 5.

    Slide 5.

    (Enlarge Slide)
  • The problem is, however, that this blockade of dopamine receptors does not only alleviate the symptoms of schizophrenia, it can also lead to side effects. On this slide, for example, you see the 4 dopaminergic pathways of the brain. First of all, there is the mesolimbic pathway. This is the important one because we think that the positive symptoms of schizophrenia arise in the limbic system, so it's important to block the dopamine receptors there. But then there is also the cortical pathway. The theory is that in the frontal cortex, dopaminergic tone is too low. So if all the antipsychotic agents antagonized dopamine receptors in these brain areas, that would actually be bad because it would produce negative symptoms, and it would also be bad for cognitive function.

    Dr. Correll: And those would be the so-called secondary negative and secondary cognitive symptoms we've seen a lot with the typical antipsychotic agents.

    Dr. Leucht: Right.

    Dr. Correll: Well, what are some of the other side effects we see with dopamine blockade that is not taking place in the mesolimbic pathway, René?

    Dr. Kahn: I think the biggest, obviously, are EPS (extrapyramidal symptoms), parkinsonism symptoms, and also the mental parkinsonism, the mental inhibition that you see with dopamine blockade, which is also a striatal effect, and the cognitive symptoms that are also sometimes a striatal effect due to dopamine blockade. Obviously in the long term, there is the tardive dyskinesia, which is very detrimental. It's a high price to pay to be treated for your psychotic symptoms.

    Dr. Correll: And then in the tuberoinfundibular pathway, too much dopamine blockade can give rise to prolactin elevation. And although the correlation with prolactin elevation and sexual symptoms is not that clear, usually there can be some sexual dysfunction, which many patients don't report unless we ask about it, but they might vote with their feet by stopping the medication.

    Dr. Kahn: Absolutely. Especially in young men you see that very often.

  • Slide 6.

    Slide 6.

    (Enlarge Slide)
  • Dr. Correll: So after the first generation of antipsychotic agents (which we are now becoming more aware are also not a homogeneous class), there were the second-generation antipsychotic agents. But let's stay briefly with the first-generation antipsychotic agents. Stefan, you wrote a very important paper in 2003[1] comparing low-potency first-generation antipsychotic agents with atypical antipsychotic agents. Tell us a little bit about that.

    Dr. Leucht: The so-called typical antipsychotics are not all the same. They have been broadly classed into 3 classes. There's the so-called low-potency class. Chlorpromazine is a prototype. It was the first antipsychotic agent that was introduced. Then there are the so-called high-potency antipsychotic agents. Haloperidol is the prototype of that. Actually, it's very unclear which drugs fit into the mid-potency class. For example, some people say that perphenazine is a mid-potency antipsychotic agent, but, actually, it's quite high potency if you look at the dopamine receptor affinity.

    Well, the clinical experience is that with the low-potency antipsychotic agent, you need a relatively high dose to get the same antagonism of dopamine receptors you get with a high-potency antipsychotic agent. These drugs are also all sedating, and that limits high dosing. The high-potency antipsychotic agents are effective at relatively low doses, and they are not so sedating, but they have a high risk of extrapyramidal side effects. So this was the trade-off before the atypical antipsychotic agents were introduced.

    There was a lot of debate, a fight between the different pharmaceutical companies who were manufacturing chlorpromazine and haloperidol. There was a big marketing story going on. In the end, the high-potency antipsychotic agents won with the argument that we can use high doses, and maybe this helps more. But really, in the end, it turned out that actually high doses are not more effective. In a way, it was actually bad for the patients because we used these high-potency drugs at high doses, which resulted in side effects, especially EPS.

    Dr. Correll: Right. In addition, in your paper, in your meta-analysis in The Lancet in 2003,[1] you've shown what we call atypicality, meaning less EPS, can be achieved with low to medium doses of low-potency typical antipsychotic agents. However, you also showed that they were not as effective as the atypical antipsychotic agents at that level, and, therefore, there might be some advantage of atypical agents. So let's talk about what makes an atypical agent atypical, René.

    Dr. Leucht: Let me just step in here because I think that's another dogma that is codified in literature: that all the antipsychotic agents have the same efficacy. But nobody has actually reviewed this literature since the late 1960s. There was a famous review by Davis from Chicago and Don Klein from New York.[2] At that time, they said there was no difference between the available agents, but nobody has looked at that since then. I think this is one of the dogmas that need to be checked.

