Endogenous and Exogenous Depression: Old Classifications and New Treatments

In the past, experts used the terms “endogenous depression” and “exogenous depression” to categorize different types of major depressive disorder (MDD) because it was believed they should be treated differently [9]. 

“Endogenous depression” suggested an internal origin, possibly linked to biology or genetics, reflecting older ideas about bodily fluids influencing health [9]. It was associated with internal factors like genetics or biology, occurring without clear triggers and often following cycles [9].

On the other hand, “exogenous depression” implied external events or stressors as the cause, indicating a connection between life circumstances and depressive symptoms [9]. However, we now understand that depression results from a mix of genetic, biological, and environmental factors, moving beyond these old distinctions [9].

Endogenous and Exogenous Depression

Depression was historically classified by mental health professionals as endogenous or exogenous based on internal or external causes [9]. Endogenous depression, associated with genetics or biology, fell out of favor due to classification challenges [9].

Endogenous depression was thought to have internal origins like genetic and biological factors, lacking clear external triggers [10-11]. It often showed cyclical patterns, making it difficult for individuals to identify external factors. Conversely, exogenous depression was linked to external events, like the death of a loved one, job loss, or experiencing a stressful or traumatic event. Patients with exogenous depression could typically identify the reasons, and psychotherapy was a common treatment [10].

Both endogenous and exogenous depression were initially considered subtypes of major depressive disorder (MDD) [9]. However, the understanding of depression has evolved to focus more on symptom patterns than rigid distinctions between internal and external causes [9]. The historical terms endogenous and exogenous are now less emphasized in modern psychiatric classifications due to challenges in defining clear boundaries. [9].

Major Depressive Disorder (MDD)

Major Depressive Disorder (MDD), or major depression, is a significant global health concern, ranked as the third leading cause of disease burden worldwide in 2008, with projections indicating it may become the leading cause by 2030 [5].


 It is important to learn to spot the symptoms of MDD and to help yourself or a loved one get timely care to manage the severity of depression symptoms to improve your level of functioning and quality of life.

The following are MDD symptoms that individuals may experience [1]:

  • Persistent low or depressed mood
  • Anhedonia (Loss of interest or pleasure in activities that were once enjoyed).
  • Guilt or hopelessness
  • Lack of energy
  • Poor concentration,
  • Changes in appetite,
  • Psychomotor agitation (e.g.,  inability to sit still, pacing, pulling, or rubbing skin).
  • Psychomotor retardation (e.g., Slow speech, thoughts, or body movements).
  • Body aches and pains
  • Sleep problems (e.g., trouble sleeping or sleeping too much).
  • Suicidal thoughts or behaviors

 Causes and Risk Factors

Major Depressive Disorder (MDD) is a complex condition, and there is a range of factors across biology, genetics, environment, and social factors [5]; these factors can include the following [5]:

Biological Factors

Initially, the focus was on neurotransmitter imbalances, particularly serotonin, norepinephrine, and dopamine, supported by medications targeting these chemicals [5]. Low serotonin levels have been linked to suicidal thoughts [5].

Newer theories highlight disruptions in broader brain systems and circuits, affecting neurotransmitters like GABA, glutamate, and glycine [5]. Individuals with depression often exhibit lower GABA levels, and GABA may help by blocking specific brain pathways [5].

Ongoing research explores NMDA receptor-blocking drugs as a potential treatment for depression [5]. Hormonal issues, including thyroid and growth hormones, are also linked to mood disorders [5]. Early-life stress can lead to long-term changes in brain function, potentially causing depression later on [5].

Genetic Influences

Family and twin studies demonstrate the impact of genetics on Major Depressive Disorder (MDD), with a higher likelihood of both twins developing MDD if one has it [5]. The risk of MDD is influenced by genetic and physiological factors, especially if a close family member has the disorder. Approximately 40% of the risk for MDD is hereditary, according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-5 [1].

