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Clear New Insights into the Genetics of Depression

Recent findings suggest novel paths to treatment


The psychologist Rollo May once described depression as “the inability to construct a future”.

According to the National Institute for Mental Health this “inability” can affect up to 14.8 million Americans – 7% of the population – in a given year, at an annual cost of $100 billion. That’s about five times the renewable energy budget of the United States. We hear many things about how great we’re getting at saving the planet with our hybrids and off-shore wind farms; we hear far less about how we’re doing in combating or preventing depression.

This month, however, has brought some potentially exciting news: two genetic studies with major ramifications for the treatment and diagnosis of Major Depressive Disorder. As a psychiatric geneticist, it is rare that I see such clear insights into distinct genetic mechanisms of psychiatric illnesses. Research into bipolar disorder and schizophrenia –- the disorders I spend most of my time working on –- would benefit a great deal from breakthrough studies such as these.

One new study, published in Nature Medicine
, suggests that a pathway called MAPK – and one gene in particular from this pathway, MPK-1 – are significantly dysregulated in certain areas of the brains of individuals with major depression. These results were obtained by looking for significant gene expression changes in post-mortem brains from 21 individuals with Major Depressive Disorder compared to 18 matched controls.

The researchers, led by Yale’s Vanja Duric, confirmed their results in rat and mouse models. And they showed that not only did raising MPK-1 levels lead to depressive symptoms, but that antidepressant treatment reduced the expression of MPK-1.

They demonstrated that MPK-1 increases during stress and can negatively regulate MAPK, a key signaling pathway involved in neuronal plasticity, function and survival. In effect, it appears that MPK-1 may be important in depression because when too much of it is around, it disturbs the growth and viability of neurons in a part of the brain known as the hippocampus, a factor believed to contribute to symptoms of major depression.

Dr. Duric’s team conclude that developing drugs to regulate MPK-1 may offer new hope for alleviating depression and related mood disorders. Drugs take many years to develop and bring to market, but knowing the mechanisms and targets can greatly help to speed up the process. We know what sort of protein MPK-1 is and we know how it works, which makes drug development a lot simpler.

A second new study, published in “Science” and led by Brian Alexander of Cornell’s Laboratory of Molecular Neurosurgery, goes a step further by applying gene therapy to mutant mice. These mice were missing a gene, p11, the deletion of which has been shown to induce depression-like behavior. The p11 gene helps regulate the signaling of serotonin, a brain chemical targeted by many antidepressants and tied to mood, sleep and memory.

Dr. Alexander’s team found that using gene therapy – essentially using a virus to deliver a “working” copy of a gene into a host whose copy is defective or missing – to restore p11 expression in specific parts of the brain was able to decrease depression-like behavior.

This gene therapy approach is also being applied to Parkinson’s disease. Gene therapy offers the tantalizing possibility of a permanent treatment, eliminating the need for daily consumption of medications. This is an important point as many people do not take medications as they should. Others suffer from adverse drug reactions. With gene therapy, you get a drug that is completely natural: it is a gene; it is part of a prescription not for medication, but for building a healthy human.

The “Science” study helps give new life to the field of gene therapy, which itself was exhibiting depression-like symptoms. The idea of using gene therapy to replace defective DNA has been around since the 70’s, but suffered a large setback in 1999 with a subject’s death and subsequent suspension of several clinical trials for ethical reasons.

The MPK-1 findings point to a host of therapeutic interventions. Gene therapy may be one, as Alexander and colleagues demonstrated for p11. Characterizing the spectrum of mutations that modify the dysregulation of the pathway is another. The latter falls into the attractive realm of "pharmacogenomics" and the idea of “tailor-made” drugs, in this case antidepressants, which would be optimized for the genetics of a given individual.

It may not be long before the sequencing of our genome becomes a routine part of medicine, and from it could arise the automated optimization of drug treatments or lifestyle recommendations (such as: do not smoke if you are at exceptionally high risk of developing lung cancer). For depression, these advances will be greatly welcomed because even though anti-depressants may be highly effective, the rates of adverse drug reaction can be high. Also, patients’ responses to a given drug vary greatly. In the world of the future, a patient’s genetic profile could help suggest which drug would work best: Would Mr. Smith do best with a drug that targets p11? Or perhaps MPK-1?  

The brain is an extremely complicated organ, with a myriad of complex loops and cycles of gene expression. It is likely that additional cascades of gene expression remain to be associated with susceptibility to depression. Genes in the MAPK pathway are unlikely to be the only “weak point” of susceptibility to the onset of Major Depressive Disorder, nor is p11. Nevertheless, every genetic mechanism for a disease that we discover is a possible path to novel pharmacological or behavioral interventions.

While there may well not be a “gene for depression”, we are quickly gaining a comprehensive, genetic understanding of the factors involved in this personally and socially crippling disorder. Depression is a prevalent, costly and harmful disorder which affects both the lives of individuals suffering from the disorder and their relatives. Finally, we may soon be in a position to help the many millions of Americans that suffer from depression to “construct a future” that is not plagued by the effects of this terrible illness.

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