Major Depressive Disorder (MDD) or depression affects millions globally. According to the World Health Organization (WHO), 280 million people suffer from depression^[1] but many people with depressive symptoms are undiagnosed, so the number may be even higher. Understanding the interplay between genetic and environmental factors is key to understanding why some people are more prone to depression than others.

What is Major Depressive Disorder

MDD is a mood disorder characterized by feeling sad, hopeless and lacking interest or pleasure in activities you once enjoyed. It’s more than just the normal emotional response to life’s challenges and can impact daily living.

Common Symptoms of Depression

Emotional Symptoms

• Sadness or emptiness
• Hopelessness or pessimism
• Irritability or frustration over small things
• Guilt or worthlessness
• Thoughts of death or suicide

Physical Symptoms

• Changes in appetite—weight loss or gain not related to dieting
• Sleep disturbances—insomnia or oversleeping
• Fatigue or low energy
• Unexplained physical problems—headaches or body pains

Cognitive Symptoms

• Difficulty concentrating, remembering or feeling anxiety while making decisions
• Slowed thinking or speech
• Indecisiveness

Depression can affect anyone regardless of age or background. But statistics show that people 18-25 have the highest risk of experiencing depressive symptoms^[2]. Symptoms can come in episodes that last weeks, months or even years if left untreated.

Environmental Factors that Contribute to Depression

While genetics play a big role, there are many environmental factors that can trigger and worsen depression. Knowing these factors is key to prevention and treatment.

Trauma and Stressful Life Events

Exposure to traumatic events like abuse, loss of a loved one or major life changes can trigger depressive episodes. Chronic stress from personal or professional challenges can also contribute to MDD^[3].

Medical Conditions

Certain illnesses like chronic pain conditions, thyroid disorders and neurological diseases can increase the risk of depression. The psychological burden of managing a chronic illness can worsen depressive symptoms^[4].

Substance Abuse

Substance use disorders and depression often co-exist. Substance abuse can change brain chemistry, which increases the risk of depression. Depression can also lead individuals to use alcohol or drugs as a form of self-medication, creating a vicious cycle^[5].

Poor Nutrition and Lifestyle Factors

Diets high in processed foods and low in nutrients can affect mental health. Lack of physical activity and poor sleep hygiene are other lifestyle factors that can contribute to depression^[6].

The Genetic Connection to Depression

Is Depression Genetic?

Research shows that genetics can play a big role in your susceptibility to depression. Family and twin studies have shown that MDD can run in families, so there’s a heritable component^[7]. But no single gene is the cause of depression. It’s polygenic – multiple genes contribute to the risk.

How Genes Affect Mental Health

Genetic Variants and Neurotransmitter Function

Some genetic variations can affect the production and regulation of neurotransmitters like serotonin, dopamine and norepinephrine, which are key to mood regulation. For example, variations in the serotonin transporter gene (5-HTTLPR) have been linked to depression risk, especially when combined with stressful life events^[8].

Gene-Environment Interactions

Genetics can influence how we respond to environmental stressors. People with a genetic predisposition may have a more intense stress response and be more likely to develop depression when exposed to adverse experiences^[9].

Epigenetics

Epigenetic changes are modifications to gene expression without changing the DNA sequence. Stress and trauma can cause epigenetic changes that increase depression risk. These changes can sometimes be passed down to future generations and affect their mental health^[10].

The Stress Response System and Depression

The Hypothalamic-Pituitary-Adrenal (HPA) Axis

The HPA axis is the central stress response system that involves the hypothalamus, pituitary gland and adrenal glands. It controls the production of cortisol, the stress hormone.

Activation of the HPA Axis

When we are stressed, the hypothalamus releases corticotropin-releasing hormone (CRH) which signals the pituitary gland to release adrenocorticotropic hormone (ACTH). ACTH then tells the adrenal glands to produce cortisol^[11].

Genetic Factors

Genetic predispositions can affect the HPA axis. Dysregulation of this system can lead to prolonged cortisol exposure, which has been linked to depression. Some people may have an overactive HPA axis and are more prone to stress-induced depression^[12].

Trauma and HPA Axis Dysregulation

Early life trauma can change the HPA axis permanently. This can make us more sensitive to stress and more likely to develop depression later in life. This is more so for those with genetic predispositions^[13].

Research on Specific Genes Linked to Depression

There is no such thing as a “depression gene,” but several genes have been linked to MDD:

1. Serotonin Transporter Gene (SLC6A4): Variations in this gene can affect serotonin reuptake in the brain and mood regulation. Research suggests people with certain variants may be more prone to depression, especially after stressful events^[14].
2. Brain-derived neurotrophic factor (BDNF): BDNF is involved in neuron survival and plasticity. Genetic variations in the BDNF gene can impact neurogenesis and are linked to depression and response to antidepressants^[15].
3. FKBP5: FKBP5 is involved in the stress response. Variants of this gene are linked to depression and stress^[16].

