Depression is a serious illness, and a leading cause of mortality, morbidity and suffering worldwide. Major, unremitting depression will be experienced by 15% of people worldwide, with 1 in 3 of us experiencing some depressive episodes at some point or points in our lives. It’s estimated that depression costs the US economy, directly and indirectly, over $43 billion per annum.
In a previous post, I described how depression was defined by Hippocrates, but despite
his insights in Ancient Greek times, it was not until an unexpected, mood-elevating side effect of a drug being tested for TB was noticed millennia later that the world came to believe that depression could be treated with drugs.
The ideal medical situation is to understand the illness and design the treatment, but in the 1950’s, working with an illness not understood at the molecular level and without the techniques and technologies modern biomedical scientists take for granted, this was impossible. Even though drugs such as imipramine were far from ideal (most notably due to a slow onset of action and the fact that as many as 50% of patients don’t respond), these drugs were studied carefully to elucidate their mechanism of action, and from determining how the drugs worked, researchers devised the monoamine hypothesis of depression to explain how the disease worked.
The monoamine hypothesis stood alone for sixty years, and still stands. But these are interesting times for depression research, in which scientists are starting to move away from the monoamine theory which was universally accepted for so long, and come up with several interesting new theories to account for depression. After decades in which our only option was to treat the symptom, could the “third wave” of research be about to yield a cure?
Stress is an interesting phenomenon – three different people could respond to the same stress in a hundred different ways. The stress that we feel is controlled by a series of chemicals acting in sequence in a very sophisticated pattern. This pattern is known as the HPA or stress axis. The more active our HPA axis is, the more stressed we are. However, even though the HPA axis is universal, how we behave when subjected to stress is highly individual – and how our bodies react to stress is also individual and unpredictable.
Depression is characterised by a number of imbalances which can be in either direction. Some patients lose weight whereas others will gain it. Sleep disturbances are common but there’s no telling whether a patient will be insomniac or hypersomniac.
Could stress be causing depression?
Clinical depression is profoundly different from simply feeling stressed, or sad, or afraid. Yet most depression is reactive – triggered by a particularly stressful event in the patient’s life. Noradrenaline (NA) is a chemical with many functions throughout the body, but it is found at high levels in the cerebrospinal fluid when the stress axis is switched on – and NA is found at high levels in depressed patients all the time, suggesting that their stress axis is in overdrive even when they report felling unstressed . Successful anti-depressants decrease the activity of or “downregulate” the stress axis – and the stress theory would explain why so many patients opt for counselling as well as drugs.
There is an obvious, and yet unanswered question though: Is stress more of a cause, or more of a consequence? Personally, I am happy to sit on the fence for the time being, but it is an interesting theory.
An equally interesting theory, and one which recently gave the world its first ever drug not based on the monoamine theory, involves the circadian rhythm. We are all familiar with the concept: I was surprised to learn that there is solid biochemical evidence for it. A case in point for this: testosterone levels peak in young men first thing in the morning, enabling them to face the day with – let’s term it “renewed vigour.”
The sleep disturbance element of depression was a particularly strong suggestion that depression is linked to a fundamental change of the circadian rhythm, and a drug originally developed for jet lag has become the first ever anti-depressant not to be based on the monoamine hypothesis. The drug, agomelatine, encourages the action of the hormone melatonin, which is responsible for keeping our circadian rhythms ticking to the right beat – and it has other, indirect effects which also boost patients’ moods and improve their quality of life, namely, sleep and sex. Agomelatine was originally developed to help people sleep after jet lag – and because it works through a completely different set of chemicals to classical monoamine antidepressants, patients do not lose sexual function.
But, for me, the most interesting new theory is BDNF-dependent neurogenesis. And the reason this is so exciting is that while everything else is a treatment, BDNF could give us the ultimate cure.
Our entire brains and bodies are wired together by electrical connections called neurons, which carry signals from one brain region to another, from our brain through our spinal cord to everywhere else in the body, and back again. If you burn your hand on a hot plate, nerves will carry a message to your brain, through the brain until it reaches the part that makes sense of it, and another set of nerves will carry a signal back to your hand, causing pain and causing you, on reflex, to take your hand away from the plate. It is impossible to understate the importance of neurons in keeping the body not only safe and healthy, but alive.
But these neurons can’t work in isolation. Just as a lamp needs to be plugged into a socket before it can transmit enough electricity to light up, a neuron has to have a special contact point to plug onto before it can transmit a signal. We now know that the hippocampus – a part of the brain important in higher cognition – has much fewer neural connection points in a depressed state than a non-depressed hippocampus. If you can imagine it, a depressed person’s brain is like a kitchen with too few plugs for the number of appliances needed, with several unused power cables left hanging for every one that is plugged in and working. All we need, to help the kitchen work to its full capacity, is more plugs.
Neurogenesis is the ability to make and refine new neurons and neural connections. Few areas in the adult brain are capable of it, but the hippocampus is. The ability to undergo neurogenesis depends on a chemical called BDNF, and the number of new neural connections produced in the hippocampus is dramatically decreased in a depressed brain, but when anti-depressant drugs work, this ability to make new neural connections is rescued . It takes time to make and refine functional new neural connections – typically four to six weeks. Exactly the same time frame before any anti-depressants we have now start to take effect.
If BDNF were given directly as a drug, it could potentially strat to build new neural connections straight away. Neurogenesis will still take time, but the fact that BDNF itself will not have to be synthesised from scratch by the body means that it could take less time before the patient starts to feel better. When a patient is seriously depressed, he or she may well be feeling suicidal – and such a person should not have to wait eight weeks for their treatment to work. Importantly, BDNF could be highly specific for depression, which will make it not only more powerful as a drug, but also much safer, with much fewer side effects. That said, it will have to be tested very carefully before being given to patients. There is a possibility that if too much BDNF is given, it won’t stop at creating new neural connections. It may also create cancer.
But there is a major obstacle in the way of the development of BDNF as a therapy.
This is where depression becomes political.
Every other drug treats the symptoms of depression – we have a range of treatments, but no cure. BDNF could be a cure. But while a cure would be good news for patients, big pharma companies will be somewhat less enthusiastic at the prospect that patients could be treated once and be cured. As long as depression treatment remains symptomatic, the majority of patients will stay on it for their entire lifetime, and anti-depressants are worth a lot of money.
Eli Lilly is a pharmaceutical giant with a wide range of interests, but when it was on patent, Prozac accounted for 20% of its annual sales. Now that it is off patent, there is a greater hope that pharmaceutical companies will look into BDNF as it will no longer be competing with other, more long-term treatments (in 2001, when Prozac came off patent, Lilly envisioned losing up to 90% of their customers to generics). Academic laboratories are no less excellent than pharmaceutical companies as far as research is concerned and don’t have the same market considerations, but it is a hard truth that even if they develop a BDNF compound, they will lack the resources to bring it to and through clinical trials.
BDNF is scientifically promising but due to financial considerations – or financial conflict, it is hard to see it coming to the clinic soon.
 Wong ML, Licinio J. Research and Treatment Approaches to Depression. Nature Reviews Neuroscience.
 Frontiers in Neuropharmacology (27) 2006 180-192.
 De Bodinat C, Guardlola-Lemaltre B, Mocaer E, Renard P, Munoz C, Millan MJ. 2010. Agomelatine, the first melatonergic antidepressant: discovery, characterisation and development. Nature Reviews Drug Discovery 9:p628.
 Olivier Berton & Eric J. Nestler. New approaches to antidepressant drug discovery: beyond monoamines. Nature Reviews Neuroscience 7, 137-151 (February 2006) [For those who are interested, I particularly recommend this paper]