Stressful Life Events and Previous Episodes in the Etiology of Major Depression in Women: An Evaluation of the “Kindling” Hypothesis
Abstract
OBJECTIVE: Although previous evidence has suggested that the etiologic role of stressful life events in major depression is reduced in recurrent versus first-onset cases, this question deserves reexamination because of potential methodological limitations of the previous studies. METHOD: Members of female-female twin pairs from a population-based registry (N=2,395), who were interviewed four times over a period of 9 years, formed a study group that contained 97,515 person-months and 1,380 onsets of major depression. Discrete-time survival, proportional hazards model, and piece-wise regression analyses were used to examine the interaction between life event exposure and number of previous depressive episodes in the prediction of episodes of major depression. RESULTS: For those with zero to nine previous depressive episodes, the depressogenic effect of stressful life events declined substantially with increasing episode number. However, the association between stressful life events and major depression was not substantially influenced by additional episodes. This pattern of results was robust to the addition of indices of event severity, measures of genetic risk, and restriction to independent stressful life events. The same pattern was also seen upon examining within-person changes in number of episodes. CONCLUSIONS: The association between previous number of depressive episodes and the pathogenic impact of stressful life events on major depression is likely causal and biphasic. Through approximately nine episodes, the association between stressful life event exposure and risk of major depression progressively declines but is largely unchanged with further episodes. These results are consistent with the kindling hypothesis but suggest a threshold at which the mind/brain is no longer additionally sensitized to the depressive state.
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A more liberal estimate including any type of preonset major life event raises the risk estimate to an odds ratio of 9.38 for a first lifetime episode of MDD.
“A more liberal estimate, which includes any type of preonset major life event, raises the risk estimate several fold to an odds ratio of 9.38 for a first lifetime episode of MDD”
From From stress to inflammation and major depressive disorder: A social signal transduction theory of depression. (2014) · cites this paper as Kendler, Thornton, & Gardner, 2000
Number of previous episodes, residual symptoms, and other factors robustly increase the risk of relapse independent of medication discontinuation.
“Many of the factors reported on here appear to have robust properties as predictors of relapse or recurrence risk independent of medication discontinuation: number of previous episodes (Berlanga et al. 1999; Kendler et al. 2000; Burcusa & Iacono, 2007; Hardeveld et al. 2010), residual symptoms (Hardeveld et al. 2010; Nierenberg et al. 2010) and other factors all robustly increase the risk of rela”
From Predicting relapse after antidepressant withdrawal – a systematic review (2017) · cites this paper as Kendler et al. 2000
In psychiatry, depression is conceptualized as heterogeneous, multifactorial in causation, and believed to arise from cumulative effects of genetics, adverse events in childhood, and ongoing life stressors.
“Moreover, in psychiatry depression is conceptualized as heterogeneous, multifactorial in causation, and it is believed to arise from the cumulative effects [56–58] of genetics [59–62], adverse events in childhood [63–66], and ongoing life stressors [67–70].”
From The Need to Separate Chronic Traumatic Encephalopathy Neuropathology from Clinical Features (2017) · cites this paper as [57]
The course of MDD shows a worsening pattern, with each episode occurring sooner, increasing in severity and becoming more resistant to effective treatments.
“The course of MDD shows a worsening pattern, with each episode occurring sooner, increasing in severity and becoming more resistant to effective treatments.10”
These results are consistent with the kindling hypothesis for MD in which, over episodes, MD becomes more autonomous and less associated with prior stressors.
“These results are consistent with the substantial literature on the “kindling hypothesis” for MD in which, over episodes, MD becomes more autonomous and less associated with prior stressors”
From The development of an environmental risk score using Swedish National Registers and its impact on subsequent episodes of major depression (2025) · cites this paper as Kendler, Thornton, & Gardner, 2000
In many individuals, depressive episodes show a worsening pattern over repeated episodes, characterised by increased severity, frequency, autonomy, and lack of responsiveness to initially effective treatments.
“research suggests that in many individuals, depressive episodes show a worsening pattern over the course of repeated episodes, characterised by increased severity, frequency, autonomy (i.e. episodes are less clearly precipitated by psychosocial stress) and lack of responsiveness to initially effective treatments (Kendler 2000; Post 1992).”
From Interventions for preventing relapse and recurrence of a depressive disorder in children and adolescents (2012) · cites this paper as Kendler 2000
There is compelling evidence that intervention in the early stage of depression may prevent the development of cognitive factors associated with recurrent episodes.
“There is compelling evidence that intervention in this early stage may prevent the development of cognitive factors associated with recurrent episodes (Kendler 2000; Lewinsohn 1999; Ma 2004).”
From Interventions for preventing relapse and recurrence of a depressive disorder in children and adolescents (2012) · cites this paper as Kendler 2000
There is commonly a dose-response relationship between the number of types of adversity and the magnitude of risk for depression.
“Moreover, there is commonly a dose-response relationship between the number of types of adversity associated and the magnitude of the risk for depression.4-11”
From Early life adversity and the epigenetic programming of hypothalamic-pituitary-adrenal function (2014) · cites this paper as [9]
A higher number of previous depressive episodes is associated with a greater risk of relapse.
“A higher number of previous episodes (Berwian, Walter, Seifritz, & Huys, 2017; Kendler, Thornton, & Gardner, 2000), more residual symptoms (Berwian et al., 2017; Nierenberg et al., 2010), and failure to reach remission after acute antidepressant treatment (APA, 2010; Rush et al., 2006) are associated with a greater risk of relapse”
From Relapse prevention with levomilnacipran ER in adults with major depressive disorder: a multicenter, randomized, double-blind, placebo-controlled study (2019) · cites this paper as Kendler, Thornton, & Gardner, 2000
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- Authors
- Kendler, K. S., Thornton, L. M., & Gardner, C. O.
- Affiliations
- Virginia Commonwealth University (US)
- Venue
- American Journal of Psychiatry
- Published
- 2000-08-01
- Volume
- 157
- Issue
- 8
- Pages
- 1243-1251
- ISSN
- 0002-953X (ISSN-L)
- 1535-7228
- OpenAlex
- W2150355913
- Cited by
- 721
- References
- 47
- Citations by year
- 2026: 8 · 2025: 13 · 2024: 13 · 2023: 21 · 2022: 27 · 2021: 29 · 2020: 28 · 2019: 27 · 2018: 30 · 2017: 27 · 2016: 46 · 2015: 45 · 2014: 40 · 2013: 33 · 2012: 36
- FWCI
- 11.21
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- American Journal of Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5k05mh001277-05)
- National Institute on Alcohol Abuse and Alcoholism (R01AA009095, AA-09095)
- National Institute of Mental Health (MH-01277, R01MH040828, MH 40828)
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Social Sciences › Psychology › Experimental and Cognitive Psychology › Anxiety, Depression, Psychometrics, Treatment, Cognitive Processes
- Social Sciences › Psychology › Experimental and Cognitive Psychology › Mental Health Research Topics
- Keywords
- major depressive disorder, life events, recurrent depression, women, depressive episodes, etiology of depression, twin pairs, genetic risk, event severity, within-person change
- MeSH terms
- Adult, Depressive Disorder, Diseases in Twins, Female, Humans, Kindling, Neurologic, Life Change Events, Longitudinal Studies, Models, Psychological, Recurrence, Research Design, Risk Factors, Proportional Hazards Models, Odds Ratio, Survival Analysis, Genetic Predisposition to Disease
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