Root Causes of Depression

Depression is characterized clinically by a low mood, apathy, and in some cases fatigue. It affects close to 15 million American adults and incurs an enormous economic burden, in the order of tens of billions of dollars each year in the United States alone. Serotonergic medications represent the vast majority of treatment options for depression and is predicated on the Serotonin Hypothesis. However, favorable treatment responses using pharmacological therapies are limited to 40-60% of individuals which necessitates continued research and investigation in this space. 

The Serotonin Hypothesis

The Serotonin Hypothesis has been the dominant explanation for depression during the past fifty years and essentially states that low concentrations of serotonin induce depressive episodes. Based on this premise, SSRIs are often used as a first line therapy with goal of increasing concentrations of serotonin in the brain to ameliorate symptoms of depression.

In the past 5 years this hypothesis has been explicitly challenged by a multitude of scientific publications. The most recent of which, a landmark research paper in Nature Molecular Psychiatry, assessed several areas of research surrounding the Serotonin Hypothesis and found that “the main areas of serotonin research provide no consistent evidence of there being an association between serotonin and depression, and no support for the hypothesis that depression is caused by lowered serotonin activity or concentrations.”

This scientific challenge has generated many alternative explanations to elucidate the true underlying pathophysiology of depression. In truth, there are a multitude of suspected mechanisms, but we will only explore a few key areas with the most robust research.

Underlying Mechanisms of Depression

Novel research conducted within the last few years suggests that dysfunction of both glutamatergic and gamma-aminobutyric acid (GABAergic) systems play a role in the pathophysiology of depression. Gamma-aminobutyric acid (GABA) is an inhibitory neurotransmitter that prevents excessive neuronal excitability and is the primary molecular target of anxiolytic drugs like Xanax and Valium. By contrast, glutamate, an excitatory neurotransmitter, is involved in neuroplasticity, cognitive function, and memory consolidation.

Gut health has continued to evolve over the past decade but recently has warranted more attention in the treatment of depression. Newer studies are showing that the microbiome, or the collection of trillions of neurons in our gut, have a direct impact on our mood and cognition primarily mediated through Vagal Nerve signaling.

The Hypothalamic Pituitary Adrenal Axis has also been directly implicated in the physiology of depression. The HPA axis mediates the homeostatic stress response and is responsible for the generation of cortisol. HPA axis dysfunction, usually secondary to chronic stress, may precipitate depression by negatively impacting neuroplasticity, increasing neural inflammation, and leading to structural changes in the brain’s memory center.

Not surprisingly, chronic inflammation has also been correlated with depression. In the presence of neural inflammation, Tryptophan, the serotonergic precursor, is shunted away from serotonin production and towards the production of a neurotoxin called quinolinic acid. Which has been implicated in depression.

Lastly, and possibly the most important, Neuroplasticity has begun to gain more attention in the role of depression. Researchers are finding that there may be issues with neuronal structure and the brains ability to form new synapses in individuals with depression. However, new research is showing that nutritional modifications, medications, aerobic exercise, and possibly the medical use of specific psychedelics may positively influence neuroplasticity.

The further away you are from shore, the deeper the ocean gets, and it seems we are just now scratching the surface of some key neurobiological principles and the influence they have on depression.