    Dr. Correll: Well, I think comparative efficacy might be beyond the scope of this discussion, but you have written a meta-analysis on it.[3] Let's focus a little bit on mechanisms right now. René, what makes an atypical agent atypical?

    Dr. Kahn: We don't know. Because as you well know, we've done the EUFEST study,[4] where we compared various drugs. And for instance, a very interesting drug is amisulpride, which is a selective dopamine antagonist. Nevertheless, it induces less EPS and has some atypical effects, but not as much as some of the others. There is another atypical drug like olanzapine, which has clear 5-HT2 blocking effect and dopamine blocking effect. And you have aripiprazole, which is another atypical agent, which is possibly a partial dopamine agonist, possibly, we don't exactly know. So there is no single explanation why a drug is atypical.

    Dr. Correll: I hear that one potential definition of a drug being seen as atypical is having less EPS, but maybe also less prolactin elevation. Then there was discussion about a lower incidence of secondary negative symptoms or even a reversal of negative symptoms, but our data don't really seem to support that.

    Dr. Kahn: Those were the initial claims, maybe less negative symptoms but maybe that was due to less EPS. And as you well know, some of the drugs have sexual side effects and some induce prolactin elevation. So the whole concept of atypicality isn't that clear-cut.

    Dr. Correll: So if we look at the 4 or 5 criteria for atypicality, can you summarize this, Stefan?

    Dr. Leucht: The first mechanism that was put forward is actually that these drugs don't only block dopamine receptors, but also serotonergic receptors and this idea was held very strongly. The prototype drug was clozapine, and then many others were developed based on this concept. But then as René already said, amisulpride became available and is a very selective dopamine receptor antagonist that doesn't have anything to do with serotonergic mechanisms. This drug is thought to be atypical because it's selective at the mesolimbic system, so it doesn't block these nigrostriatal pathways. Then there are other drugs such as aripiprazole, which seems to be a partial agonist. And, finally, there's a very interesting, intriguing theory that came up in the past year. This is the fast association theory, meaning that those drugs bind only transiently to the receptors, so they bind and they get off, and they bind again, and this is also associated with low EPS.

    Dr. Correll: And a prototypical drug would be like quetiapine or clozapine for this looser-binding, maybe fast association. But as you both said, these are theories and we don't really know. We just try to understand or explain some of the different clinical features that these drugs have.

  • Slide 7.

    Slide 7.

    (Enlarge Slide)
  • To understand this better, I think what we've been doing is looking at receptor binding, like the constant of inhibition, how much nanomolar concentration is needed until 50% are occupied of a certain receptor. These tables are quite complicated, but important for everybody who looks at them. A lower number means tighter binding. I think what people have done in the past is to compare drugs across 1 receptor, and that doesn't really work as well because we need to look at the binding relative to dopamine. So if anything is blocked earlier or tighter than dopamine, this is part of the concept. That's why atypical antipsychotic agents, except for amisulpride and aripiprazole, bind more tightly to 5-HT2A, for example, the serotonin 2A receptors. And the "-pines," olanzapine, clozapine, quetiapine, also bind very tightly to cholinergic and histaminergic receptors.

    We believe these might be side effect receptors, like cholinergic receptors giving you dry mouth, constipation, and maybe also cognitive disability. There are interesting data from Sophia Vinogradov[5] that learning may be impaired. Histaminergic blockade can give you weight gain, sedation, maybe metabolic abnormalities. But then, there might also be some positive effects. Some people like to use the "-pines" because they are also anxiolytic. We haven't talked about it much, but often with an "ideal" antipsychotic agent, we might also want to treat some of the comorbidities which are quite difficult to treat.

    So any other thoughts about the mechanisms or the other receptors that are blocked? What would they bring to the table? Good things; not so good things.

    Dr. Kahn: Well, I think most important, for instance, is the serotonergic mechanism. Don't forget that almost all the patients with schizophrenia or who are psychotic have anxiety symptoms, they have depressive symptoms. They have anhedonia. Possibly these effects on the serotonin system may alleviate some of those. Also what I find clinically very important that with the "-pines," as you call them, the patient may feel better. Whether it's a very general effect, I don't know, but various receptor profiles have effects on various symptom profiles.

