Why do we develop depression?

By Nicola Stevenson

Hippocrates (ca. 460–377 B.C.) was the first person to describe depression. His clinical description is similar to how we describe depression today, including symptoms such as a deep loss in the ability to feel pleasure, severe despondency, and a loss of drive. ¹

Depression is very difficult to study and treat because individuals who meet the criteria for a diagnosis can experience a large variety in their symptoms or have no overlap at all. Some experience insomnia while others have hypersomnia (excessive sleeping), some experience an increased appetite while others have a decreased appetite. There are several types of depression shown below in Figure 1. This article is going to focus on Major depressive disorder (MDD).¹

MDD is further complicated as this categorical diagnosis is based entirely on explanations by patients and has no validated biological markers. It relies on patient self-report and clinical observation. Therefore, there is a desperate need to discover biological markers distinctive to MDD.¹

What do we know?

We know that genetic factors play a role in MDD but two-thirds of the factors cannot be explained by genetics. There is a consensus that physical, sexual, and emotional abuse in childhood is associated with an increased risk of developing MDD as well as substance and alcohol abuse, more recent life stressors, social isolation, air pollution, socioeconomic status, and educational attainment.¹ There is a possibility that different environmental stimuli can trigger MDD in different ways depending on the individual’s genetic susceptibility.² However, how these different environmental factors impact our genetic predisposition is not yet known and is of great interest to scientists. 

MDD has several different etiologies (the cause of the disease) including genetic, epigenetic (when environmental conditions affect the expression of your genes – these changes can be inherited) and environmental factors, together resulting in the development of MDD.³ The three hypotheses for the pathophysiology (what goes wrong in the body as a result of the etiologies) of MDD include the monamine neurotransmission hypothesis, hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis, and hindrance of neurogenesis.

The first hypothesis is the monoamine neurotransmission hypothesis which speculates that MDD is caused by the disturbance of excitatory and inhibitory signalling in the brain such as serotonin (5-HT), norepinephrine (NE) and dopamine (DA). Two reasons this hypothesis came about is because they found reduced levels of 5-HT metabolites in patients diagnosed with MDD and that antidepressants increase levels of 5-HT in the brain. However, this hypothesis has several flaws, a few of which we will mention.

Firstly, anti-depressants increase 5-HT levels almost immediately however, patients only feel symptomatic relief 3-5 weeks later.  Secondly, over 35% of depressed patients fail to respond to antidepressants. Thirdly, in studies where they depleted the levels of monoamines in the brain only 15% of the individuals became depressed. This shows that MDD can not be attributed to only the level of monoamines present in the brain.

The second theory is based on the hyperactivity/dysregulation of the HPA axis which results in altered cortisol levels. Excess cortisol in the body can increase inflammation by suppressing the immune system as well as disrupt the balance of neurotransmitters and shrink the hippocampus. Evidence shows that HPA axis dysregulation for extended periods can contribute to the development of MDD or exacerbate symptoms. However, not everyone with HPA-axis dysfunction will develop MDD, it will depend on the other contributing factors and the general susceptibility of an individual.¹ 

The third theory proposes that a decrease in the rate of neurogenesis and neuroplasticity can contribute to the development of MDD. They found that depressed individuals often have lower serum levels of brain-derived neurotrophic factor (BDNF) which is involved in neurogenesis and often have a smaller hippocampus or decreased neurogenesis in their hippocampus.³

Recently, they have found a clear connection between chronic inflammation, the immune system and MDD as evident changes occur in the adaptive and innate immune systems in MDD patients.¹ ² ³  ⁵  The strongest evidence shows an increase in c-reactive protein (CRP), and pro-inflammatory cytokines such as interleukin-1-beta (IL-B), interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF). The data suggests that chemokines have a significant role in neurotransmission which is believed to be implicated in the pathogenesis of MDD, therefore this relationship needs to be studied further as there have been studies showing chemokines which could possible biological markers.¹

Figure 2: A diagram showing a summary of all the factors involved in the pathophysiology of MDD.

We are realising that MDD probably doesn’t have a single cause and that multiple factors might be at play or that there may be similar pathways leading to the same condition. We have just started working on the complicated puzzle of MDD and begun to build the outline however, there is still so much we don’t yet know and many puzzle pieces that still have to be put in the correct place. 

What is the takeaway message?

MDD is a complex condition with a multifaceted aetiology, and our understanding of its underlying causes and mechanisms is still incomplete. There are significant challenges in diagnosing and studying depression due to the variability in symptoms and the absence of validated biological markers. There are various hypotheses regarding the pathophysiology of MDD but none alone can fully explain the condition. More research is needed to better understand MDD and to discover distinctive biological markers to improve the diagnosis and treatment of this debilitating condition. 

References:

  1. Nemeroff CB. The State of Our Understanding of the Pathophysiology and Optimal Treatment of Depression: Glass Half Full or Half Empty? American Journal of Psychiatry. 2020 Aug 1;177(8):671–85.
  2. Flint J, Kendler Kenneth S. The Genetics of Major Depression. Neuron. 2014 Feb;81(3):484–503.
  3. Dean J, Keshavan M. The neurobiology of depression: An integrated view. Asian Journal of Psychiatry. 2017 Jun;27(27):101–11.
  4. Milenkovic VM, Stanton EH, Nothdurfter C, Rupprecht R, Wetzel CH. The Role of Chemokines in the Pathophysiology of Major Depressive Disorder. International Journal of Molecular Sciences. 2019 May 9;20(9).
  5. Jesulola E, Micalos P, Baguley IJ. Understanding the pathophysiology of depression: From monoamines to the neurogenesis hypothesis model – are we there yet? Behavioural Brain Research. 2018 Apr;341:79–90. 
  6. Otte C, Gold SM, Penninx BW, Pariante CM, Etkin A, Fava M, et al. Major depressive disorder. Nature Reviews Disease Primers. 2016 Sep 15;2(1).
  7. Brigitta B. Pathophysiology of depression and mechanisms of treatment. Pathophysiology of Depression. 2022 Apr 1;4(1):7–20.