Fitness consequences of depressive symptoms vary between generations: Evidence from a large cohort of women across the 20th century

Abstract

Citation: Gurguis CI, Duckworth RA, Bucaro NM, Walss-Bass C (2024) Fitness consequences of depressive symptoms vary between generations: Evidence from a large cohort of women across the 20th century. PLoS ONE 19(9):
e0310598.

https://doi.org/10.1371/journal.pone.0310598

Editor: Liliana G. Ciobanu, The University of Adelaide, AUSTRALIA

Received: February 22, 2024; Accepted: September 2, 2024; Published: September 30, 2024

Copyright: © 2024 Gurguis et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All data are available for download from the NHANES databases and there is no unique accession number. The data was accessed from the NHANES site for the years mentioned in our manuscript from the following link: https://wwwn.cdc.gov/nchs/nhanes/Default.aspx.

Funding: The author(s) received no specific funding for this work.

Competing interests: The authors have declared that no competing interests exist.

Introduction

Understanding the maintenance of genetic variation in traits under consistent selection is a classic problem in evolutionary biology [1]. Mental illness is commonly claimed to represent an example of this problem because many disorders are common, heritable, and harmful. Under consistent negative selection, genetic variation for mental illness and its prevalence in populations should decrease [2]. Yet, over the 20^th century, the prevalence and heritability of mental illness has increased [3,4]. This pattern is inconsistent with the generally held assumption that natural selection against mental illness is strong. Further complicating resolution of this paradox are different concepts of harm in evolutionary biology and psychiatry. In evolutionary biology, harm refers to negative fitness consequences, which are rarely measured for mental illness. In psychiatry, harm refers to functional impacts in one’s professional or personal domains but does not necessarily entail fitness loss.

Evolutionary psychiatrists have proposed several possible mechanisms to resolve this apparent paradox, including neutral evolution, fluctuating selection, and mutation-selection balance [2]. These solutions are largely based on verbal arguments and narrative reviews of the literature. While no explicit empirical tests of these mechanisms have been published, a few studies have examined the fitness consequences of various psychiatric disorders. In most studies, the common approach is to compare fitness components of individuals affected by mental illness to those of their unaffected siblings or the general population. Those diagnosed with bipolar disorder and schizophrenia show decreased fecundity [5–7], whereas the relationship between fecundity and diagnoses of depressive or anxiety disorders is more complex [8–12]. Only one study examined the quantitative relationships between psychiatric symptoms and fitness components and they found that anxiety had a positive relationship with the number of children, grandchildren, and great-grandchildren 15 years later [10]. This lack of evidence is problematic since depressive symptoms measured in the general population are known to be heritable–a key component in predicting response of a trait to selection [13].

Evolutionary studies of mental illness that focus on explaining the persistence of clinical syndromes (e.g. schizophrenia, bipolar disorder, major depressive disorder) examine extreme expressions of the traits involved and ignore the fact that many symptoms (e.g. low mood) vary continuously within populations. Coding mental illness as a dichotomous phenotype is problematic because selection on a trait is the covariance between that trait and fitness and focusing on individuals only at the extremes of a trait distribution (i.e. those with diagnosed mental illness) can result in misleading or spurious relationships [14,15]. Understanding the fitness consequences of mental illness depends on accurately measuring the relationship between psychiatric symptoms and fitness across the population, rather than focusing on clinically diagnosed syndromes which are arbitrarily defined with respect to biology and fitness and may miss being diagnosed depending on individual access to health care [16].

Depression provides a unique opportunity to study the evolution of mental illness because the symptoms of depression are expressed widely across the population. Depressive disorders affect 4.4% of the global population and are a leading cause of disability worldwide [17]. The lifetime prevalence of major depressive episodes may be as high as 20% and these episodes may occur as part of different psychiatric disorders [18]. The symptoms of major depressive episodes are also expressed in individuals unaffected by mental illness and are readily measured with self-report screening, allowing for a quantitative measurement of depressive symptoms across the population [19]. Here, we use a large dataset from the National Health and Nutrition Examination Survey (NHANES) spanning four generational cohorts of women from across the United States (U.S.) to test the widely held assumption that mental illness has negative fitness consequences and to assess the possibility that variation in depressive symptoms is maintained through fluctuations in natural selection. Of note, while this dataset spans over 50 years and 4 generations, the last generation included (see definitions below) is still reproducing and therefore data collected from them is interrupted by right censored. We discuss this limitation and its implications for interpretation of results in detail below (see Discussion).

Methods

Results

Contrary to widely held assumptions, there was consistently positive selection on depressive symptoms for all three fitness components; however, the strength of selection changed over time (Fig 1). The positive relationship between relative number of sexual partners and PHQ-9 score became progressively stronger across generations (Fig 1A): it was positive, but not significant, for the Silent Generation (Adjusted R² (Adj. R²)=0.0041, F=3.50, standardized β (β_ST)=0.076, df=1, 602, P=0.062) and increasingly strong and positive for the Baby Boomer Generation (Adj. R²=0.0096, F=75.06, β_ST=0.10, df=1, 3970, P <0.0001), Generation X (Adj. R²=0.022, F=75.06, β_ST=0.15, df=1, 3221, P <0.0001), and the Millenial Generation (Adj. R²=0.051, F=120.05, β_ST=0.23, df=1, 2229, P <0.0001; Fig 1).

