Celso Arango: moving systematically to reducing major psychiatric disorders.
After a booming career as a young Spanish psychiatrist diving into schizophrenia and bipolar disorders, Celso Arango calculated that the real work had to be done at an earlier stage. Proper care for patients with schizophrenia he considered a hygiene factor – but boring to him and not efficacious at all. Now he is digging into the genetic origins of these disorders. Obviously with high ambition, although he modestly puts it like: “To give advice to women who will become mothers, in reducing the likelihood of having offsprings that later in life will develop mental disorders.”
“That would apply normally to schizophrenia. Just like the majority of mental disorders and neurodevelopmental disorders, as we conceptualize it now for many years, schizophrenia has been in the hand of adult psychiatry. Because it starts usually at the age of seventeen, eighteen, twenty to 25. So by the time these patients have their first psychotic symptoms, most of them – more than two thirds – are already adults. That is why bipolar disorders and other developmental disorders have always been considered disorders of adulthood. But it has always been there. And most evidence from different studies shows that the risk factors that predict schizophrenia are either there at conception – because they are genetic factors that are there forever – or there are environmental factors that are taking place during pregnancy in the uterus, prenatally, or right after birth.”
Shift towards prevention
“So all the evidence points towards very early times, either around the conception, prenatally, perinatally or early in childhood where more risk factors that interact with genes modulate brain development”. When we want to prevent these neurodevelopmental disorders, it has to be at that time. So there has been a shift in treating the critic condition, towards prevention. This can only be done very early in development.”
Traditionally child psychiatrists are hesitant to name symptoms in children as a real psychosis.
“That is the point. By treating so early, we are not treating schizophrenia, we are not treating bipolar disorders and we are not treating real psychotic symptoms. Because those symptoms are just the final pathway that shows that something has gone wrong at a much earlier stage. So the type of prevention we are doing – and this is again another change in the paradigm – is not prevention of schizophrenia. I am not even talking about prevention of psychosis. I am talking about prevention of abnormal brain trajectories, or abnormal neurodevelopment in the brain.”
Psychotic genes don’t exist
“The thing is: we will never have a gene just for schizophrenia. And we will never have a gene that exclusively increases the risk for psychosis or any other disease by itself; we have genes that increase the risk of having bad brains. Brains that develop in an abnormal way. And those genes have shown to be common for autism, schizophrenia, bipolar disorders, OCD and ADHD. Those genes are no genes for a given disorder. Genes do not know about DSM-5. And the way the brain develops does not have any relation with DSM-5 either. The DSM-5 only gives us artificial criteria that allow us to speak in a common language. That is very positive in a way, but it has nothing to do with nature. How genes codify for proteins and how our brain is configured normally or abnormally it the key issue. So I’m not saying we are preventing schizophrenia. I am just saying there are some risk factors for which we may merely provide conditions in which the brain may develop in a less abnormal way.”
What is the earliest age to detect symptoms of psychosis?
“You could seek schizophrenia earlier than the age of fourteen – that is an age often mentioned in the literature. They are very rare, but you could find the diagnosis as early as at the age of eight. Our youngest patient is eight, we have some who are nine and ten years old and after that there is an exponential increase in adolescence. I am talking about real diagnosis here, not just suspicious symptoms.”
Your line of study focuses on genetic and environmental interaction?
“Yes, my research is about epigenetics and how people with the same genes, even identical twins, may show different disorders. These so-called identical twins give a nice example: most say that the concordance for identical twins is around fifty per cent, which is of course fifty times more than the general population. But the other half of the cases do not have schizophrenia. If you look carefully in that other fifty per cent, the vast majority will have another DSM-5 disorder. So this is telling you that the same genes may end up with different conditions, one being schizophrenia and another one. So between these twins there may have been different environmental factors that ended up with ADHD or anxiety or depression. This is a positive message as ‘wrong’ genes may end up in psychiatric conditions that have very different levels of disability.”
No exclusive pathway
“The message here is that there is not one exclusive pathway, as if you could start with one gene here and you end up with one diagnosis there. It does not work that way. Many things may have happened in the middle. By influencing the conditions ‘in the middle’, we may end up with less severe disorders – such as anxiety or depression – than schizophrenia and bipolar disorders. It’s all about having less of those risk factors. Some of those are preventable and some are not. We have good examples of prevention like reducing the hypoxia during delivery or giving medication – folic acid, choline – to mothers who are pregnant and how that helps maturing the brain of the child. These are nice examples of primary prevention if the mother is carrying risks.”
