Translating genes to real-world concepts

It is well established that many psychiatric disorders have a strong hereditary link; genetic influences account for 80% of the risk of developing bipolar disorder. Despite this knowledge, almost 100 genes have been identified for schizophrenia but far fewer have been identified for bipolar disorder. While past genetic studies have revealed inconsistencies in findings, recently the focus has changed towards genomics, and molecular tools have become much more powerful.

New and improved molecular tools

One example of these tools are genome-wide association studies (GWAS), which are very powerful and allow us to perform case-control studies in thousands of samples. Thanks to GWAS, new risk loci have been discovered for bipolar disorder.

However, he reminded us that it is not only single genes that are identified as risk factors – it is really all about polygenicity. Each of the variants that has been identified for bipolar disorder only carries a very small risk for developing bipolar disorder so all the variants must be considered together to get a complete clinical picture.

GWAS are complemented by approaches to identify rare variants, such as copy number variations (CNV). These are rare but there are some copy variants that are associated with a huge risk for development of psychiatric disorders.

Choosing a sample population

Prof. Schulze has been performing studies in large Amish groups, which provide a good sample population because they live in a stable farm-based environment and have several children, making them ideal for genetic analysis! There are also increased levels of inbreeding compared to the general population, so there are higher chances of rare variants being increased in frequency. Once these variants have been identified, they can be tested in a wider outbred population.

What are the implications for clinical practice?

Prof. Schulze acknowledged that genetic findings are all well and good but what are the clinical implications – do the findings have any tangible translational value?

In the US, there is already direct marketing of single-nucleotide polymorphism (SNP) arrays to patients and relatives. But how accurate can these tests be?

He gave the example of CYPD26 where slow metabolisers accumulate the drug more than others whereas high metabolisers break down the drug rapidly and therefore, might need a higher dosage. However, evidence suggests that CYP pharmacogenetic testing is not useful for standard care.

So while genetic testing is certainly a growing business area, it must currently be used with caution as there is currently no conclusive evidence for a clear benefit of molecular personalised approaches based on common variants. Though perhaps as molecular tools evolve to be more sophisticated, this will change.

The differences in cognitive function between bipolar disorder and schizophrenia

Professor Sachs, Austria, then went on to give an interesting talk on the differential aspects of cognitive function.

There are several differences between bipolar disorder and schizophrenia in terms of cognitive function. For example, ‘sustained attention’ is much more impaired in schizophrenia patients compared to bipolar patients. Schizophrenia patients also demonstrate much more impairment for social and non-social cognition.

This morning’s session certainly highlighted that there are clear differences between bipolar disorder and schizophrenia, most likely because schizophrenia has a neurodevelopmental origin. This will have an impact on future research and potential treatment targets, and perhaps future genetic research will uncover more insights into the genes responsible for bipolar disorder.

Practical approaches to bipolar

For the afternoon symposium on day 2, this correspondent had the pleasure of attending the sessions chaired by Professor Scott in the Makedonia Hall.

Unfortunately Doctor Etain was unwell and unable to deliver her presentation on how childhood trauma influences the clinical expression of bipolar disorders, but we were amply served by Prof. Scott and Professor González-Pinto.

A model of modernity

Prof Scott opened the session with a discussion of clinical staging models in bipolar. Contrasting bipolar with conditions such as coronary diseases, she noted that the medical view of heart disease had moved on from viewing it as single condition that should be treated as it occurs, to a greater awareness of risk factors and a renewed focus on prevention.

Unfortunately, this ‘forward-looking’ way of thinking is not prevalent in bipolar, but the use of staging models may help to bring increased attention to at-risk groups.

Practice makes perfect

Prof. González-Pinto’s presentation was informed by her extensive clinical experience, and gave me the sense of a medical professional who is deeply involved in the day-to-day practice of mental health care.

Starting, as all talks must, with a recognition of Kraeplin as one of the progenitors of the modern view of mixed states, she then moved on to discuss the on-going development of the DSM criteria.

Taking the recognition of mixed specifiers in DSM-5 as a jumping-off point, she highlighted the increase in hospitalisation, drug abuse and suicide attempts among these patients, as well as their poor treatment response. Some, but not all, of these factors may be explained by the early age of onset of bipolar mania with depressive features.

Prof. González-Pinto then discussed the role of psychological treatment, stressing: early intervention; the treatment of anxiety (a severe trait in mixed patients); the treatment of drug abuse, psycho-education to inform the patient of the necessity and likely outcomes of treatment; and finally cognitive behavioural therapy, which would aim to tackle patients’ cognitive distortions.

She closed her presentation by talking about the rehabilitation programme that she conducts at her hospital, detailing how they promote patient activity, learning and work in a setting that values optimism and a sense of humour. The rehabilitation is supported by medical staff and mental health nurses are heavily involved in the process.

The road ahead

While assessment and treatment are obviously the core focus of IRPB, this correspondent found it heartening to hear about the later stages in the treatment process, and the hope of on-going rehabilitation.

Changing trends in bipolar disorder

In Saturday afternoon’s symposium, chaired by Professors Fountoulakis and Gonda, Doctor Dimellis gave a review of the pharmacoepidemiology of bipolar disorder. Pharmacoepidemiology, a mixture of pharmacology and epidemiology, reflects the prescription pattern of the average, everyday psychiatrist. This is crucial for accurate exploration of various aspects of the use of psychotropic drugs such as economic, medical, efficacy, tolerability and safety considerations.

Guidelines versus experience

He noted that the diagnosis and treatment of bipolar disorder are still unclear. For example there are still several difficulties regarding terminology and prevalence, in particular ‘mixed episodes’ and ‘rapid cycling’. In addition, there are different criteria for diagnosis and these vary between DSM and ICD. One other issue with the current guidelines is that they simply contain too many recommendations, making it hard to distinguish between antipsychotics in terms of their efficacy for particular aspects of bipolar disorder, which makes it much easier to rely on personal experience than guidelines. It seems that even with appropriate guidelines and criteria there will always be a conflict between following guidelines and letting your experience from everyday clinical practice guide your decisions.

Treatment evolves but brings new problems

Dr Dimellis took us through a timeline of treatment, noting that in the 1970s clinicians preferred first generation antipsychotics to lithium. However in the 1980s antipsychotic monotherapy decreased, while the use of lithium/carbazemine in combination with antipsychotics became more popular. Treatment has evolved as our evidence base has changed and drugs with new mechanisms of action have become available. A consistent problem over the years is that of too much antidepressant use in patients who are manic or hypomanic, possibly because they have had depression which switched to mania because of the antidepressant use. Another more recent problem is that of polypharmacy – do patients really need to be taking three different drugs?

This session certainly raised a lot of issues, such as the need for clearer and more user-friendly guidelines, but how easy it will be to resolve these issues remains to be seen.