The relationship between relative pregnancy success and PHQ-9 score was consistently positive across all generations but varied in strength (Fig 1B), being strongest in the Baby Boomer Generation and slightly weaker in other generations (Silent Generation: Adj. R²=0.0046, F=3.81, β_ST=0.079, df=1, 602, P=0.051, Baby Boomer Generation: Adj. R²=0.019, F=28.63, β_ST=0.14, df=1, 3970, P <0.0001, Generation X: Adj. R²=0.017, F=55.54, β_ST=0.13, df=1, 3221, P <0.0001, and the Millenial Generation: Adj. R²=0.012, F=28.63, β_ST=0.11, df=1, 2229, P <0.0001; Fig 1).

There was no relationship between relative birth success and PHQ-9 score (Fig 1C) for the Silent Generation (Adj. R²=-0.0015, F=0.12, β_ST=0.014, df=1, 602, P=0.73), but a weakly positive relationship for the Baby Boomer Generation (Adj. R²=0.0093, F=38.29, β_ST=0.098, df=1, 3970, P <0.0001), Generation X (Adj. R²=0.0043, F=14.78, β_ST=0.068, df=1, 3221, P <0.0001), and the Millenial Generation (Adj. R²=0.0069, F=16.59, β_ST=0.086, df=1, 2229, P <0.0001; Fig 1).

Among outcome variables, PHQ-9 score differed between generations as did the number of male sexual partners, pregnancies, and live births in independent ANOVAs (Table 1). Overall, the number of male sexual partners appears to be relatively stable over the sample period, but the number of pregnancies and live births is consistent until the 1970s with a decline in these fitness components for women from Generation X and the Millenial Generation (Fig 2). Among important covariates, age differed between generations, as did BMI, frequency of respondents from different racial/ethnic groups differed significantly between generations frequency of respondents from different reported family income levels, and frequency of respondents with different reported levels of education (Table 1). Including these covariates in the models (generation, BMI, race/ethnicity, level of education, and family income) did not change our finding of positive selection on depressive symptoms (Table 2).

Discussion

Mental illness can have devastating, life-long impacts on an individual’s ability to function in various domains of life. Because of the disruptive effects of mental illness on interpersonal relationships, it is widely assumed that it will have negative fitness consequences [32]. Attempts to assess this assumption have found decreased fecundity in individuals with schizophrenia and bipolar disorder and early menopause in individuals with major depressive disorder [5,33]. Women with mental illness are also more likely to experience recurrent miscarriage [12]. Some studies have shown that individuals with depressive pathology have lower fecundity and are less likely to ever have children [9,11]. These patterns contrast with other findings that individuals with major depressive disorder have similar lifetime fecundity compared to unaffected siblings or the general population and may have an earlier age at first reproduction [5,8,11]. The symptoms of mental illness, however, overlap between diagnostic categories and are commonly experienced by individuals who do not meet criteria for any psychiatric diagnosis. Due to this phenotypic heterogeneity, prior work that focuses solely on the extreme expression of these traits can produce misleading results.

Here, using a unique long-term study that assessed depressive symptoms across a wide distribution of women, most of whom have never been diagnosed with mental illness, we found consistent evidence of positive selection on depressive symptoms using three separate metrics of fitness. These findings contrast with widely held assumptions and provide a new explanation for the maintenance of genetic variation in depression in human populations. Across the 20^th Century, we show that women with more depressive symptoms tended to have more sexual partners, more pregnancies, and more live births (Fig 1). While this relationship was weaker in the Silent Generation, it was striking that we did not find negative selection on depressive symptoms for any fitness component in any generation. The relationship between depressive symptoms and fitness was also robust to inclusion of important covariates, including BMI, race/ethnicity, family income, and level of education as well as significant interaction terms (Table 2).

Our results suggest that fluctuations in the strength of selection may play a role in the maintenance of variation in depressive symptoms [34]. While we did not detect fluctuations in the direction of selection, the strength of this relationship did vary over time (Fig 1). For relative number of sexual partners, the relationship strengthened over time (Fig 1A). This finding is consistent with a recent Mendelian randomization study which demonstrated increased number of sexual partners causally worsened the risk of depression [35]. These observed patterns also raise the possibility of conflict between episodes of selection, where the relationship between depression and one fitness component may be strengthening while simultaneously not changing or weakening with another [29]. Most importantly, our results highlight the fact that negative fitness consequences of depressive symptoms cannot be simply assumed based on clinical distress or dysfunction. A possible explanation for why our results differ from prior results lies in the fact that we examined depressive symptoms across the population, as opposed to comparing individuals with and without a psychiatric syndrome. Our results should not be interpreted as indicative of positive selection on depressive syndromes, but rather as evidence of positive selection on depressive symptoms.