    Dr. Leucht: Well, I think one thing that should also be mentioned is that clozapine, which is the most efficacious drug that we have, it's also the dirtiest drug that we have. It has an effect on many, many other receptors, and has many side effects. I think the agranulocytosis partly is actually a little bit overemphasized because there are many other things like sedation, like hypersalivation, constipation, and diabetes.

    Dr. Correll: And most likely, clozapine has a receptor X that we haven't identified because we haven't been able to replicate that superior efficacy.

  • Slide 8.

    Slide 8.

    (Enlarge Slide)
  • So just summarizing where we're at right now, it seems that we have fairly good drugs for positive symptoms because we've understood that the dopamine system is involved; we can block that fairly efficiently. The evolution of novel agents has given us an armamentarium of drugs that have different side effects, and maybe in some areas lower side effects, which is good. But the unmet need is still negative symptoms, cognitive symptoms, functionality, quality of life, and maybe also insight into the illness, if there is a receptor for that.

    So for the rest of the program, we should focus on what other novel mechanisms have been explored; what other things we think will move schizophrenia treatment ahead. Some thoughts that you might be having on that?

    Dr. Leucht: Well, certainly, I think there's this big gap that has been discussed for a couple of years now that all the drugs that we have they alleviate the positive symptoms pretty well, but there are really big gaps concerning negative symptoms, cognition, and even more so now. Now, many people say well, what do these drugs do concerning mortality for example, due to the side effects, do they rather increase mortality or do they reduce the suicide risk? So that's one aspect. Do the antipsychotic agents really help patients to be able to work? I think there's a big pharmacoeconomic debate going on right now, and I think these are all new targets for new agents, and cognition definitely plays a big role in them.

  • Slide 9.

    Slide 9.

    (Enlarge Slide)
  • Dr. Kahn: I think if you look at specific biologic mechanisms, the most classical one is dopamine-1 agonism. What you'd like actually to do is stimulate dopamine receptors in the frontal cortex, because as you said, it may be that that system is primary. Actually, Ken Davis, Michael Davidson, and I published a paper in the early 1990s,[6] suggesting that the core dopaminergic deficit may not be increased function in the striatum, but actually decreased function in the frontal cortex, specifically binding at dopamine receptors. So the first thing that comes to mind is dopamine agonism at the dopamine-1 receptor. Now, that's not easy to manufacture because it has to be selective. You don't want to increase dopamine activity in the striatum, clearly. So that would be one.

    Another would be cholinergic systems because we know in Alzheimer disease, for instance, that these agonists may be effective in improving cognition. You have the glutamatergic system based on the phencyclidine model of psychosis. Those are just 3, and there may be many more.

    Dr. Correll: I think, in addition, we need the individualization of care: which drug goes to which patient. We also need novel pathways to address these gaps. Some things that come to mind, obviously, we only have 1 partial D2 agonist. There's another one that's currently developed by Otsuka, OPC-34712 that's currently in phase 3 studies.

    Nowadays, antipsychotic agents are also studied for different indications. The D3 selectivity that cariprazine might have -- that's a Forest medication that is currently in phase 3 studies. Then we have a novel drug by IntraCellular Therapeutics where they look at dopamine phosphorylation protein modulation in addition to 5-HT2A, and in addition to serotonin transporter inhibition. So that is an interesting concept. That's still revolving around the dopamine receptor.

  • Slide 10.

    Slide 10.

    (Enlarge Slide)
  • And then since we've talked about 5-HT2A, maybe to reduce the side effects of D2 blockade or add efficacy, there has been a push to look at 5-HT2A blockers that are selective. Pimavanserin comes to mind. But here, the data have been somewhat ambiguous because it seems to work only when you augment a low dose or medium dose of risperidone, but at higher doses, it doesn't really work.

    So that's for the psychosis. But as you've already addressed, well, what about cognition? And so, in addition to the D1 agonism, the cholinergic signaling alpha-7 agonism and alpha-4 beta-2 agonists have been explored. There are also histamine-3 antagonists that are being looked at. And also, looking at GABAergic signaling, GABA A subtype receptor, alpha-2 beta-2 partial agonists, and MK0777 were examined. But none of these have really yet gotten us to a breakthrough.

    That brings me to a question. You've done a lot of research on this, that there might be shrinkage of the brain in chronic disease. And we, looking at the prodrome, also see some demise of brain structure. What about neural protection, anti-apoptotic agents, is that an alley we should explore further?

