How Stress Lays the Groundwork for Depression

Depression is a pervasive and debilitating mental health disorder that affects more than 300 million people, with a myriad of factors that underlie its development. This week, we examine how stress itself — often thought of as merely a symptom — actually lays the groundwork for depression by changing the structure of key regions of the brain. See last week’s post here.


The Impact of Stress on Biology 

Perhaps someone is constantly worried about money, performance at work, or there is a romantic relationship that produces persistent anxiety — maybe there is a mix of the three, and maybe even a few more. Though it might appear as if this type of omnipresent stress merely affects one’s mood in the short-term, the reality is that this kind of chronic stress may be wreaking havoc on a much deeper level — an epigenetic level, thus leading to long-term changes in protein expression in the brain. Being exposed to stress, especially on a long-term basis, can cause pathophysiologic changes in the brain that may lead to behavioral, cognitive, and/or mood disorders — depression being of them

One of these changes is neuronal loss and impaired functioning of the hippocampus. Pathological anxiety and chronic stress can lead to neuron death and structural degeneration of the hippocampus. The hippocampus provides inputs to other brain regions — such as the prefrontal cortex, cingulate cortex, and amygdala — that significantly contribute to altered mood and emotion in depression. It is therefore thought that altered neurogenesis in the hippocampus contributes directly to some aspects of depression, and may indirectly influence other symptoms of mood disorders including post-traumatic stress disorder (PTSD).

Another significant biological impact of stress is on the hypothalamic-pituitary-adrenal (HPA) axis — the body’s central stress response system. While the stress response is intended to promote survival, prolonged exposure to stressors may cause changes in HPA axis reactivity that can lead to overproduction or underproduction of cortisol — both of which have been linked to depression. Research has also shown that early-life stress can be particularly harmful, as it can alter the lifelong responsiveness of the HPA axis to stressors. Studies that examine the consequences of childhood trauma on the stress response have found strong links to mental and physical health problems in adulthood, as well as with alterations in HPA axis function. This is thought to be one explanation as to why childhood adversity is such a risk factor for depression in adulthood, as well as alcohol and other drug abuse. Between 35% and 65% of depressed individuals demonstrate clear HPA axis abnormalities, and persistent HPA dysfunction has been associated with higher rates of relapse and chronicity


Stressful and Major Life Events 

The finding that stressful and/or major life events significantly increases a person’s risk for depression is perhaps one of the most well-documented in depression research. A great financial loss, the termination of a close relationship, physical or emotional abuse, major health setbacks, the death of a loved one, and the loss of a job all fall into this category, and can lead to severe cognitive upheaval that greatly alters a person’s goals, plans, and hopes for the future.

When solely considering events unrelated to a person’s actions or behaviors, researchers estimate that there is a 2.5-fold greater likelihood that a depressed patient experienced a major life event prior to the onset of the disease versus someone who was not depressed during the same time period. When considering any type of major life event prior to the onset of the disease (i.e., even those directly caused or affected by a patient’s behavior, such as substance abuse), the risk estimate significantly increases to an odds ratio of 9.38. Based on such data, major life stress is thought to be one of the greatest risk factors for depression, with upwards of 80% of cases in the general population preceded by such events. Findings such as these have been witnessed across all age groups and have been found to be particularly strong for women.

Perhaps one of the most troubling findings concerning major life stress is the subsequent and lasting effects produced when it occurs in early life. Adverse events experienced by children, adolescents, and young adults create deeper and longer lasting impacts than when they occur later in life, as they often negatively impact the crucial developmental processes happening during these life stages. Research on the topic indicates that: 

People who experience childhood abuse are three to four times more likely to develop major depression in their lifetime.

Adults with major depression are much more likely to have a history of emotional abuse, neglect, and physical abuse compared with healthy adults.

Those who experience early childhood abuse often have earlier onset, longer duration, more severe symptoms, greater impairment, and more episodes of depression

Modern life stresses, such as cyberbullying and problematic mobile phone use, were likely contributors to significant rises in the prevalence of depression in adolescent girls between 2004 and 2014 — from 13.1% to 17.3%, respectively


Join us as we continue to examine the top 8 factors contributing to the depression epidemic (and don’t forget to sign up for our weekly newsletter to stay up to date with all the latest news in biotech, mental health innovation, and much more). See last week’s post here.



Christian Angermayer

Founder

Strategy and investor relations

Lars Wilde

Co-Founder

Advising on drug discovery and compound sourcing

The Eight Most Significant Factors Contributing to Today’s Depression Epidemic (sources)

