Study of ‘brain urine’ to reveal the destructive role that inflammation appears to play in depression and psychosis

Any experienced detective knows the situation: Something destructive is going on – and some particular suspects keep turning up when you’re investigating what lies behind it.

The problem is that there is no concrete proof – and until there is, there is very little you can do to stop it.

This is similar to the current situation in psychiatry when it comes to understanding why, in many cases, a variety of inflammations seem to be present in many cases in connection with the overall picture of depression and psychosis.

From Danish and international studies, we know that serious infections, such as infections of the bloodstream, may increase the risk of developing depression. We also know that the human immune system, which fights infections, can also affect the brain and thereby increase the risk of psychiatric disorders. It is also known that there is a genetic overlap between genes that affect the immune system and a number of genes associated with a risk of developing psychic disorders.

“But the precise relationships between these are far from being mapped out, so it makes sense to examine whether – and if so, how – a number of different inflammatory conditions can play a role in mental illness,” says Prof. Michael Eriksen Benros, research director at Psykiatrisk Center København (Psychiatric Centre Copenhagen) and the Department of Immunology and Microbiology at the University of Copenhagen.

Prof. Benros is leading a scientific inquiry which is seeking answers to a number of these questions. The project is principally funded by a research grant from the Lundbeck Foundation, and the first results will be published in one to two years’ time.

A so-called biobank has already been created, however, which holds a collection of biological samples, health information and background information from 340 volunteers. When all this information is analysed, it will paint a picture of how the human psyche reacts when the body and brain are attacked by infection.

Brain cleansing

In the biological material analysed, samples of CSF play a key role.

CSF (cerebrospinal fluid) is the fluid that flushes through the brain. In layman’s terms this is often simply called brain fluid, but in Denmark it also has a popular name, “brain urine”. This is not without a certain basis in fact, because when the liquid rinses and cleanses the brain – which happens, for example, while we sleep – it removes a large number of waste products. Analysing these can provide a biochemical snapshot with a wealth of interesting information – for example about ongoing infections, and about how strongly the body reacts to these inflammations by mobilising the immune system.

“Consequently, analysis of the brain fluid of the 340 subjects plays a core role in the biobank we are building up,” says Prof. Benros, adding:

“This will be the first study of its kind in the world. We’re doing something that has not previously been done, because we’re comparing brain fluid samples from people in three equally large groups who are very similar to each other in age group, social factors, and a number of other areas. It will be the first high-quality study in the area. The participants are all aged 18-50, and the first group consists of people who have recently, and for the first time, been diagnosed with depression. The second group consists of people who have been diagnosed with psychosis, and finally we have a control group in which the participants have neither a depression diagnosis nor a psychosis diagnosis.”

Studies have been carried out in the past, including abroad, on possible links between infections and mental illness. Some of these were to some extent structured like the current Danish study, but were not nearly as extensive, and only in very few cases have they examined CSF, says Prof. Benros:

“We wanted to have a healthy control group in the hope of being able to see whether there are any special features of inflammatory reactions that occur in connection with mental disorders. The reason why we have chosen to work with brain fluid rather than blood samples is that although blood tests can tell us a lot, they clearly have their limitations in relation to conditions that arise in the brain. More information can often be obtained from cerebrospinal fluid.”

The reason for this is the blood-brain barrier: This is a dense membrane which, in humans and other mammals, secures a constant biochemical environment in the brain and consequently prevents most substances from entering the brain via the bloodstream. Accordingly, what actually happens in the brain from a biochemical point of view will often be better illuminated by a brain fluid test than by a blood test, explains Prof. Benros.

At the same time, however, there are various research results indicating that the blood-brain barrier in patients with depression or psychosis appears to be more easily penetrated by external substances than it is in healthy patients.

“Exactly how these factors are related, and what significance they may have, is something else that we hope to learn more about,” says Prof. Benros.

A sample is taken

The 340 volunteers involved in the study of the links between inflammation and mental disorders are all asked to provide a few millilitres of cerebral fluid, which in itself is a routine matter, says Prof. Benros:

“It’s a common technique used in neurology, and is done quickly. The person lies on a plank bed in a certain position, and is given a local anaesthetic. Then a small needle is inserted between two vertebrae, and some fluid is drawn out.”

The brain fluid is then analysed for a number of parameters, including: How many immune cells does it contain? Are there any traces of infections, and if so, which ones?

In addition, all of the participants are interviewed about their dietary and exercise habits and consumption of tobacco, alcohol and drugs, and undergo cognitive tests, psychiatric tests and a neurological examination. They are also DNA-tested and have their gut bacterial flora analysed.

Finally, the researchers, once they have obtained data registration permits and the individual consent of all participants, are given access to some anonymised data about the individual in various Danish health databases.

When all this is systematised, together with the information obtained from analysing the brain fluid samples, the biobank will be a reality, says Prof. Benros:

“Then we should be able to obtain a better understanding of the genetic factors that govern our immune system, and of how the immune system may play a role in and influence mental disorders associated with infections. The hope is to be able to use this knowledge to help us to make more accurate diagnoses and improve the treatment of people with depression and psychosis.”

The percentage of patients with depression and psychosis who may be affected by inflammatory conditions is not something that the research team behind the biobank is yet willing to estimate.

Another question which remains so far unresolved concerns when in the course of a disease an infection typically exerts its negative influence: Could infection act as a trigger if you are predisposed to depression, for example? Or would it more typically exacerbate an existing condition?

“These are some of the many other issues that also need to be examined,” says Prof. Benros.

 

Fact

Professor Michael Eriksen Benros has been researching the effect of the immune system on psychic disorders for many years. He is a member of the board of the Immunology Section of both the World Psychiatric Association and the European College of Neuropsychopharmacology (ECNP).

The biobank that Prof. Benros is establishing will be gradually expanded in the coming years. More patient studies will be carried out, and a number of new issues relating to the influence of the immune system and other biological systems on mental health disorders will be addressed.

Part of the methodology used to build the new biobank is described in these two scientific articles:  www.ncbi.nlm.nih.gov and A study protocol - PubMed (nih.gov)