In this segment of the course, we're going to begin to talk about biological approaches to treatment of schizophrenia. We've talked a little bit already about the neuroscience of the disorder, about some of the changes in the brain that are often associated with the diagnosis of schizophrenia. And, what I'll be doing today is focusing more on looking at what medications are most effective in the reduction of symptoms of schizophrenia. It's clear that the first line of treatment for symptoms of schizophrenia is the use of anti-psychotic medications. Anti-psychotic medications treat two major aspects of the disorder of schizophrenia. They treat or affect delusions and they have an influence and can affect hallucinations as well. So, those two positive symptoms, what we've described before in the course as being examples of positive symptoms, are affected by anti-psychotic medication. It's important to also know what aspects of the disorder are not affected by anti-psychotic medication. That is to say, the negative symptoms that we've talked about, the cognitive difficulties that we've talked about, the social cognitive difficulties that we've talked about, in the disorder. They are resistant or tend to be much less responsive to the effects of anti-psychotic medication than are the positive symptoms of delusions and hallucinations. So, as should be clear from this description, the appropriate treatment of people with schizophrenia involves a comprehensive approach in which both medications are utilized, anti-psychotic medications are utilized, but very carefully in coordination with a variety of psychosocial interventions that we will be talking about in the course, to really try and attempt to treat the entire client with the disorder and address the vast array of difficulties that people with schizophrenia may experience. So, in terms of biological treatments we can talk about two major classes of anti-psychotic medication. One major class is what's been called the first generation anti-psychotic medications. And these relate to the first anti-psychotic medications that were discovered for the use of schizophrenia. And then, a second generation of anti-psychotic medications that emerged largely in the 1980s that also are designed to address the delusions, hallucinations that people with the disorder often experience. As we talked about in a previous segment, it has been shown in a variety of studies that anti-psychotic medications appear to have their effect by affecting a substance in the brain known as dopamine. Dopamine is one of a group of 20 or even more brain chemicals that are involved in signaling between different neurons. And again, neurons are the sort of elementary units that make up the brain. Right? The sort of elementary functioning units that make up the brain. We've talked about the first generation anti-psychotics and their important role in blocking D2 receptors in the brain. And specifically, they appear to target D2 receptors which are located largely in what we've talked about as being the substantia nigra projection or the Nigrostriatal projection and in the Mesolimbic dopamine system. And, that these drugs appear to block Dopamine 2 receptors making it more difficult for dopamine to signal between two neurons. And, this may be the mechanism by which delusions and hallucinations are decreased in the disorder. Now, at the same time, some questions came up about the sort of biological mechanism for treatment with the emergence of what had been called the second generation anti-psychotic medications. The second generation anti-psychotic medications are characterized by reducing positive symptoms. So, just like the first generation they are effective at reducing hallucinations and delusions, but their mechanism of action appears to be quite different. That is to say, they don't have the same affinity or attraction to dopamine 2 receptors. The best example of this type of a drug would be Clozaril or Clozapine. Clozapine is a drug that was rediscovered in the 1980s. That had been used prior to that, but in the 1980s underwent, was used in a major randomized control trial, and in this randomized control trial, they took people with schizophrenia who had had poor responses to three different types of anti-psychotic meds. So, these are folks who really were non-responsive to anti-psychotic medication. And, they took these folks who were non-responsive to three anti-psychotic meds and randomly assign them to receive either Chlorpromazine for six weeks or this rediscovered drug, or this newer drug, known as Clozapine. And, what they found is in these very hard-to-treat clients, these clients really had just shown very little response to any of the medications, that 30% of the folks that were in the Clozaril condition actually showed significant improvement in their symptoms. This contrasted with 4% in the Chlorpromazine group. This was interesting for a number of reasons. For one reason, it was important because it showed that you could have a medication that was effective for people who seemed to do poorly on many different medications. That is, it seemed to be a drug that might be effective for people who just didn't respond other medication. So, that was exciting and a real innovation, number one. But number two, the other thing that was interesting about this drug Clozapine, is that it had not such a high attraction to these D2 receptors that we talked about, as being so crucial