Mental illnesses are on the rise in many societies around the globe, and

depression is the most common among them. It affects up to as many as 1

• Depression in 4 people and is the leading cause of disability worldwide. With symptoms

• Monoamine such as persistent sadness, fatigue, and difficulty completing everyday

• Serotonin tasks it can be extremely difficult for those suffering to live a normal life.
On top of having this disorder people will also have to deal with the stigma
• Stress
that comes along with it. Many people still hold onto the belief that
• HPA Axis
depression is a choice, or ‘all in your head’. However, scientific research
• Cortisol
increasingly shows that there are strong biological factors that can cause it.

It’s All in Your Brain

Synapses, the junctions between neurons,
allow different parts of the nervous system
to communicate with each other. Once an
action potential reaches the end of a neuron
chemicals called neurotransmitters are
released into the synapse. These bind to
receptors on the next neuron causing it to
generate its own action potential. One
group of neurotransmitters is called
monoamines (see figure 1). This includes
serotonin, noradrenaline, and dopamine.
They play a role in many important cognitive
abilities such as memory and emotion. Low
levels of monoamines, and particularly Figure 1 - Synapse between two neurons showing
how an action potential travels from one neuron to
serotonin, are thought to cause or
the next
contribute to depression. This is called the ‘monoamine deficiency hypothesis’ and has been the
main biological theory of depression for decades.
In the 1950’s a drug called Iproniazid was
developed to treat tuberculosis. This drug
irreversibly inhibited an enzyme called
monoamine oxidase, which breaks down
monoamine neurotransmitters after they are
released into the synapse. This inhibition
causes an increase in monoamine activity
since they are not broken down as quickly
(see figure 2). It caused euphoria and
hyperactivity in the patients who took it, and Figure 2 - The function of monoamine oxidase and
it was the first clue scientists got that these how Iproniazid affects it
neurotransmitters may be involved in
depression. More evidence came when drugs that lowered monoamine levels seemed to induce
depression. Since then many antidepressant drugs have been developed, most of which increase
serotonin levels in the brain.

Further research has given even more evidence to this theory. Tryptophan is an essential amino acid
which the body converts into serotonin. It has been shown that people with depression have low
levels of tryptophan and removing it in recovered patients can cause a relapse. Additionally,
monoamine oxidase levels are higher throughout the brain in depressed people in comparison to
those who are healthy. Alleles of genes associated with monoamine systems have been found that
are more common in people with depression. One of these is the gene for the serotonin transporter,
which lowers serotonin activity by taking it back into the neuron. There is a short allele and a long
allele, with the shorter one being less efficient. This alone, however, does not cause depression
except in those who have had added environmental factors such as abuse.

This theory is not

without criticism.
Drugs which increase • Action Potential – electrical impulse that travels along neurons

serotonin levels act • Neurotransmitter – chemicals that allow action potentials to pass

immediately but from one neuron to the next

symptoms of • Monoamine – a type of neurotransmitter

depression take • Negative Feedback – inhibition of a system by the product it forms

weeks to improve, and • Allele – alternative forms of a gene

in some people don’t • Epigenetics – environmental impacts on gene expression

at all. Also, drugs with • Methylation – addition of a methyl group to DNA stopping

other modes of action transcription, and epigenetic mechanism

are sometimes effective suggesting there may be more to it. There are many different types of
depression, and each person experiences it differently. This theory cannot explain why that would
be the case and therefore there must be other factors involved.

Stress and Depression

Cortisol is the stress hormone in humans and
its release is controlled by the hypothalamic-
pituitary-adrenal, or HPA, axis. This is a
negative feedback loop that connects the
hypothalamus in your brain, the anterior
pituitary gland, and the adrenal cortex. The
hypothalamus produces corticotropin releasing
hormone, or CRH, which sends a signal to the
anterior pituitary to produce
adrenocorticotropic hormone, or ACTH. This
then goes to the adrenal cortex where cortisol
is produced. When a person becomes stressed
their levels of cortisol increase. Cortisol can
then act on both the hypothalamus and
anterior pituitary to lower the levels of CRH
Figure 3 - Hypothalamic-pituitary-adrenal axis
and ACTH respectively. This in turn decreases showing feedback effects of cortisol
the amount of cortisol reduced (see figure 3).

