Depression Is Still a Mystery – We Need a New Model.

By Deepak Chopra, M.D., FACP, Murali Doraiswamy, MD, Professor of Psychiatry, Duke University Medical Center, Durham, North Carolina and Rudolph E. Tanzi, Ph.D., Joseph P. and Rose F. Kennedy Professor of Neurology at Harvard University, and Director of the Genetics and Aging Research Unit at Massachusetts General Hospital (MGH).

The magazine ScienceNews begins a recent article on depression with a blanket judgment: “A massive effort to uncover genes involved in depression has largely failed.” A general reader would probably not feel the shock waves that spread from this assessment. Gene research is always going up and down. That doesn’t change the public’s general sense that depression is being handled pretty well. Billion-dollar antidepressants continue to flourish. Somewhere in the future, better ones will improve the situation even more.

Informed opinion on the subject is very different, however, because the model for depression that has been accepted for decades counts it as a brain disorder, and brain disorders are rooted in genetics. The failure to find the genes involved in depression strongly suggest – as more than one prominent researcher now concedes – that the genes of depressed people are not damaged or distorted compared with the genes of people who aren’t depressed. Alternatively, it may just be very difficult to find genes for a condition that is so pervasive in society today regardless of genetic composition. What follows is another false assumption. The most popular antidepressants supposedly worked by repairing chemical imbalances in the synapses – the gaps between two nerve endings – where the culprit seemed to be an imbalance of serotonin. But serotonin is directly regulated by genes, and some key research indicates that drugs aimed at fixing the serotonin problem either don’t work that way or that there wasn’t a serotonin problem in the first place.

The ScienceNews report doesn’t leave much wiggle room for a laissez-faire attitude on this point: “By combing through the DNA of 34,549 volunteers, an international team of 86 scientists hoped to uncover genetic influences that affect a person’s vulnerability to depression. But the analysis turned up nothing.” Nothing doesn’t mean something.

If the chain of explanation running from genes to the synapses and finally to the pharmaceutical lab is broken, a host of doubts arises. Is depression a brain disease in the first place, or is it, as psychiatry assumed before the arrival of modern drug treatment, a disorder of the mind? The latest theories haven’t gone back to square one. What we know isn’t black and white. There are many variables in depression, which leads to some fairly good conclusions:

• There are many kinds of depression.
• Each depressed person displays their own mixture of causes and symptoms.
• The mental component in depression includes upbringing, learned behavior, core beliefs, and judgment about the self.

The brain component includes wired-in neural pathways, with suggested overactivity or underactivity in certain areas of the brain whose cause isn’t understood. But depression isn’t localized just in a single region in the brain. The interaction of multiple regions is involved.
The genetic component may explain why depression runs in families, but no gene or group of genes seems to guarantee that a person will become depressed. We are talking instead about genes that make you susceptible to the disorder. What triggers these (unknown) genes remains a mystery. In any case, genes are not fixed but fluid in their output, so the genetic situation is changeable. Of course, we must also remember that finding genes for depression is much more difficult than trying to find genes for other more obvious disorders, like heart disease. This is because a depressed family member who may actually have genetic predisposition to depression may increase the odds that other family members also become depressed, even if they are not genetically predisposed. Depression can spread among family and close friends! In carrying out a genetic study to find “depression genes”, one must tell the computer program who in the family is suspected of carrying a depression gene.

Finally, there is an X factor, or maybe more than one. The X factor could be predisposition in young children that doesn’t blossom into depression for years. It could be social interactions that create a sense of helplessness or victimization.

A skeptic could look at this list and say, “so anything and everything can make me depressed.” That’s not really true. About 20% of people will experience a severe depression some time in their lives. At the moment there is a rash of depression among combat soldiers who served in Afghanistan (this would be directly related to a sudden increase in suicides, which is generally linked to depression) and among laid-off workers who are enduring long-term unemployment. In both cases, an outside event led to the depression, but we do not know why, in the sense that only a proportion of people become depressed under the same stimulus (war and losing your job).

In our opinion, a major issue in the failure to solve this mystery is the difficulty in accurately encoding in the analysis who is clinically depressed and who is not. Depression "spreads" in families and among friends without the need for an inherited gene. One can be sure that there are genes which predispose a person to depression, but finding them requires accurately telling the genetic algorithm which family member is a likely carrier versus not–this is almost impossible.
The study about the failure to find the genes responsible for depression, which was published in the January 3 issue of Biological Psychiatry, took an unusual approach by focusing on individual depression symptoms (e.g. poor appetite) rather than on people with clinically diagnosed depression. This wasn’t necessarily better, only different. Relying solely on symptoms reported by people (without a doctor verifying the cause) can result in a lower number of those who would be considered clinically depressed if some people are in denial or don’t know the difference between depression and ordinary sadness. But more importantly, symptoms change not just over a lifetime but often on a daily or weekly basis; there is a sliding scale for each sufferer and also for the disorder as a whole.

In the end, the situation is too cloudy for anyone to offer either a pessimistic or optimistic prediction about where depression is heading. Drug treatment remains hugely popular, no matter what the basic science says. In cases of mild to moderate depression – the most common type – antidepressants produce remission of symptoms in only about a third of individuals, and in most recent studies, this is about the same as the placebo effect. Some symptoms of severe depression remain intractable, and yet in other cases, the chronically or more severely depressed perform the best with drug treatment. Hope is always better than giving up.
Our purpose was simply to underline that depression is joining other mental disorders, particularly schizophrenia, where no simple disease model works. There are too many variables, and patients follow highly individual paths as the disorder sets in. The mind-body connection has yet to be fully understood, but the present impasse suggests that we have to solve it, not rely on drugs that simply mask the underlying disorder by relieving symptoms. Human beings are sensitive creatures. Hearing the words “I don’t love you anymore” or “You’re fired” can lead to a complex downward spiral. Is there any doubt that this spiral originates in the mind, not the brain? It is time to give the mind its due importance while connecting its responses to secondary mechanisms in the brain.

Deepak Chopra, MD is the author of more than 70 books with twenty-one New York Times bestsellers and co-author with Rudolph Tanzi of Super Brain: Unleashing the Explosive Power of Your Mind to Maximize Health, Happiness, and Spiritual Well-being. (Harmony)

Murali Doraiswamy, M.D., Professor of Psychiatry, Duke University Medical Center, Durham, North Carolina and a leading physician scientist in the area of mental health, cognitive neuroscience and mind-body medicine.

Rudolph E. Tanzi, Ph.D., Joseph P. and Rose F. Kennedy Professor of Neurology at Harvard University, and Director of the Genetics and Aging Research Unit at Massachusetts General Hospital (MGH), co author with Deepak Chopra of Super Brain: Unleashing the Explosive Power of Your Mind to Maximize Health, Happiness, and Spiritual Well-being. (Harmony)