“So this is not about prevention of schizophrenia, with an outcome like: schizophrenia yes / schizophrenia no. The outcome may be anything from a huge range of developmental disorders. With a heterogeneous diversity of disabilities.”
Could it be that some of the people under risk do not have a particular gene ‘switched on’?
“Yes, we know that the majority of our genes are not switched on. And if they switch on or not depends on the environment. The exact pluripotential stem cell, depending on the context, depending on ‘how you grow this cell’ could end up as two completely different cells – such as a neurone or a hepatocyte. Depending on the context where it grows it may end up very differently, even if it comes from exactly the same cells.”
Is this why you changed from adult psychiatry to child and adolescent psychiatry?
“Believe it or not, Spain is one of the very few countries where there’s no specialty in child psychiatry. So there are no ‘official’ child psychiatrists in my country. Child psychiatry in Spain is trial and error. Psychiatry residents have four months of training in child psychiatry and when they have finished their four years of study they start seeing kids just like that. We have no proper training. That is probably going to change. After fighting hard for this, our government has promised that in 2014 for the first time ever we are going to have a specialized child psychiatry curriculum.”
Treating the early phases
“From that situation, after my studies I went to the United States where I did a fellowship in schizophrenia research. There I noticed that it would be much more efficient to study psychosis from the childhood than from the adulthood. This is about treating the early phases which will increase the chances to for preventing psychotic estates.”
“I pictured myself running a large hospital ward with a lot of chronic patients, for whom very little can be done. Of course you could treat them so that they have less relapses, you could make life more comfortable for them by having the basic needs covered and taking care of cognitive rehabilitation… But to me that seemed quite boring. So for me it was much more challenging to study and train and see patients before they become psychotic, although they have the genes and the environmental factors to become psychotic. Because once they become psychotic, it is probably too late.”
You conduct research in psychopharmacology as well?
“Yes, I have always been interested in psychopharmacology. Child psychopharmacology has been neglected for many years. Fortunately now, regulatory agencies like the U.S. Food and Drug Administration and the European Medicines Agency before they licence a drug, they force pharmaceutical companies to do clinical trials with children and adolescents.”
“But it is not correct to say that the only treatment that helps psychotic patients is medication. Medication is like skiing equipment: you cannot ski if you don’t have the equipment. But if you have the best ski gear in the world without having the skills to ski, and they put you on the top of the mountain, you will never be able to make it to the valley. So you will need someone to teach you how to use those ski’s and to learn the techniques to get down the mountain.”
“The antipsychotic drugs have side-effects, but they are very good at reducing positive symptoms – I don’t say negative symptoms and I don’t say improving cognition – such as delusions and hallucinations, and preventing relapses. When a kid has psychotic symptoms, and they are part of a disease or a disorder that affects this kid’s life, then we have to treat it. However, more than eight percent of children have hallucinations and that is considered normal. Obviously we cannot treat normality. I am saying that we should treat positive symptoms if they are part of a disorder when they interrupt normal life – but in that case, the drugs are not enough. We may have wonderful drugs to reduce positive symptoms, but what happens if the kids don’t take them? We need to explain to the kids and the parents why they need to take those drugs. And once the symptoms go away there are many things that will have gone wrong and that we need to treat. Picture this kid who has been psychotic for a couple of months. This kid has been in class and the peers may have been making fun about him. He was getting isolated, and he got in trouble with his classmates. The others considered him as being weird and mad…. So the moment we have made sure that he psychotic symptoms have gone away, there are many things that this kid will have to face when going back to class. He will need psychosocial intervention, like psychotherapy, in how to integrate in his life what has happened to him. And how he will be able to confront the rest of his life. For that, drugs are surely not enough.”
In your research you use neuro-imaging as an important method?