Stress first became important in research on depression when scientists observed that cortisol
levels were around 50% higher in depressed people. Their pituitary and adrenal glands also tended
to be larger and more active than in healthy people. After this was noted research tried to find more
evidence that the HPA axis could be involved in depression. Several studies were conducted which
gives both depressed patients and healthy people synthetic cortisol pills. In the healthy subject’s
overall cortisol levels were reduced for twenty-four hours because of cortisol’s negative feedback
effects. In depressed patients, however, their cortisol levels did not change that much. This showed
that feedback was impaired in those with depression.

One reason the HPA axis hypothesis became so popular is that it can incorporate environmental
factors too. For example, if an infant primate is separated from its mother for a long time then it
increases the activity in the HPA axis for the rest of the primate’s life. There is even some evidence
for this in humans. Depressed women who had experienced childhood abuse had cortisol levels six
times higher than control subjects when exposed to stress. This can occur due to what is called
epigenetics; when the
environment influences
gene transcription. If a
woman in her third
trimester of pregnancy
experiences depressed
or anxious moods this
can cause methylation
in the DNA of the
foetus. Methylation is
when a methyl group Figure 4 - The process of methylation and how it stops transcription
(CH3) is added to a DNA
base stopping the gene being expressed. In this instance it is the gene for cortisol’s receptor (see
figure 4). This cause higher levels of cortisol at three months old.

There is also genetic evidence to back this theory up. Certain alleles are present in higher levels in
depressed populations compared to healthy ones, and due to the differences present between
people it can explain why different symptoms of depression may occur in different people. An
example of this an allele in the gene for the CRH receptor which was more common in those whose
depression had seasonal patterns and started at a younger age. It can also explain the differences in
response to treatments with antidepressants. Patients who showed a faster response to
antidepressant treatment also had a specific allele in the gene for the glucocorticoid receptor, which
binds cortisol.

Research on the HPA axis’s involvement in depression has greatly increased understanding about
the disorder. It links it to stress and the environment you are brought up in which, logically, play an
important role in the development of the disorder. Again, this cannot alone be the cause of
depression as levels of cortisol are only increased in around half of depressed patients. However it
has opened up new areas of research about depression and paved the way for more, and better,
treatment options for those suffering.

Why Does it Matter?

Researching and discovering potential biological causes of depression can be extremely beneficial
in many ways. The most obvious of those ways being the development of new and improved
treatments to help those with the disorder manage it and get better. Antidepressants nowadays
have mainly been based on the monoamine deficiency hypothesis. Selective serotonin reuptake
inhibitors, or SSRIs, are the most common prescribed and they increase levels of serotonin by
stopping uptake back into neurons. These are generally effective but do not work in everyone and
come with a range of side effects. SSRI antidepressant have also been shown to cause changes to
the HPA axis.

Some drugs specifically targeting the HPA axis are undergoing trails right now. The most effective of
these are antagonists of the CRH receptor. One specifically was shown to improve the symptoms of
depression while also keeping normal production of cortisol making it very promising. Other new
treatments not focused on these two theories are also undergoing human trials and seem to show
very promising results. Right now psychedelic drugs are being looked at as a potential ‘cure’ for
depression. This is done by ‘microdosing’; taking a small amount of the drug on a regular basis. The
most common drugs used for this are LSD and psilocybin (or magic mushrooms). Studies have
shown this can be extremely effective, even in people who don’t respond to normal treatments.

Another reason it is beneficial to research depression in this way is that having a strong biological
cause behind a disorder can often be an effective way to reduce stigma. Many people believe that
depression is somehow a choice and that it can be fixed simply by change in attitude. If it was more
common knowledge that
depression can be caused
by your biology then it
• For a slightly more in depth look visit:
may start to be seen more
https://www.health.harvard.edu/mind-and-mood/what-
like a ‘real illness’. This
causes-depression
will lead to more people
• To watch a video about this topic:
asking for help allowing
https://www.youtube.com/watch?v=GOK1tKFFIQI
them to get treatment,
leading to a better quality • More information on stress and depression:
http://sciencenordic.com/how-stress-can-cause-depression
of life for millions of
people around the world.

If you think you may be suffering from depression it is important to receive help.

• Samaritans (confidential support helpline): 116 123

• Papyrus (youth suicide helpline): 0800 068 41 41
• From more information on how to get help: https://www.nhs.uk/conditions/stress-
anxiety-depression/low-mood-and-depression