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The Wisdom of Psychopaths
In this engrossing journey into the lives of psychopaths and their infamously crafty behaviors, the renowned psychologist Kevin Dutton reveals that there is a...
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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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12 Comments
Add CommentIs there a way to distinguish disease-producing biochemical changes from disease-induced epigenetic biochemical changes ? May be organic and psychological ethiologies just converge in the same point.
Reply | Report Abuse | Link to thisI'm a retired psychotherapist well acquainted with the effects of Major Depression. I can only hope that the development of a medicine will not be long in coming. The research/investigation is monumental work and I trust it will keep moving forward. To the investigators I say well done.
Reply | Report Abuse | Link to thisAre there any numbers on the causes of depression, specifically, the percentage of genetic dysfunction versus environmental dysfunction. Kind of like the variability of causal factors that contribute to one being cold --environmental factors (it's cold, lack of clothes, etc) versus a biological dysfunction.
Reply | Report Abuse | Link to thisWhat a load of greedy nonsense.
Reply | Report Abuse | Link to thisI suffered from Major Depressive Disorder from 1959 to 2001. The fact that my father was also a sufferer suggests a genetic vulnerability, but does NOT show that the cause was genetic in either his case or mine.
The solution is simple, free and laid out for all to see in "The Neurobiology of Depression", Scientific American, June, 1998. You just have to read it and concentrate on the "cognition" part of Cognitive Behaviour Therapy.
That same free self-therapy also works for a number of other "mental" (brain) faults as elucidated in "Faulty Circuits", Scientific American, April, 2010.
It's all about chronic stress, whether environmental or internal in origin.
I'm heartily sick of seeing diseases "created" and therapies contrived primarily for profit. We're all in this together.
Depression is mainly aroused after industrialisation.No concern with genetic.Before machine age very few people suffered from depression. Where industrialization not spread so vast there depression is not so serious.In India mainly rural area there people rarely suffer from depression.
Reply | Report Abuse | Link to this'Rollo May described depression as “the inability to construct a future”'????
Reply | Report Abuse | Link to thisNO, IT'S NOT. IT'S absolutely INCORRECT. When I'm depressed I'm very able to construct a future - just my predictions are very unhappy. One can say there's a difference between a 'clinical' depression and just 'bad mood'. I know what a 'real' clinical depression is.
My opinion - to be depressed in our society is the 'normal' state of the mentally healthy people who are able to figure out that the future for that kind of society is not great.
When we are 'happy' we block negative information and try to 'live in a moment' without thinking about possible 'bad' consequences. It means that it's actually that the 'HAPPINESS' is “the inability to construct a future.”
Good question. The nature/nurture argument. I would say it will be tricky to tease apart the amount of variance in MDD that each contributed to. Regardless, some understanding of the genetic component and successful modulation it is a definite step in the right direction.
Reply | Report Abuse | Link to thisI don't disagree with you here. The cause might not be genetic, but the susceptibility might be. As you write, it may all be about chronic stress. Why are some people more affected than others? I think CBT and drug development should go hand in hand. They may not only complement each other sometimes, but even inform each other at some stage. Ultimately, knowledge of pre-disposition to MDD from an early age might help eliminate alot of suffering via e.g. preemptive CBT etc.
Reply | Report Abuse | Link to thisI don't know how many people were depressed in the past and, even if I did, numerous other factors come into play; people live closer together, life is more hectic etc. I agree with you though - genetically speaking, we are in environments that we did not evolve to spend all out time in (e.g. offices) and doing things (generally far less laborious, itself a possible issue (biofeedback etc.)) that we never did in the past.
Reply | Report Abuse | Link to thisI think susceptibility --is-- genetic, and the variability is there on purpose. If we didn't get cold when we do we wouldn't do something about it. Why variability? I guess because nature found that it works, some individuals forewarn, some can endure more, the average makes things move, especially as the multitude of other contributing factors to the situation at hand come into consideration.
Reply | Report Abuse | Link to thisHow do we avoid, the most possible, the kind of environments that individuals develop in and later lead to them having a higher chance of experiencing depression.
Aboriginal language knowledge and youth suicide:
http://www.eric.ed.gov/ERICWebPortal/search/detailmini.jsp?_nfpb=true&_&ERICExtSearch_SearchValue_0=EJ765043&ERICExtSearch_SearchType_0=no&accno=EJ765043
Psychosocial dwarphism:
http://en.wikipedia.org/wiki/Psychosocial_short_stature
The nature-nurture argument for depression is still unsettled. I understand that people like myself with major depression feel very strongly about their own experiences but must realize that a data point of one is not valid in generalizing to all patients in the scientific quest for understanding and treatment. I do know that for me the medications make it possible for me to get up in the morning and maintain a semblance of a normal life. They are necessary for me and I hope that people here who don’t benefit from medication don’t vilify medication to the point where they are made unavailable to me. I also realize that it is unrealistic to expect that they can medicate me into a good life situation. I suspect that some people vilify medications because of exactly that expectation. Pills make me functional, not happy.
Reply | Report Abuse | Link to thisThe idea that it is related to industrialization is also countered by numerous published studies that show that depression in other cultures is not always dealt with and frequently left unrecognized and untreated. Think back to your experience in India and take a good hard look at the people labeled “lazy”, paralyzed by looking at only that bad that can happen from any proposed course of action, etc..
In my own situation Depression did not reveal itself until my situation exceeded my coping skills and I just shut down. This does not prove environmental cause; perhaps my ability to cope with extreme circumstances is less than others. An example (not mine) is in WWII, some solders got shell shock and others did not when exposed to the same circumstances side by side.
In my opinion, the big effort should be made on finding long lasting cures for diseases such as gene therapy and/or prevention rather than spending time, effort and money in generating drugs for medication. Of course some large interest companies that are founding research will oppose to this.
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