“In neuro-imaging we do longitudinal studies. My impression is that in psychiatry for many decades we have been focusing on the static pictures, not on dynamic pictures. When adult psychiatrists see a patient, they ask: ‘What happened to you in the last month?’ They very rarely go back to childhood. Nor do they look at possible problems with motoric skills or at the relationships with mates at school. These things are important because they tell that there is something going wrong during early development. Often the symptoms were not severe enough to draw attention and to be treated. This is where the neuro-imaging studies are important. When we do a cross sectional study, we may not pick out the differences between kids and their different psychotic conditions and healthy controls. But when we do longitudinal studies, doing MRI scans for two to five years, then we start seeing these differences in developmental trajectories. A nice example is a paper by Rapoport in the prestigious journal Nature shows that IQ does not relate to cross sectional measures of the brain, but to longitudinal development of the brain. The researchers found that the relationship between cortex thickness and IQ varied with age, particularly in the prefrontal cortex, seat of abstract reasoning, planning, and other ‘executive’ functions. The smartest seven year olds tended to start out with a relatively thinner cortex that thickened rapidly, peaking by age eleven or twelve before thinning. In their peers with average IQ, an initially thicker cortex peaked by age eight, with gradual thinning thereafter. So depending at what age the MRI was done the differences were in a different direction. This nicely shows that we cannot easily interpret cross sectional neuroimaging studies and the importance is the maturational trajectory. So we learn about that by looking at the dynamic picture.”
How important is international cooperation for these studies?
“It is not only important it is a must. For instance we are conducting a very large study called EU-GEI, for gene-environment interactions with more than ten European countries participating, in which we are looking at gene variables and environmental variables in more than ten thousand schizophrenia spectrum disorder patients. Among the environmental variables are trauma, physical abuse, sexual abuse, urbanicity, use of drugs, canabis in adolescents, being a minority… It would be totally impossible to do studies like this within one country – European cooperation is an absolute necessity here.”
Cardiology sets the example
“Also, we have to learn from other medical disciplines. Cardiology has a tradition of doing extremely large studies over many years. In a way they face the same problems as child psychiatry in some of their conditions. Like hypertension, which is a hereditary complex disorder, like schizophrenia, with many different genes increasing a small percentage of risk. And also similar is the large amount of environmental factors. So you have these very huge cardiology studies they have been doing for some twenty to thirty years with very promising results. And that I think is the way to go.”
What is your ambition in terms of improving treatment?
“I would like to give effective advice to families at high risk. These are disorders of a low prevalence so progress takes time. Realizing prevention in the general population is probably too ambitious. That will take a while. But if you look at the high risk families who already have a kid with a neurodevelopmental disorder, or that have the genes for that because it runs in the family: to those families and children I hope to give advice on how to reduce the chances that their offsprings will end up with schizophrenia or another major mental disorder. It may only be secondary prevention of more severe disorders. But if I can do that, I would be very happy.”
When should this advice be given?
“Before pregnancy. This advice would be about paternal age, the maternal care during pregnancy, physical abuse during pregnancy, mental stress during pregnancy, treating mothers with psychiatric conditions in pregnancy. Reducing the cortisol that those mothers have during pregnancy. Improving the attachment right after birth. This is already done in some cases, but I think its not being done systematically and intensively in those high-risk cases. Generally it is done properly in some countries depending on how rich that country is. It is probably done better in Switzerland than here in Spain for sure, and surely much more than in some African countries. The point is that we are now practicing this type of advice as common sense – we don’t do it to systematically reduce major psychiatric disorders. This is why it is very important to have perinatal psychiatric units in hospitals. With psychiatrists that deal with the risks before conception, during pregnancy, right after the child is born and keeping track during childhood.”
“This would be a very cost effective way of practicing medicine, because while we are reducing the number of diagnoses, we will also be saving governmental money. Because disorders like schizophrenia lean very heavy on our health budgets. A known example in the United Kingdom is that exactly ten years ago, the government made it mandatory to open psychosis units in the different districts. Some of those units deal with children and adolescents. In 2013 there was a report published by authors from the London School of Economics about the economic impact of early intervention services for children and adolescents with psychosis in the UK. This report shows very nicely how children and adolescents treated in these quite expensive intensive units – with well trained staff – but yet it was cost effective. These units saved money to the National Health Service by offering early treatment to children and adolescents: they had less hospitalization – which is the most expensive part of treatment –, they needed less drugs, they had a better outcome in terms of percentages of patients that could again function in society, work and school. So at the end of the day this approach seems to be the best way to save money in the long term.”