    Dr. Kahn: I absolutely think so. If we're talking about schizophrenia, again, as Kraepelin suggested, it may be a premature dementia, an early-onset dementia. It's not the same as an Alzheimer dementia, but it may be either developmental or progressive in nature, or probably it is a combination. So I think yes, eventually, and the same holds true for Alzheimer disease. The cholinergic agents are not going to cure Alzheimer disease, although they may improve some of the cognitive deficits. So, we need drugs that stop the progressive brain changes in schizophrenia, and I don't think we're even close there yet, but that's eventually what we'll need.

    Dr. Correll: And there, again, the pathophysiology is escaping us yet, but we're not too far off from other medical disorders.

    Dr. Kahn: I think the genetic studies also are helping us to find what pathways are involved. There's a big time lag, obviously, between having clarified the mechanism and having a drug on the market. There may be a long time period in between.

    Dr. Correll: That's actually a good point that the novel tools that we have, pharmacogenomics, imaging, maybe even electrophysiology might help us to identify targets that can be explored further.

    I think one area that we should spend a little bit more time on is negative symptoms. What about the agents that look at glutamatergic signaling? For example, glycine transporter-1 inhibitors have now been looked at because d-serine, d-cycloserine, glycine, all of this has been very mixed in terms of the results, maybe because too much glutamate in the brain can be neurotoxic, and the brain just simply pumps out the glutamate. So now blocking the pump might be something interesting. So Roche is currently looking at this drug that had a phase 2b result that we'll discuss in a minute, but what do you think about that kind of a mechanism?

    Dr. Kahn: Well, I think it theoretically makes sense. Unfortunately, there's a large gap between theory and practice, so we'll have to wait and see. But I think it's very brave, and I think very useful. The drug companies are indeed investing in these kinds of receptor systems to see whether it makes sense. And, again, theoretically, it does make sense, but we'll have to wait and see whether it really works on the negative symptoms, because these, as we know, have proven to be quite treatment-refractory over the past 100 years, so we'll have to wait.

    Dr. Leucht: I fully agree on that. I think 1 problem in the past 10 years was that the companies focused too much on the old model, the 5-HT2D2. I think it's very promising that now we see a whole list of agents, and you had listed some that really tried to look at different mechanisms. The problem that we have, of course, is the old one that we don't have good animal models, so this is the big problem that we are facing in psychiatry. We do not know whether the animals hear voices or whether they're delusional. It's very indirect.

    Dr. Kahn: But in fact, the promising thing is that negative symptoms and cognitive symptoms may actually be easier to model in animals, because negative symptoms are social interaction. Well, animals have social interaction, and they have cognition, more limited than we do, but they have cognition. So, actually, it may be easier to use animals to develop drugs for these symptoms than it was for positive symptoms. And there it was serendipity that helped us.

  • Slide 11.

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  • Dr. Correll: We might want to look at 2 agents that are pretty far along in phase 3. One is the glycine transporter-1 inhibitor that Roche is developing. That was a study where basically 312 patients were randomized to 15, 30, or 60 mg. This was an 8-week study, and 2 analyses were done, intent to treat or per protocol (patients who really adhered to the protocol). In the intent to treat -- it's a phase 2b study, so it's not a large enough study because there are 4 arms against placebo -- there was a trend toward significance, but only in the lower 2 doses. But in the per-protocol group, there was actually a significant result in reducing negative symptoms. Strangely, not cognitive symptoms, but it seemed to be somewhat specific for negative symptoms. This is, obviously, suggestive and needs to be followed up further. What also is interesting is that the higher dose did not seem to work, replicating other findings that there is an inverted U-shaped curve: too little glutamate is not good for you, but too much is also not good for you. So trying to find the right balance here for individual patients will also pose a challenge. That's, I think, something we need to look into further. And it's very promising that we have finally a novel mechanism where there is something significant that will be pursued further.

  • Slide 12.

    Slide 12.

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  • The other study is a different mechanism that might not only help negative symptoms, but also help positive symptoms. That is Lilly's metabotropic glutamate 2/3 agonist. There was some finding that really spurred a lot of interest and also enthusiasm. Does anybody want to say something about that study?

