What is the relationship between mental health and the immune system?
A brief history of “Immunopsychiatry” and why a new (scientific) star is born
Studying the relationship between mental health and the immune system is a hot area in psychiatry and neuroscience, so much so that a new term has been coined to define the field: immunopsychiatry. A new (scientific) star is born.
The emphasis nowadays is in particular on the relationship between mental health and inflammation — the secret killer, as Time magazine defined inflammation exactly fifteen years ago.
The changes in this scientific area over time is very clear: only 200 scientific papers were published on “depression and inflammation” in the five years between 2005 and 2009, while more than one thousand have been published in the last five years!
It is not surprising that recently a whole special issue of the scientific journal Psychoneuroendocrinology has been dedicated to the field of immunopsychiatry.
And a book has just been published, with this same name:
And yes, you guessed right — I have a chapter in this book.
A short preface, entitled “A brief history of immunopsychiatry”.
Because nothing is ever new in science, and there is always a history.
Did you know that the initial evidence linking immune activation to psychiatric disorders comes from studies in patients with infections, like syphilis, some conducted more than a century ago?
When this discipline started, the term psychoneuroimmunology was used ubiquitously to indicate the study of the bidirectional communication between the brain and the immune system. The established scientific society that represents most of the scientists in this field, the Psychoneuroimmunology Research Society, still uses this term.
However, I have argued before that these two names — psychoneuroimmunology and immunopsychiatry — are really different in their emphasis and meanings, and that the order of the words that compose these names implies different hierarchical models, indicating who dominates whom.
Psycho — neuro — immunology is based on the assumption that psychological phenomena regulate neural process in order to influence the immune system.
Immuno — psychiatry is based on the assumption that the immune system regulates psychological and behavioural processes and eventually leads to psychiatric disorders.
The apparently minimal difference between these two names hides an incredible shift in our understanding of the relationship between the brain and the body: before (in the era of psychoneuroimmunology), depression was a mental state that was able to influence the immune system; today (in the era of immunopsychiatry), depression is caused by changes in peripheral (body) immune mechanisms.
When the term “psychoneuroimmunology” first reached a wider audience in the 80s, as the title of the pivotal book edited in 1981 by the late Rober Ader, the main interest was exactly the understanding of how psychological and brain phenomena influence the immune system.
In their seminal work, Ader and his colleagues conducted an experiment that was based on the ‘pavlovian model’ of associating a bell with food to lead to salivation, until eventually the bell was enough to induce the salivation.
In their work, they first associated the administration of saccharin ( a sugary substance; the bell) with cyclophosphamide (a powerful immunosuppressant; the food) and saw the immune system being suppressed (salivation).
Then, eventually, they were able to induce the immunosuppression (salivation) without the cyclophosphamide (food), just with saccharin (the bell).
The hierarchical model was very clear: a simple nerve impulse due to a taste stimulus could have profound effects on the immune system.
Unfortunately, translated in the human context, this model did not deliver the health improvements that had been anticipated.
Dozens of studies in the 80s examined the relationship between major depression and the immune system, again based on the model that depression as a mental state was able to influence the immune system.
However, a turning-point paper in 1991 highlighted the lack of substantial evidence supporting this association. By the way, this is was one of the first paper that I read on this topic, and I have been hooked by this research areas since!
Moreover, the initial enthusiasm about the possibility that psychosocial interventions could prolong survival in cancer patients by improving immune function was difficult to replicate consistently.
So were the attempts to modify the immune system through hypnosis and relaxation, which again proved unsuccessful.
Undoubtedly the strongest work in those years was that looking at the effects of psychological stress on the immune system.
However, research in animal models was already showing that stress alters immune function not via its psychological effects but rather through direct peripheral communications between the brain and the immune system in the body, through the autonomic nervous system or the secretion of hormones like cortisol.
It is not unreasonable to say that Psycho — Neuro — Immunology, as a hierarchical model with psycho at the top, was not delivering on its promises.
As in all complex cultural phenomena, it is difficult to pinpoint an exact date or the driving force behind the conceptual shift in the field that ultimately has led to the reversal of the hierarchy between the brain and the immune system that we see today with the introduction of Immuno — Psychiatry.
However, I would argue that the clinical use of pro-inflammatory cytokine therapies for cancers and chronic viral hepatitis, which started in the late 80s and consolidated in the early 90s, has probably been the largest contributing factor.