“This is again a matter of moving from statics to dynamics. We tend to mainly look at what will happen with a patient in the next two or three years – at least in my country. The problem is that politicians never look forward more than four years. They just want to be re-elected. While the development of our children takes place from conception to at least an age of 25. What child psychiatrists can do, does not happen in two or three years but in the long term.”
Does Europe need guidelines for this?
“I think that prenatal psychiatry needs more development. And we need to look more into evidence. We have evidence for example about the increase of maternal mental stress, turning into schizophrenia twenty to thirty years after birth. This is important knowledge to build on. I think we have enough evidence to develop guidelines to give advice to practitioners about the treatment of these very early age stages.”
“Of course it would be cost effective to work on common guidelines, in stead of having these criteria for every country on its own. My experience, for instance at the ECNP, the European College of Neuropsychopharmacology is that they bring together a lot of specialized knowledge. ECNP initiatives include addressing the lack of a common database for European researchers, but within ECNP we also have European guidelines, and some of them are about treatment of childhood conditions.”
What could ESCAP contribute to European cooperation?
“Like our colleagues in the United States, in the American Academy of Child and Adolescent Psychiatry, have their guidelines on best practices in child mental health, ESCAP could do the same thing. These American guidelines are not always applicable in Europe because they are far away from our clinical practice. But I think it makes no sense to have different guidelines for the UK, the Netherlands, Italy or France. I don’t see why there should be any difference in the treatment of patients with ADHD or bipolar disorders or schizophrenia between the ESCAP member countries.”
Are you going to mention the guidelines topic in your position paper and your Madrid lecture as a Field Advisor for ESCAP?
“That for sure would be a recommendation. I think that ESCAP is in the best position to do that on a European level in terms of the treatment of children and adolescents. The ECNP shows the example for neuropsychopharmacology. But the field of child psychiatry is much broader. The integrity of treatment is the main thing. ESCAP is in the best position to address the whole picture.”
“In my position paper I will comment on issues that we have discussed, like moving from static to dynamic psychiatry, that we need the longitudinal picture, the need to invest more money in the very early stages and for sure I will mention that there is a lack of European guidelines in how to give advice to women who will become mothers in reducing the likelihood of having offsprings that later in life will develop mental disorders.”
Will you be elaborating on medication in your lecture and position paper?
“When things go wrong we need those medications. But I would rather focus on what happens before that. Although in Europe, there has been an enormous increase of these drugs in the last ten years. We use antipsychotics eight more times than we used them ten years ago. Not only that: we also use them for a longer period of time. We seem to have this wrong perception that these drugs are safe. Yes, in some ways they are effective but they cause many side effects. We have them since chlorpromazine was introduced in 1952 in Paris. It was used for anesthesia before Jean Delay and Pierre Deniker first tried it as an antipsychotic. Since those days the development of antipsychotic drugs has never been revolutionary. There has been a slow improvement perhaps of decreasing some of the side effects, but we have not improved at all in terms of mechanism of action. This is important: we have not advanced in the development of antipsychotic medication because we do not know the pathophysiology of what we want to treat. And if you don’t know what to change, how could you possibly create a useful drug? A long time ago we discovered that this drug works with psychosis, so what we have done is producing more of the same. That´s why they are called me-too drugs.”
“We may need completely different drugs”
“In cardiology they have done a better job. They have studied the development of the disease over a long period of time and they develop drugs that have tackled the abnormal pathophysiology.”
“The problem is that we test a drug in adults. Then we try it in children. Not to see if it is efficacious, but mainly to see if the side effects are acceptable. It may be the case that we need completely different drugs for children and adolescents than for adults. Drugs with mechanisms of action other than classical increase or decrease of monoamines should be considered in paediatric population. Agents with neurotrophic, neuromodulatory, antiapoptotic and antiinflammatory and antioxidant capacity could be good candidates for specific drugs for brains in early maturation. So the paradigm is nowadays: we come up with a drug that works in adults and we try it in children – but we never start the other way around, although that would make al lot more sense. Simply because the industry finds this economically too risky. First, they cannot foresee if the regulation authorities will approve preventive drugs that must be used before a disorder appears. Then it is not clear what the market would be – we may be targeting a very small population of children. Still, I am not accusing the industry. I am accusing the governments. Traditionally the governments have left it up to the industry to do everything. But we have to face that the industry is there to earn money – I don’t blame Apple for selling many computers and making a profit out of it. It’s their business. But the health of our children is the business of our governments. The US government takes its responsibility by starting these huge new programmes in NIH to conduct pre-clinical and Phase I and Phase II clinical trials with public money. For rare disorders it is a matter of: if the industry does not do it, it is up to the governments. This is feasible in Europe as well. We have a common research wallet in the EU Framework Programme for Research and Innovation. The Seventh Framework is now moving into the so-called Horizon 2020 programme that started in January 2014. The budget for this programme is eighty billion euro’s over seven years. In terms of research Europe should have one agenda and that is Horizon 2020. Inside this programme it is up to the EU to prioritize the development of drugs for rare disorders.”
