This post is by associate Triage Practitioner, and guest blogger, Matthew Savage
Depression is a complex condition which continues to place a high level of burden on healthcare systems globally. It is the most common psychiatric disorder, with over 400 million people worldwide experiencing a depressive disorder at one time (WHO, 2018). 10% of women and 6% of men will suffer from the condition during their lives, reducing the quality of life for millions and leading to the unnecessary suicide of around 800,000 people a year (World Health Organisation, 2018). It is an affective disorder and classed as a change in mood or affect (DSM-5, ICD-10, 2020). In a general context, it is characterised with a pervasive lowering of mood (for at least two weeks) and most patients have a reduced level of enjoyment (known as anhedonia or the inability to feel pleasure in normal activities).
Furthermore, a negative pattern of thinking, fatigue and low energy are common amongst those suffering depressive disorders. Associate symptoms also include, disturbed sleep, poor concentration, indecisiveness (someone who used to be quick starts to dither is an early warning sign of depression), low self-confidence, poor or increased appetite, suicidal thoughts or acts, guilt or self-blame and agitation or slowing of movements.
Classification of Depressive Disorders
Due to the wide variation in symptomatology and in symptom severity, depressive disorders have a complex classification and can be categorised as endogenous (more to do with genetics and phenotype), reactive (caused as a response to life experiences that can be current or can be a build up over time), neurotic vs psychotic and major vs minor. Because of this complexity, research of depressive conditions remains extensive, and a wide variety of causes are explored today compared to just 30 years ago. Today, many neuropsychiatrists, psychologists and neuroscientists believe we should discuss and research depression as a brain disorder, and not just a psychological condition, a shift from previous perspectives and an examination of more than just neurotransmitters. Many theories exist today, supported by compelling experimental studies, with the hypothetical neurobiological causes of mental disorders, including depression, considered to fall into the following categories:
Anatomical – This involves network changes, and it is believed that deficiency, loss of neural networks or even hyperconnectivity of networks could be the cause of depressive disorders.
Synaptic – The structural and functional deformities and changes are also believed to be contributors to depressive conditions. For example, presynaptic functional abnormalities (such as too little of a neurotransmitter being produced and/or released) and other dysfunction of receptors and secondary messenger systems can lead to mood disorders.
Genetic – As with many common conditions and disorders today, there is a search for genes associated with depression. Previously, one single gene was searched for but this is no longer believed to be the cause. It is now believed there are numerous different genes for much more complex and complicated depressive disorders. Associated genes are far more likely and clusters of genes are potentially associated with a depression.
Depression – Multi-factorial Aetiology
Because of the above considerations, it is now understood that there is no one cause of depression so numerous theories have been developed and explored to understand more about the condition, shifting away from the traditional focus on pharmacological interventions. Particularly since the early 1990s, pharmacological interventions have been the main treatment for depressive disorders. These were often medications known as serotonin selective reuptake inhibitors, or SSRIs, with the best-known example being Prozac. Prozac behaves in a way to increase serotonin availability, based on the monoamine hypothesis. This is a theory following observations that monoamine metabolites (particular neurotransmitters such as dopamine, noradrenaline and serotonin) in cerebral spinal fluid and urine are reduced in depressed patients. However, this is an approach to depression that is being discredited as only 50% of patients benefit from SSRIs, providing a strong argument for the heterogeneous nature of depression. Today, genetic risk factors, neuroendocrine factors (such as the dysregulated of the hyptothalamo-pituitary-adrenal (HPA) axis), brain inflammation, environmental risk factors (such as early life adversity) and abnormal neurochemistry (such as the monoamine hypothesis) are all considered as potential causes of depressive conditions.
The Genetics of Depression – Associated Genes
Although not completely a new idea, many advances have been made in examining the genetics of depression in recent years. For example, Howard and colleagues (2019) undertook a genome-wide meta-analysis of depression identifiers looking at 807,553 individuals with replication in a further 1.5 million. Their research highlighted the importance of the prefrontal brain regions in depression, identifying 102 independent variants, 269 genes and 15-gene sets associated with depression. The research found both genes and gene pathways were associated with synaptic structure and neurotransmission. Such associated gene research is very useful for new antidepression medication development, allowing more targets for examination and potentially more successful outcomes therapeutically if genetically targeted medications become more commonplace. These may vary by individual, based on gene expression.
Stress and the Hypothalamic-pituitary Adrenal Axis
This theory looks at the role of neuroendocrine in depression. The hypothalamic-pituitary adrenal axis (HPA) theory looks at the bodies stress response and the function of the HPA, a system which is self-regulating in healthy people. It functions as follows:
- The hypothalamus (an area of the brain) is the first responder to stress and triggers changes in the body
- Through hormonal responses, the production of Cortico-releasing-hormone occurs (stress hormones)
- This triggers the pituitary gland to produce ACTH (adrenal cortical Tropic Hormone) which is released to circulate in the blood
- This then triggers adrenal gland activity which leads to the release of Glucocorticoids
- These negatively feedback to the brain, calming down the hypothalamus and reducing activation.