It became soon apparent that a large proportion of patients exposed to these cytokines develop psychiatric adverse effects, ranging from clinically significant depression and anxiety to, in rarer cases, psychotic episodes or suicidal attempts. I was among the first to study this phenomena in an Italian sample.
It was not long before research groups worldwide started to investigate the mechanisms by which a pharmacologically-induced immune activation could lead to such a range of psychological and behavioural changes.
Around the same time, studies began to appear showing that depression per se, even unrelated to medical illnesses, was associated with immune activation.
This was followed by studies showing that increased inflammation in otherwise healthy individuals, for example as a consequence of childhood experiences of stress, was a risk factor for the future onset of depression.
In parallel with these clinical studies, scientists started to use animal models to look at the biological mechanisms by which increased inflammation leads to behavioural changes resembling depression.
Eventually the time was ripe for asserting a “causal” role of increased inflammation in the pathogenesis of depression, and in general for affirming that the immune system can “subjugate the brain” in inducing behavioural changes and psychiatric symptoms.
In 2006 the first trial using an anti-inflammatory drug (aspirin) as added strategy to an antidepressants was published, and the rest, as the old saying goes, is history.
A number of randomised controlled studies using anti-inflammatories for depression has followed in the last few years, finding some evidence of therapeutic effects at least in subgroup of patients, and extending the use of these drugs to other psychiatric disorders, finally delivering translational impact in mental health.
Moreover, while possibly research in depression is ahead of that in other mental disorders, recent studies have shown that increased inflammation is present in a vast number of psychiatric disorders: addiction, bipolar disorder, depression, dementias, eating disorders, post-traumatic stress disorder, and schizophrenia.
At the same time, we have gained sophisticated insight into the mechanisms by which the immune system affects the brain, at a microscopic and macroscopic levels.
Interestingly, a recent paper from a journalist has also confirmed that immunopsychiatry will extend its remit eyond the academic community and into the pharmaceutical sector, and proposes that some of the psychiatric medications of the future may come from drugs targeting the immune system.
This is welcome news, considering that approximately one third of patients with depression or psychosis does not respond to currently available medications.
Moreover, I also think that using novel medications that have well-defined mechanisms and specific pharmacological targets, potentially outside the brain, will help closing the gap between psychiatry and the rest of medicine, and therefore reducing the stigma associated with psychiatric disorders.
Where does this history leave psychoneuroimmunology?
It is important to emphasise that this theoretical shift in the brain-body hierarchy does not minimise the enormous importance of psychosocial factors for both mental and physical health.
For example, there is outstanding work showing that psychosocial interventions improve quality of life and survival in cancer patients; but the point here is that there is no consistent evidence showing that this might be due to changes in immune function rather than, for example, to improved compliance with medications or to a healthier life style.
Similarly, there is overwhelming evidence that stress disrupt immune function, for example leading to a reduced ability of the body to heal its wounds; but again the point here is that there is no consistent evidence that psychological processes can improve wound healing in any clinically-meaningful way.
Introducing “immunopsychiatry” as a new name may have the advantage of focussing the attention of the scientific community on a set of specific research questions that propose (perhaps unconsciously) the biological dominance of the immune system in the brain-body relationship; but, in so much that this is step leading to a more successful impact of psychoneuroimmunology as a discipline (not as a hierarchical model) in both clinical and basic science, it is a welcome change.
Where is the future going? What will the next edition of a book on immunopsychiatry, published, let’s say, in 2028, look like?
I am certain that the next edition of this book will focus on the novel treatments for psychiatric disorders that this research will have generated by then.
But we will also know more about the biological and molecular mechanism underpinning the relationship between brain, the immune system, and mental health.
Many more questions will have answers by then.
How does the immune system affect the brain, both in adulthood and during the development?
What is the role of the microbiota-gut-brain axis?
How does the immune system provides information that the brain processes and integrates with other information, almost like a sixth and even a seventh sense?
How can wellbeing approaches — nutrition, meditation, physical eactivity, social inclusion, spirituality — affect the immune system and improve mental health?
Answering all these questions will allow us to understand really how the body, the brain and the mind communicate and act as a single unity.
Not only there is no health without mental health. There is no difference between mental and physical health. It is only health.
Then, and only then, we will truly know whether or not immunopsychiatry deserve its new name.
Disclaimer: My research work, and the work of our research group, is funded mostly by the UK National Health Service, and other governmental and charitable organisations. We also receive some research funding from pharmaceutical companies interested in the development of anti-inflammatory strategies for depression; however, this blog, and similar blogs we post on these topics, are completely independent, and only based on the best scientific and clinical evidence.