“I am hopeful about Horizon 2020. If I look at ROAMER, the roadmap for mental health research in Europe which has warm connections with ESCAP, they are doing a good job in laying out a roadmap of where the money should be invested by Horizon 2020. There we should prioritize child psychiatry. We should prioritize developmental psychiatry. And we should prioritize the search for new drugs that specifically tackle what goes wrong in the brain in childhood.”
“To speak with one voice in Brussels is very important. That is where the decisions are made. The European Brain Council, EBC, does that on behalf of most of the relevant neuro-scientific societies and industries in Europe. This is an organized lobby in which the majority of European societies are represented. By doing it together these public affairs trajectories are affordable. It would be very useful for ESCAP to become active on the EBC platform. EBC is lobbying for brain research – and more money for brain research automatically means more money for child psychiatry.”
Celso Arango is a scientist, clinician, and professor of psychiatry. His main area of interest is in the field of early-onset psychosis, especially early-onset schizophrenia. Arango has the largest cohort of first-episode early-onset psychosis patients followed for more than ten years now. As a child psychiatrist, he has always been interested in translational research in early neurodevelopment (and also has published on autism and other neurodevelopmental disorders). He runs the largest department of child and adolescent psychiatry in Spain, published the first longitudinal studies comparing children and adolescents with different psychotic disorders (e.g., schizophrenia vs. bipolar disorders) showing that there are progressive brain disorders with loss of frontal gray matter in those developing schizophrenia, and has also shown that this loss of gray matter is a marker of poor prognosis and is related to lower antioxidant levels (e.g., glutathione, GSH). The professor has also published extensively in the field of antipsychotics, mainly on their lack of effectiveness in negative symptoms and on their safety and tolerability in children and adolescents. Arango sees patients two days a week in the first episode clinic at his university hospital and he runs a clinic for patients with 22q11 syndrome once a week. He is a professor of psychiatry both in Madrid and in the US (University of Maryland) and very active in educational organizations (e.g., president of the ECNP educational committee for the past six years).
Celso Arango has been the scientific director of the Spanish Center for Biomedical Research in Mental Health (CIBERSAM, www.cibersam.es) funded by the Spanish Ministry of Economy and Competitiveness since its inception in 2008. The CIBERSAM is composed of 24 clinical and basic research groups belonging to 8 Autonomous Communities, which primarily research mental disorders such as schizophrenia, depression, and bipolar disorder, as well as anxiety disorders, child and adolescent diseases, geriatric and neurodegenerative diseases and, in general, any neuroscientific aspect related to health and mental illness. The approach to studying these diseases has a clear translational component, seeking synergies among groups that perform their work in hospitals, research centers, and universities. The CIBERSAM comprises a human team of about 400 researchers, with a staff of more than 120 professionals hired by the Center, the rest being members of personnel groups attached to the CIBERSAM. Arango has served on many executive committees for the most prestigious societies and am currently president-elect of the European College of Neuropsychopharmacology (ECNP).
Dr Arango has participated in more than 73 competitively funded research projects, as Principal Investigator in 55 of them. The research projects have been funded by the Spanish Ministry of Health, Spanish Ministry of Science and Innovation, NIMH, NARSAD, Stanley Foundation, Fundación Alicia Koplowitz, Caja Navarra, and the Department of Health in the State of Madrid, and he is currently participating in eight EU projects funded by the VII Framework. He has been coordinator of the Spanish Network in Early Onset Psychosis and the Mental Disease - Affective Disorders and Psychosis Research Network funded by the Ministry of Health.
