Theorists historically have sought explanations from two spheres in the attempt to understand the antecedents of psychopathology. One perspective that has long been held is that individuals who develop psychiatric disorders differ premorbidly from those who do not (Monroe & Simons, 1991). These differences were believed to be constitutional in origin. More than 100 years ago, for example, the terminology of a diathesis for mental disorders was relatively active in the psychological vocabulary (e.g. Beard, 1881). A divergent outlook that also has long been held is that stress is a critical influence in the development of psychological disorders (Hawkes, 1857; Hinkle, 1977; Rees, 1976; Rosen, 1959). However, it has been acknowledged that not all individuals, even when exposed to the most calamitous of environmental circumstances, experience a breakdown (Dohrenwend, B. P. & Dohrenwend, B. S., 1979; Grinker & Spiegel, 1963). Meehl (1962) was among the first to bring these two positions together in a more integrated approach, and Bleuler (1963) and Rosenthal (1963) were among the first to develop the specific terminology of diathesis-stress connections. The diathesis-stress model was first presented as an attempt to explain schizophrenia and its course as resulting from an interaction between a predispositional vulnerability and stress caused by life experiences. More recently, the model was adopted for the theories of depression (Abramson, Metalsky, & Alloy, 1989; Bebbington, 1987; Beck, 1987; McGuffin, Katz, & Bebbington, 1988; Robins & Block, 1989). The diathesis may be from genetic, psychological, biological, or situational factors. Stress may be conceptualized as an event or series of events that disturbs a person’s psychological equilibrium and may act as a facilitator for the development of a disorder. Thus, the diathesis–stress model operates to investigate how biological or genetic traits (diatheses) interact with environmental influences (stressors) to generate disorders such as depression. The model posits that if the combined predisposition and stress exceed a threshold, the individual will develop a disorder.
A fundamentally different and competing view is that of the differential susceptibility hypothesis which states that individuals do not vary only in the degree to which they are vulnerable to the negative effects of adverse experience, but rather in more general terms, they vary in their developmental plasticity. It presents the idea that more plastic or malleable individuals are more susceptible than others to environmental influences both for better and for worse. These individuals are susceptible to both negative developmental effects of adverse events and positive developmental consequences of supportive environments. Less susceptible individuals are less influenced by their environments whether they be supportive or unfavorable.
In recent years, much research from the perspective of these two models has been conducted. Since advances in technologies such as genetic sequencing, researchers have been focusing on much of the biological predispositions that may interact with stressors to produce psychological disorders. For instance, a twin study with a sample of 5,221 individuals conducted in Australia examined phenotypic and genetic data in relation to depression (Colodro-Conde, et al., 2017). Phenotypic data included depression scores from the Delusions-Symptoms States Inventory and the Symptom Checklist, stressful life event scores from the List of Threatening Experiences, and perceived social support from the Kessler Perceived Social Support Measure. The researchers also obtained Lifetime DSM-IV depression diagnoses from the participants through telephone interviews. The genetic data was obtained by DNA collections from blood that was genotyped using commercial arrays and imputed from a common single-nucleotide polymorphism (SNP) set to the 1000 Genomes reference panel. This allowed genotype data from different arrays to be combined. Polygenic risk scores (PRS), genetic indicators of the aggregate effect from risk alleles carried by an individual weighted by their allelic effect, were then calculated from the imputed genotype dosages using Genome-Wide Association Study (GWAS) summary statistics from the most recent Psychiatric Genomics Consortium Major Depressive Disorder (PGC MDD) release. Additionally, researchers accounted for covariates such as age and sex.
The researchers fitted linear mixed models controlling for relatedness for the whole sample as well as stratified by sex in order to estimate the variance in depression explained by the genetic vulnerability, the stressors and their interactions. They found a significant interaction of the PRS with personal stressful life events contributing positively to the risk of depression. Their results also indicated possible differences in the etiology of depression between men and women. These findings are supportive of the diathesis-stress model because they point to an increased risk for individuals with combined vulnerability and a high number of reported personal life events beyond what would be expected from the additive contributions of these factors to the liability for depression.
A similar study conducted by researchers in the United Kingdom used a sample of 4,919 unrelated white British participants to replicate previous research in relation to the diathesis-stress model and to assess differences between men and women (Arnau-Soler, et al., 2018). Phenotypic data included individual’s current depressive scores calculated from depressive symptoms as measured by a 28-item scaled version of the General Health Questionnaire. It also included data from a brief life events questionnaire based on the List of Threatening Experiences and self-reported by participants to construct a total stressful life events (TSLE) score from the previous six months. The TSLE was divided into two categories to reflect stressful life events in which the stressful life event is influenced by genetic factors and those that are not influenced by genetic factors. For instance, a stressful life event that may be influenced by genetic factors is having a serious problem with a friend as it may be subject to the respondent’s own behavior, and a stressful life event that may not be influenced by genetic factors is the assault of a close relative as it is potentially independent of the respondent’s own behavior. PRS were calculated using the genotype data of the participants in much the same way as the Colondro-Conde et al. study (2017) and also accounted for covariates such as age and sex.
The researchers found that the depression PRS’ significantly predicted the depression score in the whole sample, and when stratified by sex, the PRS’ significantly predicted the depression scores in both sexes (Arnau-Soler, et al., 2018). TSLE significantly predicted symptoms of depression in the whole sample and stratified by sex. However, significant differences were not found in the direct effect of the TSLE between men and women. The “dependent” category of the TSLE, or stressful life events influenced by genetic factors, represented 28% of the items, but explained 93% of the variance explained by the TSLE. The “independent” category of the TSLE, or stressful life events not influenced by genetic factors, represented over 69% of the items, and explained 57% of the variance explained by the TSLE. When the dependent and independent categories where combined into a single model, the findings suggested that the dependent group has a greater effect on liability to depressive symptoms that the independent group. Researchers also detected significant gene by environment effects on depression scores as conceptualized in the diathesis-stress model. The PRS interaction with TSLE was significant in the full cohort and slightly stronger in women. Findings also suggested that the risk of depressive symptoms was higher in participants who reported greater numbers of stressful life events, whereas participants who reported no stressful life events in the previous six months had the same risk of depression symptoms regardless of their diathesis risk.
Findings from this study (Arnau-Soler, et al., 2018) replicated those of Colondro-Conde et al. (2018) and suggested possible sex-specific differences in genetic risk of MDD in response to the dependent category of TSLE, or stressful life events influenced by genetic factors. They found a significant gene by environment effect in liability to depression at the population level and in women, but not in men. The study suggests that individuals with a genetic predisposition to MDD and who report a higher number of recent stressful life events are at an increased risk of depressive symptoms due to gene-by-environment effects which supports the diathesis-stress theory. Increased power in future studies could more accurately determine the presence and magnitude of the gene-by-environment interaction in depression.
Advancements in biochemistry have led to better understandings of how specific systems such as the functioning of serotonergic (5-HT) systems and the hypothalamic-pituitary-adrenal (HPA) axis are associated with depression (Booij, Wang, Lévesque, Tremblay, & Szyf, 2013). Serotonin receptors or 5-HT receptors are found in the central and peripheral nervous system and mediate neurotransmission