    Dr. Kahn: I think that it was published in Nature Medicine, so, clearly, the field thought this was really a breakthrough, which, at least in theory, it is because it differentiated from placebo. Unfortunately, in the second study -- actually it was a failed study, it didn't differentiate from placebo, and it didn't differentiate from olanzapine. Olanzapine wasn't different from placebo, which is strange because, obviously, this drug is highly effective, so you would not expect this. That's why you call it a failed study. It shows the difficulty in doing trials with new drugs. You need many trials. The population of patients with schizophrenia in trials now is very different from that of 30 years ago. So these are major challenges, I think: for the field to replicate our own results and to find good patients.

    Dr. Correll: This study had also some peculiarities. It was done only in Russia. Actually, the placebo patients got worse, which we rarely see in other trials. But maybe we should argue they should get worse because they get placebo and they are still very sick. And both olanzapine and the new agent separated from placebo quite substantially at each time point from week 1 to week 4. And that was really promising, having an agent that maybe indirectly modulates dopamine. But then as you said, the next set of studies failed because actually olanzapine didn't separate either. Now, they are being redone.

    However, it's an interesting mechanism we shouldn't discount, and also it's now being studied not just as monotherapy, but it could be used as augmentation; having a different mechanism added gives us the opportunity for rational polypharmacy. At the moment, what doctors are often doing is adding 1 antipsychotic drug on top of another. Stefan and I did a meta-analysis[7] on that, finding that maybe under some circumstances 2 antipsychotic agents might work, but mostly only with clozapine. So we need more rational polypharmacy. Hopefully, these novel alleys into mechanisms will help us with that.

    So, there are multiple phase 2 or 3 trials that are currently ongoing looking at different agents -- glycine transporter inhibitor we've talked about, the glutamate agonist, and then also some of the alpha-7 nicotinic receptor agonists. Those are the currently most promising targets. There are some nicotinic receptor agonists that have other properties, histamine-H3 antagonists, as well as neuroprotective modulation of microtubule stability. This is all forthcoming, and we can only keep our fingers crossed that these agents will make it through the regulatory hurdles; that they will separate; and that they will also separate in what we said in the beginning, in heterogeneous samples. If they don't, I hope that the industry will not throw out the baby with the bathwater, but maybe refine the samples, and just look at an enhancement of negative symptoms or cognitive symptoms, because that is crucial to show an effect.

    Do you have any other advice to the field? Where should we go to advance schizophrenia treatment?

  • Slide 13.

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  • Dr. Leucht: I think it's really crucial what has already mentioned that we need to work on the methodology of our clinical trials right now. We've all had the big debate about the antidepressant drugs, which even made it into the lay press. Some people are saying that antidepressant drugs are not efficacious at all. I think what people forget when they present these data is how difficult it currently is to conduct placebo-controlled trials. There are probably 20 different antidepressant drugs around. With the antipsychotic agents, it might be 30, depending on the country. So it's very difficult for a patient to be motivated to go into a clinical trial. I think this really holds us back. We lose a lot of time. So this would certainly be a very important investment to do.

    Dr. Kahn: Another issue is certainly if you want to look at negative symptoms, and even more so at cognitive symptoms, you need to be early in the illness, because we discussed the brain changes over time. Once the illness has progressed to a certain point, I think you may not be able to find changes, certainly in cognition and maybe even in negative symptoms. Most of the studies are being done in patients with chronic disease. So we may want to study patients earlier in the disease, especially if we do add-on trials with cognitive enhancers.

    Dr. Correll: I agree entirely with what the two of you have said. I want to add 1 thing. I think it's a little naive to think that we just improve the hardware and make the patient more able to think or more able to experience pleasure and go out without actually putting them into these situations. So we need to add cognitive remediation and then compare the learning effect with the agent against placebo. We need to give them psychosocial stimulation and psychosocial rehabilitation, and maybe then the drug really separates. But the companies, so far, have been very reluctant to actually do this because then it's dual treatment, but this is real life. We need to get patients better. And just providing a better brain without outside stimulation in patients with often very chronic disease might not do the trick.

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  • Well, time is up. Thank you very much for the discussion. I think we covered the theory of schizophrenia; the current drugs; and, hopefully, the drugs that are on the market or on the horizon I should rather say it in order to come on the market, hopefully, to help our patients, to improve outcomes. I want to thank you, Drs. Kahn and Leucht, for this discussion. I also hope that the audience has taken something out of this that will be helpful for the treatment of their patients.

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Supported by an independent educational grant from Genentech.