DepressionMental health

Treating Depression: Are we on the Right Track?


– MSc

Affiliations : UCL, London, UK

Journal reference: doi:10.1016/j.neuropharm.2015.10.034

Summary: While a variety of treatments exists for depression, classical serotonin approaches take weeks to act effectively and many patients remain treatment-resistant. Ongoing studies are thus trying to find novel therapeutics. Read this article to find out more.

What is Depression?

Everyone knows at least one person who appeared to be generally lower on mood than others – that one person that withdrew from your group of friends and is suddenly incredibly difficult to contact and meet. Depression can have many different facets and symptoms, but is primarily defined by low mood, low motivation, and, in some cases, suicidal thoughts. 

Up to this day, researchers and clinicians are still not entirely sure how depression is presented in the brain and how we can treat it most effectively. However, a new modern approach on depression may cast light on the obscurity of this disabling mental health condition.

Depression and the Brain

  • Traditional Idea of Depression

In 1965 Joseph Schildkraut developed the Monoamine Hypothesis which states that low levels of Serotonin (a neurotransmitter from the family of monoamines and of which, to date, the functions are not entirely understood) in the brain causes depressive symptoms

  • Traditional Treatment of Depression

Based on the idea that low Serotonin results in depression traditional antidepressants aim at increasing Serotonin levels and thereby reducing depressive symptoms


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Figure 1 by Gabriel Luiz Bundies

Problems with the Traditional Concept

One major problem with the traditional idea of depression is that antidepressants increasing serotonin do not appear to work as anticipated. Amongst researchers and clinicians, it is well known that antidepressants typically take weeks and sometimes months to work. It is also known that approximately 30% of patients are not responding to serotonin-based antidepressants. 

Another issue with the traditional approach is that studies, which have deliberately reduced serotonin levels in healthy participants, were not able to trigger depressive symptoms, despite the reduced serotonin.

Lastly, current research has discovered drugs that are not serotonin-based, but effectively reduce depressive symptoms within hours. All of this suggests that the role of serotonin in the treatment of depression may be smaller than initially anticipated. 

So what does really happen in the brain during antidepressant treatment and are we on the right track with how we treat depression? 

Unravelling the “Mess”

This article is based on a scientific paper written by Dr. Carl Björkholm and Prof. Dr. Lisa M. Monteggia who reviewed and summarised what we know about new potential explanations of depression and how we could treat depression in the future.

New Perspectives on Antidepressant Treatment

A Protein with Healing-Properties

There are FOUR key letters that make up the core of this article: B-D-N-F. BDNF stands for “Brain Derived Neurotrophic Factor”, however, to understand this article, simply remembering BDNF will absolutely suffice! BDNF is a protein that is widely present in our Central Nervous System (the CNS consisting of the brain + spinal cord), where it is responsible for creating connections between brain cells (called neurons). It is also known to change the strength of these connections (called synapses) and repair damage that has been caused to the brain cells. Over the years, researchers suggested that BDNF may be associated with depression and other mental health conditions. Although scientists are still trying to understand how BDNF is involved in the development of depression, they may already have an idea of how it may be involved in its treatment.

BDNF in Antidepressant Treatment

To understand how BDNF may be involved in antidepressant treatment, we have to take a look at what currently approved antidepressant treatments do inside the brain.

1. Serotonin-based (“traditional”) antidepressants 

As mentioned earlier, serotonin-based antidepressants take longer to work, despite quickly starting to raise serotonin levels in the brain. Recent findings show that once the antidepressant effect does start, the amount of BDNF appears to be rising in two specific regions of the brain: The hippocampus and the prefrontal cortex. 

2. Electroconvulsive Therapy (ECT)

In ECT, the depressed patient receives electric shocks that cause little seizures in the brain. Despite following a controversial method, ECT has been shown effective in rapidly reducing depressive symptoms and suicidality. Recent studies reveal that, after administration, BDNF levels are increased in the hippocampus.

3. Ketamine 

Ketamine was initially only used as an anaesthetic, however, after thorough investigations and research, ketamine was developed into an antidepressant, due to its mood-lifting properties. It rapidly elevates mood which can persist for weeks. Again, research suggests that not only mood is lifted, but BDNF levels in the hippocampus are also remarkably higher.

The Hippocampus 

All effective treatments that are currently in use hint to an involvement of the hippocampus in the treatment of depression. The hippocampus lies in the middle of each side of the brain and is known to be involved in memory. The hippocampus is also responsible for downregulating (that is, reducing or suppressing) the release of stress hormones. Many suggestions have been made that the hippocampus is not functioning properly during depressed episodes or may be even damaged from excessive stress. 

Now, we know that BDNF levels are increased in the hippocampus by all sorts of antidepressant treatment, and that BDNF can repair neurons that are damaged by stress and create new synapses. Based on that, it is assumed that BDNF may repair potential damage and regain the stress-regulation functions of the hippocampus, thereby reducing depressive symptoms. 

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Figure 2: 

Treating Depression: Are we on the Right Track?

Yes and no. Although serotonin may not be the key for treating depression, the fact that serotonin-based antidepressants are still effective shows that serotonin may be still an important factor in triggering antidepressants effect. They still increase BDNF levels and reduce depressive symptoms, just as ECT or ketamine do, even though it might take traditional antidepressants longer to show its effect.

It appears that besides BDNF, other complex biological mechanisms are involved, limiting our current understanding of BDNF actions in antidepressant treatment. We are on a novel and interesting track, however, only further research into this topic can tell whether it’s the right track.

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