The Confounding Contradiction of Depression

If you currently have or have had depression then you may already be able to tell your MAOIs from your SSRIs, but if you haven’t then what you read here might actually help. Knowledge is power and I believe learning a little something about depression could contribute a bit of control to an otherwise daunting and often underestimated medical condition.

Depression is perhaps the ultimate “common complex disorder”. Unlike pathogens or mutations that affect physical body tissue; depression is a condition that alters the very consciousness and emotional state of an individual making it a truly unique affliction. Throughout the course of our lives 1 in 5 of us will experience depression or anxiety of some kind, yet the majority of people conceive depression  simply as a disease of “sadness” when the truth is much more complex. “Anhedonia”, an inability to feel joy in anything and “congruent memory bias,” the inability to remember or altered recall of specific memories, are extremely common cognitive behaviours in depression that we often inflict upon ourselves on a day to day basis.

It may surprise you to know that modern science can say with little certainty what neuro-physiological changes initiate depression, and linking those that we do think are involved to the broad psychiatric manifestations seen in cases of depression is even harder as human experience and consciousness is beyond the understanding of molecular neuroscience (and by extension, definitely me). But from the murky depths of our own minds patterns do emerge, and as such there are a few good theories out there:

Rather confusingly the best fitting theory of depression is actually based on the drugs WE ALREADY USE to treat it, not a common theme in medicine I might add. “The monoamine theory of depression” states that depressed brains have reduced signalling between neurons via a group of specific chemical neurotransmitters called monoamines. Two in particular called 5-hydroxytryptophan (hereafter referred to as serotonin) and dopamine are released into a synapse to induce electrical signals between neurons in the midbrain. These two neurotransmitters and the resulting electrical signals are most notably perceived as feelings of joy, euphoria, reward and attention. And there is some evidence to back this up, depletion of tryptophan, an amino acid essential for serotonin synthesis in the brain caused mood congruent memory bias, and altered reward-related behaviours. Biochemical evidence exists too, abnormalities of the protein that binds serotonin in the brain called the 1A receptor have been noted in multiple brain areas of MDD patients. Why does serotonin decline in patients with depression? Well search my pockets, you will find no answers.

Rather reassuringly this hasn’t stopped treatment of depression at all, and several drugs for which the theory is named are all targeted at increasing serotonin, and so good feelings, within the brain. The so named selective serotonin re-uptake inhibitors (Those “SSRIs” I snuck in earlier, such as fluoxetine and Sertraline) are the most prescribed group of antidepressants and work in a way best aided pictographically:
neuronSerotonin is synthesised in the presynaptic neuron from tryptophan, from here it is packaged into vesicles and upon nerve impulse firing (see previous article “shedding light on neural networks”) is released in the synaptic cleft (the space between neurons).  Serotonin then binds to receptors on the postsynaptic neuron, stimulating a similar nerve impulse. However, serotonin is also able to control its own release: By binding to the 1A receptor on the presynaptic neuron it prevents continued release of serotonin, allowing the proposed channel protein SCL6A4 to re-absorb serotonin in the presynaptic neuron to be destroyed.

This is where SSRIs come in. Believed to bind to SCL6A4 and prevent the re-absorption of serotonin, it allows serotonin to remain in the synaptic cleft for longer and therefore stimulate nerve impulses in the post synaptic neuron for longer, and so increase the degree of monoamine signalling.

Let’s not forget our friend dopamine:

Dopamine too is a monoamine consistently found reduced in the blood of patients with depression, as a result of decreased synthesis and degradation in the brains of these patients. Neurons that signal using dopamine (as opposed to serotonin) are found in a region of the brain called the substantia nigra that degenerates during Parkinson’s disease. Interestingly the motor impairment (shaking) in this disease is often preceeded by major depressive disorder in 50% of Parkinson’s cases!

This brings me quite nicely to my final point. Since so little is known about the basis of psychiatric disorders their treatment has been almost purely symptomatic for the last 60 years. Thomas Insel, director of the US National Institute for Mental Health was quoted in 2013 as saying “In the rest of medicine, this would be equivalent to creating diagnostic systems based on the nature of chest pain, or the quality of fever.” This was following the release of the 5th edition of the diagnostic and statistical manual of mental disorders (DSM-5), that diagnoses psychiatric conditions based on common symptoms presented by each condition. Despite the strong agreement with Insel by many psychiatrists that this method is outdated, the shift to a more objective and molecular diagnostic is years away given the outstanding complexity of these diseases. But keep the hope, recent booms in neuroscience research are a sure step towards a less archaic means of treating depression and other mental disorders.

A new approach spearheaded by the same Thomas Insel called “Research Domain Criteria” or RDoC is already doing just that by utilizing genomic sequencing technology, fMRI imaging techniques and cognitive science to develop an entirely new platform for diagnosis based on new data being attained all the time, rather than the laboured DSM-5 classification. While still in its infancy this new approach aims to start looking at broader groups for diagnosis rather than classification of different disorders by the symptoms they present. For instance by looking at a group of patients with different disorders but all experiencing anhedonia will not only allow a greater insight into a unifying cause for these symptoms, but also speed up treatments in the future.

Of course there are always two sides to each argument and depression does in some sense stand alone from other psychiatric disorders such as schizophrenia in that it imparts a greater emotional influence on the sufferer – if “precision medicine” were able to prescribe a pill for the treatment of emotional conditions, would you want it to? Of course this is a quandary we wont face for some time, but worth a thought.


Some interesting but by no means comprehensive reviews on depression, its far too huge for 3 articles!

Hasler G (2010). Pathophysiology of depression: do we have any solid evidence of interest to clinicians? World psychiatry : official journal of the World Psychiatric Association (WPA), 9 (3), 155-61 PMID: 20975857

Martinowich K, Manji H, & Lu B (2007). New insights into BDNF function in depression and anxiety. Nature neuroscience, 10 (9), 1089-93 PMID: 17726474

Frances, A. (2013) One manual shouldn’t dictate US mental health research Available at:…/dn23490-one-manual… (Accessed: 07/01/14).

5 responses to “The Confounding Contradiction of Depression

    • Thanks so much for sharing the blog (and your honesty about the subject!). I can’t speak for Joe (author of the blog) but the reason I mentioned to him that it might be a good topic is because there are so many people out there suffering with depression, and those that I know felt more comfortable about being on medication or just in living with the condition when they understood it. Knowledge is power!
      You’ve got some great blogs up on your site, thanks for featuring us amongst them.

  1. Hey there just wanted to give you a quick heads up.
    The words in your article seem to be running off the screen in
    Internet explorer. I’m not sure if this is a formatting
    issue or something to do with browser compatibility but I figured I’d post to let you
    know. The design and style look great though! Hope you get the
    issue fixed soon. Kudos

    • Hi,
      Thanks for letting us know! Last time this happened to me it turned out it was just that I wasn’t using an up to date version of internet explorer. Unfortunately as we host through wordpress we don’t have a huge amount of control over the webscript.
      Thanks for the comment,

  2. Although as human beings we know very little about
    how the brain actually works, scientists have been able to discover that we can alter the way our brains function so that
    we can get rid of learned behavior. I say 15-20 years because its hard to determine when the symptoms began and when they ended.
    Why is the anxiety in learning math stronger than in other subject.

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