Depression - Treatment & Needs

Ancient Greek and Roman physicians recognised and described depression or melancholia (literally meaning an excess of black bile) more than two millennia ago.

Today we know depression is a physical brain disorder, but this insight dates back less than 50 years. For most of human history, sufferers have been regarded with suspicion, often locked up for years in asylums for their own safety. Florence Nightingale and Winston Churchill, who described bouts as his "black dog", both suffered in this way

Before the mildly antidepressant effect of amphetamines was discovered in the late 1930s, nothing could be done to make life better for patients. At about the same time, electroconvulsive therapy (ECT) was used for the first time, becoming the standard treatment by the mid-1950s. ECT is still used today to treat cases of very severe, drug-resistant depression.

Today, patients having ECT are first put to sleep and given a muscle relaxant, so that they don't suffer the side-effects of earlier versions of this treatment.

What is the cause?
The changes in mood, thinking and perception in depressed people are believed to be caused by alterations to brain chemistry. Something, possibly the result of exposure to prolonged, severe stress, upsets the ability of neurotransmitters to pass messages between nerve cells. The activity of the monoamine neurotransmitters serotonin and noradrenaline is particularly important in the brain areas that control mood and emotion, and this activity is thought to be inadequate in the brains of depressed patients.

The first clues implicating neurotransmitters in depression came from studies dating from the early 1950s onwards on reserpine, a drug used to reduce high blood pressure that also causes a depressed state in some patients. Researchers found that reserpine causes a loss of serotonin from the brain and it was already known that serotonin was a neurotransmitter. So the hypothesis became that depression is caused by not enough serotonin.

The first real antidepressant was stumbled upon at about the same time. Iproniazid was being used to treat tuberculosis but it also made patients very elated. Seeing this effect, doctors wondered whether iproniazid might be helpful in depression. It was, but it proved too toxic for routine use. However, studies in animals (mainly rats, although rabbits and cats were used in some experiments) showed how iproniazid achieves its beneficial effect. It inhibits brain enzymes called monoamine oxidases, which, as their name suggests, break down the very monoamine neurotransmitters that are implicated in depression. Researchers then developed other medicines that worked in the same way and some of them are still occasionally prescribed today.

The second class of antidepressants - tricyclics - was also discovered by chance. Imipramine is an antihistamine that was used to treat allergies but it too produced elation and so was tested in depressed patients. Subsequent animal research showed that tricyclics also alter monoamine neurotransmitter activities in the brain. However they do it not like iproniazid, by disrupting the brain enzymes, but rather by preventing neurotransmitter removal via uptake by brain cells. Monoamine neurotransmitters are often recycled rather than destroyed. The new treatment meant that the neurotransmitters hung about in the gaps between brain cells for longer than usual, thus helping to counteract any deficiency in neurotransmitter activity.

The monoamine oxidase inhibitors and the tricyclics have many unwanted side effects unrelated to their effects on monoamines. So, in the 1970s, the search for cleaner drugs that blocked only the reuptake of serotonin - the selective serotonin reuptake inhibitors (SSRIs) - began. Rat brains were studied to see how they handle serotonin and molecules related to imipramine were adapted to make them more specific. The first SSRI to be launched in the UK was fluvoxamine in 1987, followed by probably the most famous SSRI, Lilly's Prozac (fluoxetine) in 1989.

Spoof ad for the most famous SSRI, Prozac. Rats were involved in its development.

To test that their candidate medicines were indeed inhibiting serotonin reuptake, the Lilly researchers treated animals - usually rats - with a chemical that is taken up into serotonin-producing nerve cells by the reuptake mechanism and then kills those same cells. A successful SSRI should stop the cell-killing chemical from reaching its destination allowing the rats to carry on making serotonin. Fluoxetine did just that. As with all new medicines, just because the researchers had found a candidate drug that did what they had hoped it would in animals, there was no guarantee that it would actually help counter depression. That would only be confirmed after safety testing in animals allowed clinical trials in patients.

All the medicines mentioned above are primarily treatments for unipolar depression. In bipolar disorder, antidepressants can be used during depressive episodes but patients are more often treated with mood-stabilising medicines such as lithium and anti-epileptics. Care must be taken not to precipitate a manic episode when mixing mood stabilisers and antidepressants.

Fluoxetine and other SSRIs have revolutionised the treatment of depression - they have fewer side-effects than older antidepressants and are much safer if patients overdose. Recent reports that SSRIs increase the risk of suicide in children and adolescents are being investigated; meanwhile psychiatrists emphasise that the risks of not treating depression must not be overlooked. Nevertheless, better antidepressants are needed and to find these we need to understand what causes depression much better. Currently, only 40-50% of patients recover on the first antidepressant they are given and it may be several weeks before patients feel the benefit of their prescription. Moreover, about 10% of patients do not respond to any currently available drug or to non-pharmacological interventions such as ECT or psychotherapy, and most people who recover from depression have relapses.

Next Section: Future Prospects