Implications for Diagnosis and Treatment

The knowledge of the genetics of depression has a lot of important implications for diagnosis and treatment.

Personalized Medicine

Genetic testing will one day help tailor treatments to your unique genetic profile, making antidepressants and other interventions more effective^[17].

Early Intervention

Knowing the genetic risk factors will allow earlier interventions for those at high risk, so you might prevent depressive episodes.

Holistic Approaches

We now know that genetics and environment are intertwined, so we need to treat the whole person—biological, psychological, and social.

Conclusion

Depression is a complex condition resulting from the interaction of genetic and environmental factors. Genetics can load the gun, but the environment pulls the trigger – trauma, stress and lifestyle choices. We need to understand these factors to diagnose and treat them properly.

By knowing the genetic bit, we can reduce stigma and be more compassionate to mental health. Research is ongoing and there’s hope for personalized treatments for all.

References

1. World Health Organization. (2021). Depression. Retrieved from https://www.who.int/news-room/fact-sheets/detail/depression
2. Substance Abuse and Mental Health Services Administration. (2020). 2020 National Survey on Drug Use and Health. Retrieved from https://www.samhsa.gov/data/
3. Kendler, K. S., Karkowski, L. M., & Prescott, C. A. (1999). Causal relationship between stressful life events and the onset of major depression. American Journal of Psychiatry, 156(6), 837-841.
4. Simon, G. E. (2001). Medical comorbidity and depression. Journal of Clinical Psychiatry, 62(Suppl 8), 30-34.
5. National Institute on Drug Abuse. (2020). Common Comorbidities with Substance Use Disorders. Retrieved from https://www.drugabuse.gov
6. Lopresti, A. L., Hood, S. D., & Drummond, P. D. (2013). A review of lifestyle factors that contribute to important pathways associated with major depression: Diet, sleep and exercise. Journal of Affective Disorders, 148(1), 12-27.
7. Sullivan, P. F., Neale, M. C., & Kendler, K. S. (2000). Genetic epidemiology of major depression: Review and meta-analysis. American Journal of Psychiatry, 157(10), 1552-1562.
8. Caspi, A., et al. (2003). Influence of life stress on depression: Moderation by a polymorphism in the 5-HTT gene. Science, 301(5631), 386-389.
9. Uher, R., & McGuffin, P. (2010). The moderation by the serotonin transporter gene of environmental adversity in the etiology of depression: 2009 update. Molecular Psychiatry, 15(1), 18-22.
10. Nestler, E. J., et al. (2016). Epigenetic basis of mental illness. Neuroscientist, 22(5), 447-463.
11. Herman, J. P., & Cullinan, W. E. (1997). Neurocircuitry of stress: Central control of the hypothalamo–pituitary–adrenocortical axis. Trends in Neurosciences, 20(2), 78-84.
12. Heim, C., Newport, D. J., & Nemeroff, C. B. (2001). Long-term neuroendocrine effects of childhood maltreatment. Journal of the American Medical Association, 286(18), 2321-2327.
13. Meaney, M. J. (2010). Epigenetics and the biological definition of gene × environment interactions. Child Development, 81(1), 41-79.
14. Karg, K., et al. (2011). The serotonin transporter promoter variant (5-HTTLPR), stress, and depression meta-analysis revisited: Evidence of genetic moderation. Archives of General Psychiatry, 68(5), 444-454.
15. Verhagen, M., et al. (2010). Meta-analysis of the BDNF Val66Met polymorphism in major depressive disorder: Effects of gender and ethnicity. Molecular Psychiatry, 15(3), 260-271.
16. Zannas, A. S., & Binder, E. B. (2014). Gene–environment interactions at the FKBP5 locus: Sensitive periods, mechanisms and pleiotropism. Genes, Brain and Behavior, 13(1), 25-37.
17. O’Donovan, M. C., et al. (2018). The genetic architecture of schizophrenia: New mutations and emerging paradigms. Annual Review of Medicine, 69, 381-394.

Authored By

Shebna N Osanmoh I, PMHNP-BC

October 8, 2024

Shebna N Osanmoh is a board-certified Psychiatric Mental Health Nurse Practitioner with extensive experience across the mental health spectrum. Holding a Master’s in Psychiatric/Mental Health Nursing from Walden University, Shebna provides compassionate, culturally sensitive care for a wide range of mental health conditions, emphasizing holistic and individualized treatment approaches to support patients in their wellness journey.