for the anti-psychotic effects of the first generation anti-psychotic medications. Instead, these drugs tended to block receptors for other neurotransmitters systems like serotonin, for acetylcholine, which is another neurotransmitter system, and they seem to act on histamine receptors in the brain as well. So, the success of Clozapine as a medication led to the development of a variety of new second generation anti-psychotic medications that were not necessarily characterized by a high affinity for these D2 receptors. This has led to questions about which of the drugs may be more effective. Are the second generation anti-psychotics most effective? Are the first generation anti-psychotics most effective? And what does it mean that the second generation anti-psychotics seem to promote their effect without necessarily blocking these D2 receptors, or at least not at the same ratio, with the same intensity as the first generation. Recently, a study was conducted called the CATIE trial. Which is the clinical anti-psychotic trial of intervention effectiveness, in which they looked at over 1,400 individuals with chronic schizophrenia at a total of 57 clinical sites. In this study, they compared four of the newer second generation anti-psychotics with one of the old first generation anti-psychotics that's been around since the 1960s. The question here was, which of these medications was more effective for people with the diagnosis of schizophrenia? Their primary outcome in this study was how long clients stayed on the drug, and they looked at other outcomes such as symptoms and functioning. The important thing to recognize from this study is that for most of the outcomes that were looked at, there was very little difference between, on the one hand, the second generation anti-psychotics, the four that were looked at, and on the other, the first generation anti-psychotics. So, despite an increase in interest, in prescription patterns that were associated with the advent of the second generation anti-psychotics, what the data suggested from this trial is there wasn't a whole lot of difference in the effectiveness of the old anti-psychotics as compared to the new anti-psychotics. And, this of course is very important when we think about the cost of these medications etc. The last idea that I would like to share with you is the most recent data that really suggests in a much even stronger way than what I presented to you so far, that the effects of these anti-psychotic medications appear to be through their blockade of these posts synoptic dopamine 2 receptors. These are studies that have used a technology called PET, Positron Emission Tomography. And like FMRI, which we've already talked about, it measures activity of the brain. It's not measuring structure but rather activity of the brain. In these PET studies, there are intravenous infusions of a molecule that is radio labeled. That it is radioactively labeled, it is infused into the blood, and this molecule is selective to bind to those posts synoptic protein receptors that we talked about earlier. So, these dopaminergic post synoptic receptors are bound to by this chemical that we introduce into the bloodstream that is radioactively labeled. This allows us to create an image, by the radioactivity that is emitted, of the areas in the brain that have the highest density of these D2 receptors. These studies have revealed several interesting findings. One interesting finding is that, in people with schizophrenia who have been administered these radio labeled molecules, these radio labeled molecules that are located specifically in the striatum, the degree to which these radio labelled molecules are displaced, gives us a sense of how many receptors there are or how much dopamine activity occurs. That is to say, if dopamine is stimulated in the striatum, we would expect larger amounts of this radio labeled chemical to be removed from the receptor sites. Because, they get displaced by the dopamine which is being transmitted. In these studies, they found that when you administer a drug that increases dopamine levels, people who have higher symptoms, higher levels of delusions and hallucinations, show more displacement of the radioactively labeled molecule. Suggesting that these increases in symptoms that are associated with a challenge or an increase in the amount of dopamine is transmitted in the brain, relates directly to the increase in symptoms that you see in these folks. Another way that people have tried to look at this is to look at folks just at baseline without any type of stimulation of dopaminergic activity. And, just ask the question: To what degree do these radio labeled receptors, to what degree are they occupied by these molecules at rest when we decrease the amount of dopamine that's being transmitted? And sure enough, people with schizophrenia, with higher numbers of symptoms or higher levels of symptoms, tend to show higher levels of radioactivity at these post synaptic receptor. Again, suggesting that there may be more activity or that just may be the presence of more dopaminergic receptors in people with schizophrenia. These findings are very important because they are occurring in the living brain, these are in people with schizophrenia who are obviously suffering from the disease, and you're actually measuring the levels of dopamine transmission in the living active brain. So, for this reason, they've been thought to be very very important.