We don't know what is wrong with the brains in people suffering from depression. On theory is that depression is connected to the amount of the neurotransmitter serotonin inside our brains. (Photo: Colourbox)

Cause of depression still eludes us, says neuroscientist

Almost 500.000 Danes suffer from depression. We don't know why they are sick and we give them medicine to treat symptoms not causes, says neuroscientist.

Albert Gjedde, MD, is a neuroscientist and probes people's heads to see how their brains work.

He is head of the Department of Neuroscience and Pharmacology at Copenhagen University. Gjedde is one of the people who look at the effect of antidepressant SSRI drugs.

Gjedde explains we don't really know what is wrong with people suffering from depression but looking at the symptoms we get a good idea of where the fault could lie within the brain.

Right now the eyes of neuroscientists are focused on the endogenous chemical in our bodies called serotonin, a neurotransmitter that regulates the intensity of our emotions, says Gjedde.

Serotonin receptors are found everywhere in the brain but are especially concentrated in the frontal region of our brains called the prefrontal cortex.

Neuroscientists believe that the prefrontal cortex regulates our personality and social behaviour. Another important function is the structuring of thoughts and actions related to our personal goals.


Regardless of the emotion being happy or sad it would seem SSRI drugs dampens the experienced intensity of the emotion.

People in treatment with SSRI dugs describe it as if the peak of their emotions are cut away.

This presumably explains why antidepressants will work on some people, says Gjedde and explains:

"With the SSRI drugs, the worst of the negative emotions isn't felt with the same intensity."

Sadness and happiness are caused by serotonin

The latest brain research point towards the improbable truth that depression is possibly inherited from previous generations.

This is called epigenetics which looks at inherited changes in our genes.

Not the depression but special genes are inherited and these genes can make us disposed to developing the illness during our lives.

The SSRI drugs will work differently on different people due to the fact that our brains are not wired in the same ways.

Human brains contain 100 billion neurons and each neuron contains thousands of receivers and transmitters individually coded to transmit a signal consisting of one or more neurotransmitters through the brain.

Each receptor is a molecule with a special structure that only allows specific types of neurotransmitters to fit on the receptor -- think of it as lock and key, says Gjedde.

Scientists working to unravel the cause of depression are especially interested in two receptors from the family of 5-HT receptors fitted for serotonin.

When the 5-HT1A and 5-HT2A receptors are hit by a serotonin molecule they respond by changing the electrical activity in its parent neuron.

When we experience the sensation of different emotions it is probably caused by these changes in neuron activity.

Neuroscientists know the 5-HT1A receptor turns up the activity while the opposite holds true for the 5-HT2A receptor, turning the activity down.

SSRIs mess up the cleanup

When a 5-HT1A or 5-HT2A receptor is busy with a serotonin molecule it is not allowed to stay in its active state for long.

To limit neuron activity, our brains are regularly swept by packs of neurotransmitter transporters which is special proteins that clear out the receptors and send the used neurotransmitters to other parts of the brain.

SSRI drugs work by blocking these transporters, in return creating a build-up of serotonin activity in the brain.

The effect seems to be, says Gjedde, that increased serotonin activity counteracts the depression.

Most of the time this holds true for patients but the complete picture is more complex than so, says Gjedde.

"5-HT1A and 5-HT2A ratios vary a lot between individuals and that means the effect will also vary," says Gjedde.

This is why people can react very differently to treatments with SSRI drugs.

Lazy neurons slow down serotonin production

Serotonin is produced inside a cluster of neurons located in a small area inside the brain stem that neuroscientists call the raphe nuclei.

Each of these neurons project a long nerve fibre known as axons and at the end of the axon sits a protein that produces neurotransmitters.

Inside the raphe nuclei, the proteins produce serotonin from tryptophan, an amino acid essential for human life.

"One of the theories on depression is simply that it is caused by laziness in the neurons producing and releasing serotonin," says Gjedde.

The neurons inside the raphe nuclei would be an obvious place to poke at to find a treatment for depression but doing so is easier said than actually possible.

"You would have to mess around inside the intricate machinery of the neuron," says Gjedde, explaining it is way more difficult than blocking the reuptake of serotonin -- which happens outside the neuron.

Another treatment attempted by neuroscientists was to give patients more tryptophan as a means to boost their serotonin production but the treatment proved limited in effect, says Gjedde.

"This suggests that serotonin isn't the only thing causing depression," he says.

Brain structure is affected by outside stimuli

Gjedde explains that neuroscientists are not only looking at serotonin receptors in the search for depression causes.

Instead it would seem the combination of both a hereditary disposition  and an outer stimuli makes a likely culprit.

So even if the brain has a less fortuitous ratio of the 5-HT1A and 5-HT2A receptors and a certain level of serotonin production in the raphe nuclei it doesn't necessarily equal depression.

A lot of people can live with the disposition and won't experience severe depression because they are not exposed to the stimuli from the world around them.

Contrary, says Gjedde, people can be exposed to the outer stimuli but won't develop depression because they don't have the disposition.

Gjedde says neuroscientists have to consider all these factors if they hope to uncover the cause of depression.

The brain is constantly changing

Brain scans have shown that the ratio between 5-HT1A and 5-HT2A serotonin receptors is also altered by outer stimuli.

This is connected to the phenomena or neuroplasticity where our brains constantly rebuilding and changing the structure of its neurons.

"Your amount of receptors keep changing throughout the day and when night comes they are rebuild anew when we sleep," explains Gjedde.

"It's a tremendously delicate mechanism and we don't know nearly enough about it," he says.

Big Pharma abandons brain research

Neuroscientists need to learn more about the brain and the only way to do so is through more research, says Gjedde.

The problem, he explains, is that 10 out of 12 of the largest pharmaceutical companies have left the brain research.

This is mainly due to the fact that it has been decades since neuroscientists had their last major breakthrough.

Instead the pharmaceutical companies have satisfied their needs with a drug that at times will prove inadequate for depression treatment, says Gjedde.

"There is no doubt that there is a relatively large group of patients where the SSRI drugs don't have any effect at all," he says.


Translated by: Kristian Secher

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