Arango, C.; Carpenter, W.T. Jr.; Queern, C.A. Research Ethics: A psychological approach. Clinical Psychology Review, 19(3): 384-5, 1999. (I.F.: 8.146).
Arango, C.; Adami, H.; Sherr, J.D.; Thacker, G.; Carpenter, W.T. Jr. Relationship of awareness of dyskinesia in schizophrenia to insight into mental illness. American Journal of Psychiatry, 156(7): 1097-99, 1999. (I.F.: 13.505).
Carpenter, W.T. Jr.; Arango, C.; Buchanan, R.W.; Kirkpatrick, B. Deficit psychopathology and a paradigm shift in schizophrenia research. Biological Psychiatry, 46: 352-60, 1999. (I.F.: 11.212).
Arango, C.; Bartko, J.J.; Gold, J.M.; Buchanan, R.W. Prediction of neuropsychological performance by neurological signs in schizophrenia. American Journal of Psychiatry, 156(9): 1358-66, 1999. (I.F.: 13.505).
Arango, C.; Calcedo, A. Jr.; Gonzalez-Salvador, T.; Calcedo, A. Violence in inpatients with schizophrenia: a prospective study. Schizophrenia Bulletin, 25(3): 493-503, 1999. (I.F.: 7.757).
Arango, C.; Kirkpatrick, B.; Buchanan, R.W. Neurological signs and the heterogeneity of schizophrenia. American Journal of Psychiatry, 157(4): 560-5, 2000. (I.F.: 13.505).
Arango, C.; Kirkpatrick, B.; Koenig, J.I. At issue: stress, hippocampal neuronal turnover and neuropsychiatric disorders. Schizophrenia Bulletin, 27(3): 477-80, 2001. (I.F.: 7.757).
Arango, C.; Rojas, M.J.; Moreno, D.; Parellada, M. Sibutramine for compulsive eating in hypothalamic deficiency. Journal of the American Academy of Child and Adolescent Psychiatry, 41(10):1147-8, 2002. (I.F.: 7.182).
Bobes, J.; García-Portilla, M.P.; Sáiz, PA.; Bascarán, M.T.; Bousoño, M.; Arango, C. High degree of tolerability for monotherapy with high doses of quetiapine: a case report. Journal of Clinical Psychiatry, 63: 1048-9, 2002. (I.F.: 5.408).
Arango, C.; Breier, A.; MacMahon, R.; Carpenter, W.T.; Buchanan, R.W. The relationship of clozapine and haloperidol treatment to prefrontal, hippocampal and caudate brain volumes. American Journal of Psychiatry, 160(8): 1421-7, 2003. (I.F.: 13.505).
Arango, C.; Summerfelt, A.; Buchanan, R.W. Olanzapine effects on auditory sensory gating in schizophrenia. American Journal of Psychiatry, 160(11): 2066-8, 2003. (I.F.: 13.505).
Buchanan, R.W.; Francis, A.; Arango, C.; Miller, K.; Lefkowitz, D.M.; McMahon, R.P.; Barta, P.E.; Pearlson, G.D. Morphometric assessment of the heteromodal cortex in schizophrenia. American Journal of Psychiatry, 161(2): 322-31, 2004. (I.F.: 13.505).
Bombín, I.; Arango, C.; Buchanan, R.W. Significance and meaning of neurological signs in schizophrenia: Two Decades Later. Schizophrenia Bulletin, 31(4): 962-77, 2005. (I.F.: 7.757).
Moreno, MD.; Burdalo M.; Reig, S.; Parellada, M.; Zabala, A.; Desco, M.; Baca-Baldomero, E.; Arango, C. Structural neuroimaging in adolescents with a first psychotic episode. Journal of the American Academy of Child and Adolescent Psychiatry, 44(11): 1151-1157, 2005. (I.F.: 7.182).
van Os, J.; Burns, T.; Cavallaro, R.; Leucht, S.; Peuskens, J.; Helldin, L.; Bernardo, M.; Arango, C.; Fleischhacker, W.; Lachaux, B.; Kane, J.M. Standardized remission criteria in schizophrenia. Acta Psychiatrica Scandinavica, 113(2): 91-5, 2006. (I.F.: 6.128).