However, this system can work differently in depressed people and the process of regulation has been shown to be dysfunctional in many depressed patients. The system can continue to overfire due to too much stress in the environment leading to a continuous “stress attack”. This constant negative feedback in the Glucocorticoid system leads to burnout, as the chief Glucocorticoid in humans is cortisol. Cortisol is important in the body in the fight and flight system, as well as waking us up in the mornings (rising just after 4am in the normal human circadic rhythm). However, too much cortisol can lead to symptoms such as low energy, sleep disturbances and other depressive symptoms. Research has shown that patients with depression often exhibit spikes in cortisol at 1pm in the afternoon, indicating impaired control of glucocorticoids in the feedback system. This can lead to impaired Glucocorticoid receptors and can result in Glucocorticoid resistance and an impared HPA feedback system (Pariante and Lightman, 2008). A better understanding of this system is providing another avenue for research.
Inflammation and its Role in Depression
Inflammation is our bodies natural response to numerous different issues which we can face. For example, following concussion, the body will release cells known as pro-inflammatory cytokines which have a purpose to protect the area of impact from further damage. However, too much inflammation can lead to oxidative stress, cell dysfunction, synaptic disfunction and can affect neurotransmitter behaviour. For example, inflammation can affect the production of precursors to serotonin, leading to the brain producing lower levels of our “happy” neurotransmitter. Inflammation is the cause of many problems in the body as it is a huge effort for the body to cope with it. For example, arthritis can be caused by raised levels of inflammation in the body, leading to pain in the joins and depression can also be a common comorbidity. This gene association means some people may need more than just one treatment to overcome depressive conditions. For example, anti-inflammatories may be an important part of treatment in patients who are inflamed.
Microbiota and Depression
How the gut microbiome regulates the brain is not clear but recent evidence suggests there is a two-way dialogue. For example, faecal microbiota transplanted from depressed rats to normal animals led to depression and anxiety like behaviours in the recipient animals (Kelly et al, 2016). Intestinal permeability can be affected by variations in gut microbiome which is extremely important because neuro-active compounds and metabolites can gain access to areas within the central nervous system (CNS) from the gut and these regulate various cognitions, emotional responses and regulation of serotonin. Such dysregulation can impact neuropsychological functions (Yarandi et al., 2016] and it is now understood that the pathways implicated in depression may be amendable by dietary manipulation. For example, the typical Western diet is known to be high in trans fats and saturated fats, high in calories, high in refined carbohydrates and sugars and low in phytochemicals, vitamins, and minerals. This type of diet can lead to an increased risk of obesity and unhealthy gut bacteria, leading to inflammation in the body, oxidative stress, a reduction in neurogenesis (neuronal regeneration) and HPA axis disruption (Marx, Lane and Hockey et al, 2020). All of these factors can increase depressive symptoms.
Conclusion
As has been shown, there are many different potential causes of depressive conditions and research continues to explore many different avenues. Modern neuropsychiatry should continue to integrate clinical and experimental research to improve treatment outcomes, examining both genetic and environmental factors. No longer are SSRIs seen as a “one size fits all” solution to depression, but other alternative treatments need further development. For example, medications such as anti-inflammatories and monoamine oxidase inhibitors (MAOIs) need continued examination, further understanding of stress at an individual level (in particular early life stressors) during therapy is needed as well as considerations of gut microbiota and dietary changes (such as increasing omega-3 fatty acid and fibre consumption to help reduce inflammation in the gut). All may help to produce better preventative, as well as reactive treatments to help fight depression in the near future.
About Matt Savage
Matthew Savage is an associate triage practitioner and neurological personal trainer. He has two masters degrees, one in psychology, another in clinical neuroscience at the distinction level and is also a Level 3 Personal trainer. Matthew combines his knowledge and interest in neuroscience, cognitive and physical rehabilitation and general wellbeing to provide positive physical and mental support to his clients.
References
Howard DM. et al (2019) Genome-wide meta-analysis of depression identifies 102 independent variants and highlights the importance of the prefrontal brain regions, Nat Neurosci. 22(3): 343–352 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6522363/
Leonard BE (2013) Impact of inflammation on neurotransmitter changes in major depression. ProgrNeuro-PsychopharmacolBiolPsych (in press) http://ac.els-cdn.com/S0278584613002406/1-s2.0-S0278584613002406-main.pdf?_tid=9a3d20c8-4bc3-11e3-89df-00000aacb360&acdnat=1384279103_db7af63da628f95e2dd53693fc57a038
Marx, W., Lane, M., Hockey, M.et al.Diet and depression: exploring the biological mechanisms of action.Mol Psychiatry(2020). https://doi.org/10.1038/s41380-020-00925-x
Pariante CM, LightmanSL. (2008) The HPA axis in major depression: classical theories and new developments. Trends Neurosci. 31(9):464-8.
Pariante CM (2017) Why are depressed patients inflamed? A reflection on 20 years of research ondepression, glucocorticoid resistance and inflammation. EurNeuropsychopharmacol. 2017 Jun;27(6):554-559. http://www.sciencedirect.com/science/article/pii/S0924977X17302109?via%3Dihub