Alternatively, selection could be acting on some other unmeasured trait that is genetically associated with depression and mediating the link between depressive symptoms and fitness detected here (i.e. correlational selection) [36]. Since the symptoms of depression in PHQ-9 are genetically correlated with each other, this could be true for any individual component. Regulation by hormones, for example, can facilitate or constrain the response of traits to selection since hormonal pleiotropy can generate adaptive suites of genetically correlated traits [37]. Given the importance of hormonal regulation to various psychiatric disorders and person perception, this area of study may be particularly fruitful [38]. Likewise, telomere dynamics involved in reproduction, senescence, and mental health provide an alternative target of selection which may underlie the selective patterns detected in our results [39–41].

The retrospective, observational nature of our study limits inferences into the direction of causality between depressive symptoms and fitness consequences in women, but some mechanisms are worth considering here. First, our study spans multiple, important cultural changes that occurred during the 20^th Century. Cultural influences on both depression and reproduction may be an important modulator of the relationship between the two. For example, pharmacological treatments for depression were not available until the 1950s and major improvements to this class of medication did not occur until the 1980s which could account for changes in strength of selection in later generations [42]. Another undoubtedly important change is a decline in fecundity in women born after 1972. This decline (Fig 2B and 2C) coincides with increased access to contraceptives and reproductive healthcare for women in the U.S. Mild fluctuations in the strength of selection may be partially influenced by a changing cultural milieu, which includes changing societal norms and attitudes toward mental illness, sex, and reproduction.

Second, depression may be mechanistically linked to hormonal changes in women associated with mood and reproduction. Risk of depression is known to be higher in women, a pattern which emerges in puberty and continues throughout life [43]. Other important life history events such as menopause are also related to risk for major depressive episodes [44]. Up to 16% of pregnant women will experience a major depressive episode [45]. Peripartum women are well-known to have increased risk of developing a depressive episode and risks mirror those observed in the general population [46,47]. Fertility disorders are also commonly associated with major depressive episodes [48]. Moreover, a strong link between mood disorders and reproductive events (e.g. menarche, pregnancy, parturition, and menopause) has been well-established [49]. Estrogen signaling plays a key role in regulation of the menstrual cycle and pregnancy while cessation of estrogen signaling is a key feature of menopause [50,51]. Estrogen simultaneously may regulate mood via its role in regulating the serotonergic and dopaminergic systems [52]. Fluctuations in estrogen during the menstrual cycle, after parturition, or with onset of menopause are thought to partly contribute to the known risk of mood disorders associated with these events [53]. Notably, systems downstream of the estrogen receptor are targeted by psychopharmacological interventions in affective disorders [54]. Stabilizing natural fluctuations in estrogen with exogenous administration of the sex hormone can also improve depressive symptoms in women [55]. Therefore, our results, in combination with the known links between hormonal aspects of female fertility cycles, may indicate that high fecundity and mood disorders are mechanistically linked where increased fecundity may play a causal role in producing depressive symptoms.

Another limitation of the present study is that part of our sample has not yet completed their reproductive years. The median age at which women have their last child is approximately 40-years-old and 90% of women have completed reproduction by age 45 [56]. In our sample, women in the Silent Generation and Baby Boomer Generation can reasonably be assumed to have completed reproduction. With a median age of 38-years-old in Generation X, most of these women will have nearly completed reproduction. The oldest woman born in the Millenial Generation in our sample is 35, suggesting significant future reproductive potential among women in this generation. This age-related effect is reflected in the lower average relative pregnancy success and relative birth success among these cohorts (Table 1). In the generalized linear models, however, the relationships between depressive symptoms and fitness components remained positive even after controlling for this generational difference (Table 2). Conclusions about the strength of the relationship between depressive symptoms and fitness components should be made with caution for these younger generations, but the finding of positive selection appears robust.

Our study is also limited by the measurement of depressive symptoms at a single timepoint. The severity of depressive symptoms measured during sampling may not reflect the average severity of symptoms at other times in an individual’s life. However, evidence indicates that mood likely shows significant repeatability across the lifespan. First, approximately 50% of individuals with major depressive disorder have experienced their first major depressive episode before age 25 [57]. Given the median age of women in our sample, most individuals with major depressive disorder would have already experienced their first episode by the time they participated in NHANES interviews. Second, even among individuals being treated with antidepressants, the relapse rate (development of a major depressive episode after remission) nears 40% within 20 years [58].

Conclusion

Overall, we have demonstrated that women with more depressive symptoms have a relatively higher number of sexual partners, pregnancies, and live births. The direction of this relationship was positive in each generation sampled, but the strength of the relationship fluctuated over time. This finding suggests that prior assumptions about the negative fitness consequences of depression are not valid, and that fluctuating selection may be an important mechanism for maintenance of variation in mental illness in human populations. Our findings also highlight the importance of measuring key psychological traits using the full spectrum of variation in the population, rather than focusing on extreme phenotypes that fall into discrete categories of disorders. We strongly urge future work on the evolution of mood disorders to consider both biological and cultural mechanisms that explicitly link depressive symptoms with fitness as well as changing societal influences on women’s reproductive decisions.

Acknowledgments

The authors would like to thank Randolph M. Nesse for insightful discussions during conceptual development of this manuscript.

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