Environmental and Social Factors

Life events and personality traits, such as a lack of control or distorted thinking, contribute to depression [5]. According to the DSM-APA, depression results from a combination of factors [1]. A negative and anxious disposition (neuroticism) increases the likelihood of MDD, especially when coupled with stressful life events [1]. Childhood trauma significantly elevates the risk of MDD, though stressful events alone do not reliably predict the course or treatment outcomes [1].

Health-related Factors

Certain health conditions, such as substance use, anxiety, and personality disorders, complicate the recognition and treatment of depression [1]. Chronic health problems like diabetes or heart disease also increase the risk of developing and prolonging major depressive episodes [1].

Research suggests that the genetic underpinnings of endogenous depression might differ from those involved in depression triggered by external stressors [3].

One study looked at how genes are different in animals experiencing long-term stress and those showing signs of depression without external stressors [3]. They found specific genes linked to the internal, or endogenous, type of depression [3]. Surprisingly, these genes were different from the ones usually associated with stress-induced depression [3].


According to diagnostic criteria in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), to be diagnosed with major depressive disorder by a mental health professional, the following needs to be true [1]:

  1. Duration: The essential feature is at least two weeks with either a depressed mood or loss of interest/pleasure in nearly all activities. The mood is often described as depressed, sad, hopeless, discouraged, or irritable (in children and adolescents).
  2. Frequency: Symptoms must be present nearly every day, except for weight change and suicidal ideation.
  3. Severity: Symptoms must result in clinically significant distress or impairment in social, occupational, or other important areas of functioning.
  4. Additional Symptoms: At least four additional symptoms from the following list must be present, persisting most of the day, nearly every day:
  • Changes in appetite or weight
  • Sleep disturbances (insomnia or hypersomnia)
  • Psychomotor changes (agitation or retardation)
  • Decreased energy or fatigue
  • Feelings of worthlessness or guilt
  • Difficulty thinking, concentrating, or making decisions.
  • Recurrent thoughts of death or suicidal ideation, plans, or attempts

Treatment Options

There is no one-size-fits-all approach to treating depression and managing its symptoms. Individuals may experience varying degrees of success with different treatments, but often, individuals may be treated with a combination of medication along with psychotherapy or other treatment options, like TMS [7]. Let’s examine some treatment options.


Depression is often treated with antidepressant medications like selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and others that influence brain chemicals related to mood. It may take several weeks for these medications to show effectiveness.


Different types of psychotherapy, such as cognitive-behavioral therapy (CBT), talk therapy, and interpersonal therapy (IPT), help individuals develop coping strategies, change negative thought patterns, and improve behavioral patterns contributing to depression. Telehealth services have expanded access to mental health care, making therapy more convenient for some.

Brain Stimulation Therapies

When medications and psychotherapy are ineffective, brain stimulation therapies may be considered, such as Transcranial Magnetic Stimulation (TMS).

TMS is an effective treatment for major depressive disorder (MDD), according to various studies.

An extensive registry of patients with MDD treated with TMS demonstrated strong effectiveness and low side effects, with notable response (58-83%) and remission (28-62%) rates [12].

A thorough analysis combining various studies indicated that TMS, including accelerated TMS, can alleviate the severity of depressive symptoms [13].

TMS demonstrated better results than the placebo treatment in a randomized, double-blind, sham-controlled, cross-over study. This was especially evident when TMS was combined with medication, offering meaningful improvement for patients struggling with treatment-resistant depression [4].

Recent studies indicate that applying daily left prefrontal Transcranial Magnetic Stimulation (TMS) over several weeks as a depression treatment demonstrates effectiveness in real-world scenarios, leading to remission in 30-40% of patients [6].

Lifestyle Changes

Outside of formal treatment, lifestyle adjustments can complement recovery [7]. Regular physical activity, consistent sleep schedules, healthy eating habits, and social connections can positively impact mood [7]. Avoiding alcohol, nicotine, or drugs is crucial, as substance use can exacerbate depression [7].

Accessing Mental Health Treatment

Understanding depression has evolved from simplistic categorizations like endogenous and exogenous to a more nuanced recognition of its complex interplay between genetics, biology, environment, and social factors.

While major depressive disorder (MDD) poses a significant global health challenge, advancements in treatments, including medications, psychotherapies, and innovative approaches like transcranial magnetic stimulation (TMS), offer hope.

