Looking on the Bright Side of Clinical Depression

A photograph showing a young man sitting alone near a beach, looking very down-hearted.

New Hope

A revolution in the treatment and understanding of clinical depression may be looming.  And specialists are already talking about one of the strongest discoveries in psychiatry for the past two decades.  For the 350 million people who suffer from the illness worldwide, this could potentially mean light at the end of the proverbial tunnel. 

If you have ever been plagued by feelings of worthlessness, sadness, and lack of hope, you may be suffering from depression.  Clinical depression is different from being in a bad mood or having a bad week – it is a debilitating condition that can prevent you from enjoying any social activities, or even cut your life prematurely short in the worst cases.


A hand-written note illustrating the idea of recovering from clinical depression... or not. The note reads "I'm Fine", but the words: "depressed", "sad", "hurt", "confused", "lonely", "unloved", "judged", "misunderstood", "insignificant", "broken", "dying insi" have been stricken through.The Science of Depression

Major depression is characterised by an episode of sadness or apathy, along with other often complex physical symptoms, that lasts for at least two consecutive weeks and is severe enough to interrupt daily activities.  Depression is NOT a sign of weakness or a negative personality.  It is a major public health problem.

But what goes on “inside” a depression sufferer?  Is there a biological basis for these intense feelings of sadness?

In the past, clinical depression has often been described as being simply a chemical imbalance in the brain.  Specifically, scientists believed that a lack of one of the key neurotransmitters was to blame – serotonin has often been referred to as the “feel good” chemical.

However, the only real evidence for this was that when some depressed people were prescribed drugs designed to increase their serotonin levels, it helped alleviate their symptoms.  But while a number of hormonal chemicals are most certainly involved in the illness, this view does not begin to capture how complex clinical depression really is.


Clinical Depression and Hippocampal Atrophy

A set of two digital imaging brain scans showing increased bilateral hippocampal activity in patients with clinical depression compared to controls. Source: Johnston et al 2015
Increased Bilateral Hippocampal Activity in Depressed Patients compared to Healthy Controls  Source: Johnston et al. (2015) “Failure of hippocampal deactivation during loss events in treatment-resistant depression”, Oxford University Press.

In recent years, medical scientists began to notice that the brain cell growth and connections may actually play a larger role.

When we look at the brain of a clinical depression sufferer, studies show that the hippocampus tends to be much smaller than average.  Other areas of the brain are also physically affected, but this particular region of the human brain controls memory and emotions.

And the longer a person has been depressed, the smaller the hippocampus becomes!

The cells and neural networks literally deteriorate over time.

As it turns out, stress may actually be the main trigger in the decrease of new neurons in this area of the brain.  Studies have shown that when this region of the brain is regenerated and new neurons are stimulated, the mood improves.

A set of PET scans showing brain activity in the depressed brain versus a control.
PET Scans of Brain Activity in Clinically Depressed Patients versus Healthy Controls Source: WebMD

Interestingly, many modern drugs including those which affect serotonin levels, have an indirect effect on the growth of brain cells, which is likely the reason why serotonin-based drugs seem to help some patients.  But not for the reasons that were previously thought.

Instead, the drugs promote the release of other chemicals that stimulate neurogenesis – the growth of new neurons.  On that basis, scientists now believe the focus should be placed on drugs which directly affect neurogenesis.

While neural cells and chemicals may be at the forefront of this process, many genetic factors have been identified as well.


The Serotonin Transporter Gene

A set of diagrams showing the allelic variation of serotonin transporter 5-HTT.
Serotonin Transporter Gene and Function.  Allelic Variation of the Serotonin Transporter Gene (5-HTT): The long (L) allele (represented in orange) of 5-HTTLPR produces significantly less 5-HTT mRNA and protein expression, than the short (S) allele (in blue), leading to higher concentrations of serotonin in the synaptic cleft. Source: Dialogues in Clinical Neuroscience

One particular study determined that a variation in the serotonin transporter gene leaves some individuals more vulnerable to depression.

Everyone has two copies of this gene – one is inherited from each parent.

The serotonin transporter gene can be either “short” or “long”.  After tracking 800 young adults over five years, the studies revealed that 33% of individuals with one short version became depressed after stressful life events.  People with two short genes fared even worse.

On the other hand, those individuals with two long genes were more resilient to clinical depression, despite experiencing similar life stresses.

Many other genes have been identified which increase the likelihood of depression.  This makes sense considering that clinical depression and bipolar disorder both run in families.

Studies of identical twins show that if one has bipolar disorder, the other twin has a 60-80% chance of developing the condition too.

There is a huge list of other variables that studies suggest might be at play: amygdala, circadian rhythm, cytokines, mono-amines, stress, trauma…

Although anti-depressant drugs and psychological treatments, such as cognitive behavioural therapy (or CBT), do help many, they are not a cure.  Many people also do not respond to existing therapies.


An Inflamed Mind?

An artwork depicting a brain in flames - The Inflamed Mind.
Is inflammation causing your depression?

The new theory relies on the idea that some people are betrayed by the errant behaviour of their body’s own defence mechanism – the idea that the immune system might be altering brain function.

The immune system can be your very best friend… or your fiercest enemy.  Inflammation is part of the immune system’s response to danger. 

Too little inflammation, infection can get out of hand.  Too much, it causes damage.

Depression and inflammation often go hand in hand.

As the immune system reacts to an infection, the body becomes inflamed and people often find that their mood changes too.  Their behaviour may change, and they can become more irritable, less sociable, feel sleepier and more withdrawn.  They may even fall into patterns of negative thinking.

Now, there is evidence suggesting inflammation may be more than something you find in some depressed patients.  It could be the cause for their illness.

The unusual correlation was noticed by doctors at an arthritis clinic at Glasgow Royal Infirmary who found that when patients were given specific anti-inflammatory drugs in order to tame their wayward immune system, their mood appeared to improve.

In future, measuring inflammation levels in the blood could become routine in the treatment of clinical depression.


Looking On the Bright Side…

A photograph showing a Fluoxetine hydrochloride capsule being held between index and thumb fingers. Photograph: NaturPhilosophie
Could the new approach to treating and understanding clinical depression spell an end to anti-depressants, at least for some individuals?  Photo: NaturPhilosophie

Whatever the root cause or causes of depression, it is crucial to remember that clinical depression is a disease with a physiological basis, with added psychological and social implications.  Not a weakness that sufferers can “get over” through sheer will power.

Just like heart disease, diabetes or cancer, shedding light onto the condition is of the utmost importance, in order to bring funding and proper research.  We must think differently if we want to see the therapeutic breakthrough that will potentially end the disability and personal suffering that result from this condition.

Although the research may not produce a panacea, a one-size-fits-all treatment, the new approach involving the immune system will certainly offer much renewed hope to the many hundreds of thousands who do not respond to conventional treatments.


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