  1. https://www.who.int/news-room/fact-sheets/detail/depression
  2. https://www.ncbi.nlm.nih.gov/pubmed/28027366
  3. https://www.who.int/mental_health/in_the_workplace
  4. https://ada.com/signs-of-depression
  5. https://www.nimh.nih.gov/health/statistics/suicide.shtml
  6. https://adaa.org/about-adaa/press-room/facts-statistics
  7. https://www.nimh.nih.gov/health/statistics/major-depression.shtml
  8. https://www.bcbs.com/the-health-of-america/reports/major-depression-the-impact-overall-health
  9. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5579396
  10. https://www.ncbi.nlm.nih.gov/pubmed/26651008
  11. https://www.ncbi.nlm.nih.gov/pubmed/15271581
  12. https://www.ncbi.nlm.nih.gov/pubmed/24269030
  13. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3889685
  14. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4006295
  15. https://www.ncbi.nlm.nih.gov/pubmed/11691695
  16. https://www.ncbi.nlm.nih.gov/pubmed/10431682
  17. https://www.ncbi.nlm.nih.gov/pubmed/19434623
  18. https://pediatrics.aappublications.org/content/138/6/e20161878
  19. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2738337
  20. https://www.cdc.gov/drugoverdose/data/statedeaths.html
  21. http://www.annfammed.org/content/14/1/54
  22. https://www.drugabuse.gov/publications/drugfacts/prescription-opioids
  23. https://www.psychiatrictimes.com/special-reports/opioid-use-elderly
  24. https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2682878
  25. https://jamanetwork.com/journals/jama/fullarticle/2684607
  26. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2841310
  27. https://psycnet.apa.org/record/2008-07755-000
  28. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4021390
  29. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4225959
  30. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5775138
  31. https://jech.bmj.com/content/68/2/110.abstract
  32. https://www.nimh.nih.gov/health/publications/chronic-illness-mental-health/index.shtml
  33. https://adaa.org/serious-chronic-or-terminal-illnesses
  34. https://www.ncbi.nlm.nih.gov/pubmed/30844397
  35. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4308579/
  36. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5017546/
  37. http://www.pointinstitute.org/wp-content/uploads/2012/10/standard_v_9.2_hpa_axis.pdf
  38. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3860380/
  39. https://www.sciencedirect.com/science/article/pii/S0747563216302552?via%3Dihub
  40. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5633215/

Florian Brand

Co-Founder and Chief Executive Officer

Executing drug development and operations

Simon Seibold

Associate

Investments and business development

Philipp Schreiber

Associate

Drug discovery and compound sourcing

ATAI is supporting the revival of treatments with prior evidence in humans, such as psilocybin and ketamine, in fighting mental health disorders

Depression, anxiety, post-traumatic stress disorder, obsessive-compulsive disorder, bipolar disorder and other psychiatric conditions are increasingly becoming a burden for patients, families and societies.

We believe that

ATAI is leveraging the potential of artificial intelligence (AI) and big data analytics to optimize and accelerate the drug development process

Technological innovation will enable us to consolidate and make sense of vast amounts of previously inaccessible data.

We believe that

Matthias Luz, MD

Chief Medical Officer

Developing clinical strategy for lead compounds

Srinivas Rao, MD, PhD

Chief Scientific Officer

Advance the science into clinical evaluation

Danny Talati

Lead, Business Development

Compound sourcing and evaluating

Allan Malievsky

Associate

Communications and Business Development

Greg Bates

Lead, Regulatory Affairs

Successful product approval

Aaron Weaver

Senior Legal Counsel

Ana Zarzosa

Team and Research Assistant

Supporting smooth communication and a high-performance team environment

Ali Mahomed

Global Venture Development

Operationally growing portfolio companies

SourcesThe Eight Most Significant Factors Contributing to Today’s Depression Epidemic (full series)

  1. https://www.who.int/news-room/fact-sheets/detail/depression
  2. https://www.ncbi.nlm.nih.gov/pubmed/28027366
  3. https://www.who.int/mental_health/in_the_workplace
  4. https://ada.com/signs-of-depression
  5. https://www.nimh.nih.gov/health/statistics/suicide.shtml
  6. https://adaa.org/about-adaa/press-room/facts-statistics
  7. https://www.nimh.nih.gov/health/statistics/major-depression.shtml
  8. https://www.bcbs.com/the-health-of-america/reports/major-depression-the-impact-overall-health
  9. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5579396
  10. https://www.ncbi.nlm.nih.gov/pubmed/26651008
  11. https://www.ncbi.nlm.nih.gov/pubmed/15271581
  12. https://www.ncbi.nlm.nih.gov/pubmed/24269030
  13. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3889685
  14. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4006295
  15. https://www.ncbi.nlm.nih.gov/pubmed/11691695
  16. https://www.ncbi.nlm.nih.gov/pubmed/10431682
  17. https://www.ncbi.nlm.nih.gov/pubmed/19434623
  18. https://pediatrics.aappublications.org/content/138/6/e20161878
  19. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2738337
  20. https://www.cdc.gov/drugoverdose/data/statedeaths.html
  21. http://www.annfammed.org/content/14/1/54
  22. https://www.drugabuse.gov/publications/drugfacts/prescription-opioids
  23. https://www.psychiatrictimes.com/special-reports/opioid-use-elderly
  24. https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2682878
  25. https://jamanetwork.com/journals/jama/fullarticle/2684607
  26. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2841310
  27. https://psycnet.apa.org/record/2008-07755-000
  28. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4021390
  29. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4225959
  30. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5775138
  31. https://jech.bmj.com/content/68/2/110.abstract
  32. https://www.nimh.nih.gov/health/publications/chronic-illness-mental-health/index.shtml
  33. https://adaa.org/serious-chronic-or-terminal-illnesses
  34. https://www.ncbi.nlm.nih.gov/pubmed/30844397
  35. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4308579/
  36. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5017546/
  37. http://www.pointinstitute.org/wp-content/uploads/2012/10/standard_v_9.2_hpa_axis.pdf
  38. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3860380/
  39. https://www.sciencedirect.com/science/article/pii/S0747563216302552?via%3Dihub
  40. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5633215/

Ali Mahomed

Global Venture Development Junior Associate

Operationally growing portfolio companies