Recognizing the complex nature of depression allows individuals to seek personalized and effective strategies for managing symptoms, emphasizing the importance of a comprehensive approach encompassing medical, psychological, and lifestyle interventions.

If you or a loved one are experiencing symptoms of depression or another mental health condition, reach out to Neuro Wellness Spa. Our expert clinical team will walk you through your treatment options whether that is through psychiatry and medication management or alternative treatments like TMS therapy. Our compassionate and skilled team is ready to provide support and guidance. Don’t hesitate—take the first step toward a brighter, healthier future.


  1. American Psychiatric Association. (2013). Depressive Disorders. In Diagnostic and Statistical Manual of Mental Disorders (5th ed.).
  2. Agboola, F., Atlas, S. J., Touchette, D. R., Fazioli, K., & Pearson, S. D. (2020). The Effectiveness and Value of Esketamine for the Management of Treatment-Resistant Depression. Journal of managed care & specialty pharmacy, 26(1), 16–20. https://doi.org/10.18553/jmcp.2020.26.1.16
  3. Andrus, B. M., Blizinsky, K., Vedell, P. T., Dennis, K., Shukla, P. K., Schaffer, D. J., Radulovic, J., Churchill, G. A., & Redei, E. E. (2012). Gene expression patterns in the hippocampus and amygdala of endogenous depression and chronic stress models. Molecular psychiatry, 17(1), 49–61. https://doi.org/10.1038/mp.2010.119
  4. Akpınar, K., Oğuzhanoğlu, N. K., & Uğurlu, T. T. (2022). Efficacy of transcranial magnetic stimulation in treatment-resistant depression. Turkish journal of medical sciences, 52(4), 1344–1354. https://doi.org/10.55730/1300-0144.5441
  5. Bains N, Abdijadid S. Major Depressive Disorder. [Updated 2023 Apr 10]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK559078/
  6. George, M. S., Taylor, J. J., & Short, E. B. (2013). The expanding evidence base for rTMS treatment of depression. Current opinion in psychiatry, 26(1), 13–18. https://doi.org/10.1097/YCO.0b013e32835ab46d
  7. National Institute of Mental Health (n.d.). Depression. https://www.nimh.nih.gov/health/topics/depression
  8. Papakostas, G. I., Salloum, N. C., Hock, R. S., Jha, M. K., Murrough, J. W., Mathew, S. J., Iosifescu, D. V., & Fava, M. (2020). Efficacy of Esketamine Augmentation in Major Depressive Disorder: A Meta-Analysis. The Journal of Clinical Psychiatry, 81(4), 19r12889. https://doi.org/10.4088/JCP.19r12889
  9. Paykel E. S. (2008). Basic concepts of depression. Dialogues in clinical neuroscience, 10(3), 279–289. https://doi.org/10.31887/DCNS.2008.10.3/espaykel
  10. Ruffalo, M. L. (2019, October 5). Beyond MDD: Understanding the Types of Depression. Psychology Today. https://www.psychologytoday.com/us/blog/freud-fluoxetine/201910/beyond-mdd-understanding-the-types-depression
  11. Rush A. J. (2007). The varied clinical presentations of major depressive disorder. The Journal of Clinical Psychiatry, 68 Suppl 8, 4–10.
  12. Sackeim, H. A., Aaronson, S. T., Carpenter, L. L., Hutton, T. M., Mina, M., Pages, K., Verdoliva, S., & West, W. S. (2020). Clinical outcomes in a large registry of patients with major depressive disorder treated with Transcranial Magnetic Stimulation. Journal of Affective Disorders, 277, 65–74. https://doi.org/10.1016/j.jad.2020.08.005
  13. Sonmez, A. I., Camsari, D. D., Nandakumar, A. L., Voort, J. L. V., Kung, S., Lewis, C. P., & Croarkin, P. E. (2019). Accelerated TMS for Depression: A systematic review and meta-analysis. Psychiatry Research, 273, 770–781. https://doi.org/10.1016/j.psychres.2018.12.041
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