“Grief and fear, when lingering, provoke melancholia.”
So wrote Hippocrates, the original father of modern medicine, after whom the doctor’s oath is named. Our world is a far cry from Hippocratic times, but his words ring truer than ever. As worldwide incidence of depression rises and the disease sets in at a younger age, our time has been dubbed the “Age of Melancholy.” In the USA, suicide, often a consequence of depression, is the eight-leading cause of death, and depression costs the US economy over $43 billion per annum. About 15% of the population worldwide will experience major, unremitting depression. Many more of us will experience some depressive episodes at some point or points in our lives – as many as 1 in 3 of us.
Incidence statistics are a valuable resource to give us a picture of how profoundly a disease affects public health, and to guide decisions as to which illnesses should be prioritised for research and funding, but they must always be taken in context. In depression, the contexts are drugs and stigma.
Much work has been done to eradicate the stigma associated with depression, and although it is certainly still there, it has hugely diminished compared to just a few generations ago, when it was socially crippling – people with depression were seen as weak. One of the symptoms of depression is persistant feelings of worthlessness or guilt, and when these are complemented by a social stigma, many depressives would have chosen to suffer in silence. Also, the advent of Prozac has probably boosted the incidence figures – we now have a well-known and readily available treatment for depression.
The massive increase in depression incidence, is, on the surface of it, depressing. But it may in fact be good news – instead of being a sign that more and more people are suffering, it could be a sign that more people who suffered are coming forward to receive help.
Depression has been with us for millenia, and is now classified as a mental illness in the Diagnostic and Statistical Manual of Mental Disorders, the “bible” of modern psychiatry. But in many ways Hippocrates’ definition is still one of the best. He differentiates depression or “melancholia” from other negative emotions such as grief or fear, and suggests that depression is caused by negative emotions which “linger” long after their stimulus has faded or been resolved. The findings of modern neuroscience show that Hippocrates was startlingly insightful – clinical depression is profoundly different from simply feeling “down,” yet most depression is reactive – triggered by a particularly stressful event in the patient’s life.
But even though we have such amazing insights from Hippocrates, going back several hundred years BC, it was only in the twentieth century that we started to think about it as an illness – an illness that could possibly be treated. Two noted thinkers of the early twentieth century, Dr. Freud and Dr. Kraeplin, wrote their opposing theories on it. While Dr. Freud believed depression resulted from internalised, unprocessed anger or grief, Dr. Kraeplin contested that it was a physiological illness, a chemical imbalance in the brain. Most modern thinking believes both.
However, whether the medical community chose to define it as a disease or not was of little consequence when there was no treatment. Occasionally a primitive form of electro-convulsive therapy was tried; more akin to torture than therapy by today’s standards. That depression could be medically treated was utterly implausible – until a clinical trial for tuberculosis in the 1950’s.
When we are ill, our bodies temporarily go into a state of very mild depression. Depression saps our energy and our motivation, making it extremely difficult for us to be active. There is an advantage to feeling this way when we are ill – we are anchored on the couch watching bad TV, and not out running marathons, giving our bodies a greater chance to recover. Iproniazid was a drug being tested for tuberculosis, and the physicians conducting the trials noticed a surprising effect – iproniazid boosted patients’ energy levels and made them feel better. For the first time ever, it looked as though there might be a drug to treat depression. Doctors and patients alike could barely believe it – but following a successful trial for depression, iproniazid was soon in widespread use. However, it was a case of quickly come, quickly go. As it proved to be very dangerous to the liver, iproniazid had to be withdrawn soon after it came on the market.
Iproniazid failed, yet it can still be hailed as one of the most important drugs discovered in the twentieth century. It was the drug that was discovered by accident and proved the world wrong, showing that a disease previously thought untreatable pharmacologically, could, in fact, be treated with drugs. And had the anti-depressant properties of iproniazid not been noted, researchers might have missed another drug, whose anti-depressant actions were also discovered by accident, and which was ultimately to write the story of depression for the next six decades.
Scientists were making tiny changes to the structure of chemical compounds used as anti-histamines in the hope of making them safer and more effective. One of the compounds born from this work, imipramine, had a pronounced mood-elevating effect and became the first safe and effective anti-depressant. Indeed, imipramine is sometimes still used in the clinic today.
In the last few decades, the advances in molecular biology techniques and technology have been breathtaking. We can put a tumour into a mouse and watch it grow in real-time, we can not only see cells, but can make them glow in the dark and watch as different cells interact with each other. Biomedical imaging is particularly invaluable for studies of the brain, which, as fits its crucial role in life, is very well protected and hard to access for study. We can now use X-rays, chemicals and magnetism to examine not only the structure of a living brain, but also how much blood each region receives and how much energy is used up, helping us to understand how the brain works when it is well and how the brain works when it is ill.
But researchers in the 1950’s didn’t have these tools. They didn’t have the work of previous scientists to guide them in their understanding of depression. What they did have was imipramine. Today, our understanding of the biochemical pathways underlying most disease is immense, and we can logically identify steps in these pathways where we can intervene to prevent and halt disease progression. This is called rational drug design. However, most drugs were discovered by accident, so it was not a case of “let’s design something that works,” rather, it was “We’ve found something that works. Let’s find out how.”
Studies of imipramine gave rise to the monoamine theory of depression. Simply put, our brains and moods are regulated by a finely balanced collection of hormones and chemical transmitters, with serotonin and noradrenaline being particularly important. Because imipramine and other, similar drugs promote the availability and action of serotonin and noradrenaline (the “monoamine” neurotransmitters ) it was deduced that depression resulted of a deficiency of these hormones in the brain and that depression was best treated by boosting monoamine activity.
The elucidation of the mechanism of action of imipramine and other monoamine oxidase inhibitors (MAO i’s) paved the way for the second wave of antidepressant drug development. During this period, spanning almost fifty years, researchers focused not on searching for new ways to treat depression, but on fine tuning existing drugs to reduce some of the side effects – side effects such as tremor, blurred vision, drowsiness, nausea, increased heartbeat and sexual dysfunction – to name just a few.
The ultimate victory for the second wave was the discovery of Prozac, which is a story in itself, spanning sixteen years of development, doubt and hope, ultimately culminating in one of the most successful drugs of the twentieth and twenty-first century to date, with total sales of $22 billion dollars by 2002.
If MAO inhibitors take up to 6 weeks before having an effect, and if they are only effective in 50-70% of patients, they wondered, was it possible that the monoamine hypothesis wasn’t the complete picture – or could it even be wrong? What if classical antidepressants were treating the symptom and not the cause? And, given that we now have such wondrous technology at our fingertips, why not use that to go back and start again? Why are we still relying on observations made on a drug discovered by chance – a drug with shortcomings – over half a century ago to tell us how a disease works, when molecular biology techniques and tools have improved so much since then?
The third wave of depression research is in its infancy, but it has already come up with some very exciting new ways to think about an old illness. Before iproniazid, it was not plausible that depression could be treated with drugs. Now, it’s starting to look like depression can be prevented – and after decades where we had no choice but to treat the symptom, it looks like we might finally have discovered a cure.
Interesting times, and exciting ones.
 Nutt DJ. The neuropharmacology of serotonin and noradrenaline in depression. 2002. Int Clin Psychopharmacology 17 Suppl 1:S1-12.
 Wong DT, Perry KW, Bymaster P. The Discovery of Fluoxetine Hydrochloride (Prozac). 2005. Nature Reviews Drug Discovery
 Wong ML, Licinio J. Research and Treatment Approaches to Depression. Nature Reviews Neuroscience.