Translating research to real-world clinical outcomes

Take early life stress, which has been shown in both animal and human models to lead to lifelong problems with anxiety, depression and cognitive dysfunction. For example adult women with a history of abuse show an increased risk of developing depression or other stress-related psychiatric disorders.

So it’s clear that early trauma is associated with long-term changes in behaviour, stress sensitivity and the risk for psychiatric disorders but the question is what are the mechanisms causing this? The answer appears to potentially be changes in gene expression through epigenetic changes.

For example, decreased glucocorticoid receptor expression is associated with depression, possibly due to the affects of the receptor on the hypothalamic-pituitary-adrenal (HPA) axis. In mice models, low maternal interaction and licking leads to increased DNA methylation leading to reduced expression of glucocorticoid receptors in the infant mice.

This research also translates to humans; those abused as children have a higher level of methylation leading to reduced glucocorticoid expression. In the symposium ‘Results from EU consortium moodinflame: integrative view on mood disorders’ (chaired by Prof. Norbert Müller and Dr Aye-Mu Myint of Germany), Prof. Stephan Claes of Belgium demonstrated that stress, anxiety and violence from an intimate partner during pregnancy all have this same effect on offspring.

All this research highlights not only the effect on glucocorticoid receptor expression but also the potential for a broad epigenetic mark that is left by early life stress.

Another interesting point raised was generating tailored treatments. Prof. Dr Hemmo Drexhage of the Netherlands discussed research that has shown that an earlier onset of bipolar disorder is associated with inflammation of monocytes and a more severe form of the illness. In a similar vein, longer duration of bipolar disorder is also associated with monocyte inflammation. The pathogenic mechanisms cause even further impairment of immune system regulation as illness progresses.

One of the most interesting discussion points raised during the talk was how to translate this type of research into clinical practice. For example, do these data suggest that patients with bipolar disorder or depression should be treated with anti-inflammatories? Unfortunately research is currently too preliminary to be able to give treatment recommendations and the most pressing priority is to develop a way of identifying and stratifying those patients with high levels of inflammation. However perhaps one day in the future we will be able to give truly personalised treatment to these patients.

Prof. Andreas Papassotiropoulos of Switzerland also reinforced the importance of using pathways to help identify genes, which could become drug targets in his plenary session ‘Genetics of human memory: from gene hunting to gene discovery’. He spoke of his work with the histamine receptor H1, which has been associated with negative memory traits. He used one of the oldest antihistamines, diphenhydramine, in a proof of concept study looking at the effect on negative memory. Indeed diphenhydramine was found to suppress delayed free recall of negative information but had no effect on positive or neutral memory recall.

Today has really demonstrated the potential role of epigenetics and gene identification in our understanding of psychiatric disorders. These gene pathway approaches in combination with brain imaging studies will help with identification of new pharmacotherapies.

My Monday at EPA started with a discussion of what psychiatrists should know about recent developments in psychopharmacology; a session housing a couple of pieces of particularly interesting information.

The first, presented by Professor Istvan Bitter, concerned treatment adherence in patients, a factor which he identified as the key determinant of treatment efficacy. This link is, perhaps, not too surprising but what particularly stood out were the levels of reported failure of compliance.

Studies have suggested loss of adherence in up to 55% of mental health patients and Professor Bitter showcased fresh data showing that clinicians expect a 57% rate of failure to comply and relatives of patients report 54%.

However, in this same dataset, patient-reported failure rate was much lower. Only 41% reported neglecting their treatment, an encouraging sign given the importance of proper compliance in preventing severe outcomes such as suicide.

The second insight was found in Professor Rene Kahn’s presentation on cognition in schizophrenia; a presentation almost as notable for a timely reminder of schizophrenia’s roots as for its implications for the field’s future.

The professor referenced Emil Kraepelin, the former Professor of Clinical Psychiatry here in Munich, who characterised schizophrenia as a cognition-linked disorder, even quoting one patient in 1919 as saying “My whole mental power has disappeared, I have sunk intellectually below the level of a beast”. However, this cognitive aspect is one which has been given increasingly less emphasis in recent years.

Kahn pushed back strongly on this shift in focus, citing twin studies in which the twin with the lower IQ was, in 90% of cases, the one who developed schizophrenia. This, along with his own GROUP study of 900 patients, indicated a definite cognitive component, with schizophrenia reducing IQ and lower childhood IQ increasing risk of schizophrenia.

As no standard pharmacological treatments had been shown to reduce this impact, he said, early identification was vital, particularly the development of genetic markers to identify high-risk individuals.

Professor Kahn’s presentation also represented one side of an interesting argument which arose across the sessions I attended today. His enthusiasm for pharmacogenetics was in stark contrast to Professor H J Möller, speaking this afternoon.

His presentation in the symposium, ‘Schizophrenia: Personalised Medicine or Stratified Medicine?’ emphasised that, despite growing excitement about the promise of genetic profiling, few of the trials of its efficacy were sufficiently rigorous and even fewer reproducible. Until the advent of larger scale trials, his hopes lay, he said, with exploration of drug characteristics and a more specific tailoring of therapies to indications rather than to individuals.

In summary, a day that began with the enthusiastic encouragement of clinical testing in psychiatry and ended with a grounding assertion of just how far we have to go to find such a test with proven reliability. Suggesting that, while new approaches to treatment and diagnosis show exciting potential, refining our current approaches may still be the most effective way to help a patient succeed.