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Treatment of negative symptoms: an unmet need of Schizophrenia

Interview with Prof. István Bitter, recorded at ECNP Congress 2016, Vienna

PROF Bitter | V1-HD 1080p

Dear colleagues, it is a great pleasure for me to address some of the questions which we have discussed today during a symposium addressing negative symptomatology in schizophrenia, and my talk was specifically about major unmet needs about the treatment of negative symptoms in schizophrenia.

The first questions which we would like to address is why so many attempts failed until today to bring a successful treatment for this very important aspect of schizophrenia to the market and for the benefit of our patients? I would like to address some issues that one, the background is that we were educated basically that schizophrenia has negative symptomatology, but its measurements started in the 1980s, so measurement skills were developed and they have different sensitivities to capture the negative aspects of schizophrenia and some skills are more sensitive, others are less. Let’s see an example.

If you use the old scale of brief psychiatric rating scale, the success rate which can be measured by effect sizes is about 0.66, so this is the effect size we can see in different studies, in case you would use the SANS, the Scale for Negative Symptomatology, developed by Nancy Andreasen, the effect size would be larger than 1. It is a big difference, and once you respond, the chance is about half of that, it is 0.5 only. There are some issues we find in negative symptomatology.

The other major point is that the pathological basis of negative symptoms have not been fully understood, so it is very difficult to develop an efficacious drug once we don’t know what we have to target. Let me just say a few examples.

Approaches to the pharmacologic treatment of negative symptoms

Dopaminergic drugs have been developed lately, D3 partial agonist stimulants, COMT inhibitors, glutamatergic drugs, such as glycine-site antagonists, glycine reuptake inhibitors, AMPA modulators; I will not list all of them, GABA agonist, serotonergic drugs, and drugs which have acetylcholine especially, or for several nicotinic agonists.

What happened was that a couple of studies were done which were successful. Here, what we can see it is important that the first study, or even the second study is successful, there is a signal that we have not a treatment for the negative symptoms, and when you start replicating this study you get no difference between placebo and your investigational drug. Unfortunately, this is what happened in the past and there are very few drugs which actually showed any signal.

In the literature, once you go in, there are two types of meta-analysis and summaries. One says that actually there are many treatment options which have some effect on negative symptoms, but these symptoms were part of the clinical picture and were associated with positive symptoms, with depression, with maybe some other symptoms, such as Parkinsonian side effects.

The other type of literature, which investigates purely negative symptomatology, such as predominant and persistent symptomatology, which means that negative symptoms are more severe than the positive symptoms, and they are present at least for six or 12 months, then these studies mostly fail. This is, unfortunately the problem which we face.

Since these symptoms are at the core of the disease, we have to do everything to improve them. Unfortunately, non-drug treatments did not prove to be very efficient; that is what our meta-analysis says, and what we see that once we combined drug treatment and non-treatment, then we can come to a better effect.

Recent development has been that some companies move back to the dopamine system, but they did not try to focus on the D2 receptors, which were at the core of antipsychotic treatment for decades, they moved again to the D3, dopamine-3 receptors, which is a very interesting system in our brain. The D2, as you may remember, has different systems which I will not repeat, major systems which are responsible for hallucinations and delusions, for Parkinsonian symptomatology, or hyperprolactinaemia is a side effect. D3 does not have such major systems and D3 is much older than D2. It is very difficult to understand what their function is. Basic research showed that D3 might be linked to some of the very human actions, such as logical thinking, such as orientation, such as taking initiatives, and basic research showed that manipulating D3 receptors might improve cognition in animals. These basic research data led to the development of a few candidates for antipsychotic treatment. One of them is cariprazine, which has been registered already in the United States by the Food and Drug Administration for schizophrenia and bipolar disorder.

In two studies, one was a retrospective analysis, the other one was a prospective study, risperidone was compared as a gold standard to cariprazine and, in both studies, both in the retrospective study and both in the prospective study, it was found that cariprazine performed much better, significantly better, both statistically and clinically, than risperidone in improving predominant and persistent negative symptoms in schizophrenia. 

I will stop at this point and if you have any other questions I will go into that.

What is your take-home message?
In the field of studies about negative symptomatology of schizophrenia, if it is a large heterogeneity in negative symptoms, such as the definition of the populations, the measurement that is used would bring us to very different conclusions.

The other issue is that negative symptoms do improve in the course of successful treatment of schizophrenia in association with positive depressive and other symptoms, such as Parkinsonian symptoms, however, once we take the population with predominant and persistent negative symptomatology, unfortunately we do not have a single treatment which would have been registered with this indication. There is an unmet need for the treatment of so-called deficit schizophrenia or schizophrenia with predominant and persistent negative symptoms.

Unfortunately, we do not understand the pathomechanism of negative symptoms; it still has to be clarified, but what we know as of today is that drugs affecting the activity of D3 receptors may be useful for that treatment.



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