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

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