Genetics could provide a pathway to understanding treatment-resistant depression
9 May 2019
Last update: 09/05/19 11:44
Treatment-resistant depression is the most unfavourable outcome for patients suffering from depression: one-third of depressed patients do not respond to at least two different treatments and they continue to suffer from depression and its consequences, including social isolation, decline in work functioning and – in the worst case – suicide.
Scientists still cannot explain exactly why these patients are so resistant to treatment. However, one hypothesis is that depression may be caused by different biological alterations. Unfortunately, the antidepressants that are currently available only target some of these, namely alterations in the balance of two neurotransmitters in the brain, called serotonin and noradrenaline.
Our article published in the British Journal of Psychiatry shows how genetic studies could help researchers to understand which different mechanisms are involved in treatment-resistant depression compared to treatment-responsive depression.
We studied more than 3,000 depressed patients who were resistant to antidepressant treatment and who had genetic variations within the whole genome. What we found revealed that single genetic variants do not explain the difference between response and resistance. This confirmed the hypothesis that antidepressant resistance is caused by the accumulation of a number of genetic variants – each of which is common in the population and individually benign but detrimental when combined with other variants.
Under this assumption, we have to look at the cumulative effect of hundreds or thousands of variants within genes that control cell functioning in the brain to find meaningful results. This type of analysis is called “pathway analysis”: by aggregating the effect of multiple variants in functionally related genes we can work out which pathways carry a higher burden of variants in treatment-resistant depression.
This approach led to the identification in our sample of two pathways enriched in genetic variants in people with treatment resistance – and they are both relevant to neuronal functioning in the brain. One controls the cascade of signals that regulates brain cell survival and differentiation – indeed, neural cell suffering and death are associated with depression, according to previous studies. The other pathway is involved in the regulation of gene expression, the process leading from DNA to protein building.
In order to help patients recover from depression, a number of changes in brain cell activity are required. This can happen because cells change the proteins they produce. In neurons this means, for example, the production of new connections with other neurons or a change in neurotransmitter production – in other words, modifications in the way neurons communicate. In patients with treatment-resistant depression, alterations in these processes may not recover and antidepressants acting directly on them may be needed to obtain a good response.
Future lines of research should focus on studying the members of these pathways and possibly identify pharmacological targets for antidepressants with alternative mechanisms of action compared to the treatments that are currently available.
Read the full article here: Genome-wide association study of treatment-resistance in depression and meta-analysis of three independent samples
Explore the rest of the articles in BJPsych’s Themed Issue: Treatment-Resistant Mood Disorders
To find out more about the RCPsych Publications, visit the RCPsych Hub!
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I suppose the main issue here is related to Gin S. Malhi et al’s editorial in the same journal issue, with the relevant question “Problematic illness or a problem in our approach?” No one contests the devastating social effects of what we call “depression,” but some of us are not convinced about a primary or predominantly biogenetic aetiology of depression (or share any optimism about new “antidepressants,” inappropriately so-named). Similar reservations apply to a lot of other psychiatric diagnoses. Historically, the way we have drawn the boundaries of psychiatric diagnoses, tells us that we most likely are not dealing with natural kinds to the point where we can realistically find direct genetic correlates or genotypes. I think this is a fundamental issue that came up with Schizophrenia as well. Again, no one contests that genes play an important part in normal thought processing, but for me, the key to future research will be to first demonstrate the scientific basis of normal thought processing and the genes involved, then we can see how genetics could provide a pathway to understanding treatment-resistant depression (a form of thought processing difficulty or disorder – in my language). That said, I suspect that in the end, it will be found that there are only a few significant faulty genes, relevant polymorphism or variations in the first place, but “treatment-resistant depression” always represented epigenetics and the irreversible effects of “psychological trauma” (the social environment, and the same devastating consequences for short).