EDITOR’S NOTE
Early-Life Environmental Factors Impacting the
Development of Psychopathology
Ned H. Kalin, M.D.
Our conceptualization of the factors that increase the risk to
develop psychiatric illness is broadly focused on gene-by-
environment interactions, as the illnesses that we deal with
are both heritable and markedly influenced by experiences
and other environmental factors. While heritability estimates
range from 20%245% for anxiety and depressive disorders to
75% and greater for bipolar disorder and schizophrenia (1),
recent research has underscored the genetic complexity
underlying the heritability of these disorders. Although some
rare genetic variants with large effects have been identified, in
general, the heritability of psychiatric illnesses involves a
multitude of interacting common gene variations that each
contribute a very small amount to the risk (2). Nongenetic
factors clearly play an important role and via epigenetic
mechanisms (e.g., DNA methylation and histone modification
of chromatin) affect gene function by modulating gene ex-
pression (3). Most of the illnesses that we deal with in psy-
chiatry have neurodevelopmental origins, which underscores
the importance of focusing on early life as an age to un-
derstand how nonheritable factors interact with the genome
to confer vulnerability. During early life, environmental in-
fluences have the potential to affect the rapid brain devel-
opment that is occurring and that underlies the acquisition
of behavioral, emotional, and cognitive abilities (4).
When considering the nonheritable factors that are crit-
ical determinants, we know from extensive research that
early-life stress, adversity, and especially trauma present
prominent risks for the later development of psychopa-
thology. Not only is it critical to understand the type and the
severity of the adversity that an individual is exposed to, it
is also important to understand how these significant
environmental exposures interact with different neuro-
developmental stages. During the prenatal period, the
developing fetus interfaces with the outside world via the
pregnant mother. Depending on the specific circumstances,
the fetus might be exposed to the consequences of prenatal
depression or other stressful maternal experiences, as well as
infections or drug exposure. We also must remember that
there is frequently a continuity across the prenatal and
postnatal periods in relation to stressors and environmental
exposures, whereas with some environmental exposures, this
may not be the case. Sadly, early-life physical abuse, sexual
abuse, and neglect are all too common, and extensive re-
search, as well as our own clinical observations, document the
Am J Psychiatry 177:1, January 2020
devastating consequences and profound effects on mental
and general medical health that result from childhood mal-
treatment (5). New molecular evidence supports the notion
that the first 5 years of life may be particularly important as a
period of vulnerability. For example, a study examining the
developmental time course of DNA methylation has dem-
onstrated that the first 5 years of life are the period during
which neurons exhibit the greatest epigenetic plasticity,
suggesting that this could be a mechanism by which envi-
ronmental events are especially influential when occurring
early in life (6).
This issue of the Journal, focused on early-life environ-
mental factors that are associated with the development and
treatment of psychopathology, provides new insights into the
biological, social, and health-related outcomes resulting from
adversity and trauma exposure. The review by Lippard and
Nemeroff (7) is the centerpiece of the issue as it comprehen-
sively addresses the re-
lation between childhood We know from extensive
maltreatment and the de- research that early-life
velopment and treat- stress, adversity, and
ment of mood disorders. especially trauma present
While maltreatment is a prominent risks for the
broad risk factor for psy- later development of
chopathology, this review psychopathology.
presents an in-depth ex-
amination of abuse and neglect in relation to mood disorders,
discussing sensitive periods, the consequences of different
types of abuse, mechanisms conveying risk to develop mood
disorders, and poor treatment outcomes.
Maier and colleagues (8) shed light on basic factors rel-
evant to social dysfunction, interpersonal distance, and re-
sponsiveness to touch in adults with a history of childhood
abuse. In addition to behavioral testing, structural and
functional MRI was performed to assess the neural correlates
of social touch in relation to varying degrees of maltreatment.
Overall, the findings suggest alterations in neural responsivity
to sensory stimulation with both fast and slow touch. Of
particular interest was the finding that severe maltreatment
was associated with decreased hippocampal responsivity
to slow touch, which tends to be associated with the
emotion-relevant, comforting aspects of touch. Dr. Martin
Teicher from McLean Hospital and Harvard Medical School,
an expert in the relation between childhood trauma and
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EDITOR’S NOTE
psychopathology, provides an editorial that further discusses
critical periods during development, the importance of un-
derstanding trauma-type selective effects, and the potential
adaptive nature of the neural and behavioral changes that
result from early trauma (9).
The study by Esteves et al. (10) is particularly thought
provoking as it links adversity occurring during the mother’s
childhood to her infant’s telomere biology. In their article, the
authors present data that speak to the intergenerational
transfer of the consequences of trauma by studying the re-
lation between a mother’s history of childhood adverse ex-
periences with telomere shortening and the infant’s mental
health. Telomeres, located at the end of chromosomes,
function to protect against chromosomal damage, and their
physical length has been linked to the aging process as well as
general medical and mental health (11). Esteves et al. report
data demonstrating an association between high levels of
adversity in mothers when they were children with increased
externalizing problems and shorter telomere length in their
offspring. Using statistical methods, the authors suggest that
there is an interaction between maternal childhood adversity
and telomere length on the outcome of externalizing prob-
lems. Dr. Elissa Epel from the University of California, San
Francisco, a leader in understanding psychological stress and
telomere biology, provides an editorial that discusses these
findings in the context of other work in the field (12). In her
piece, she highlights the potential importance of the reported
intergenerational findings and discusses the multiple
mechanisms that could underlie the linkage between ma-
ternal early-life experience and offspring telomere length.
Michopoulos and colleagues (13) examine immune-
related predictors for developing posttraumatic stress dis-
order (PTSD) in acutely traumatized adults in a unique study
that was performed in the emergency department at Atlanta’s
Grady Memorial Hospital. In this study, the researchers used
a prospective longitudinal design to explore the relation
between immune factors that are assessed in close proximity
to the trauma with the long-term consequences of the trauma.
The authors found that decreased levels of the proinflam-
matory markers tumor necrosis factor a and interferon-g
were predictive of a chronic PTSD course. This result was
somewhat surprising as much research has suggested that
increased inflammatory markers are associated with PTSD.
Nevertheless, the experimental design used here, along with
the findings, highlight the possibility that such measures
collected immediately after a traumatic event may provide
information regarding individuals at greatest risk of de-
veloping disabling symptoms and who therefore may benefit
from early interventions. Dr. Christine Heim, an expert in
stress and trauma, professor at the Institute of Medical
Psychology of the Charité university hospital in Berlin, and
professor of biobehavioral health at Penn State University,
offers insights into the importance of this finding in her
editorial (14). She speculates on the meaning of the finding
that the development of chronic PTSD is associated with a
reduction in proinflammatory markers and relates this to
2 ajp.psychiatryonline.org
other work, addressing relations among trauma, pituitary-
adrenal alterations, and PTSD.
Moving to prenatal influences that increase the risk for
developing psychiatric illness, Lee and colleagues (15) pre-
sent data linking bacterial infections during pregnancy to
psychotic disorders in offspring. Although it is not news that
prenatal infections, especially viral infections such as in-
fluenza, are associated with schizophrenia (reviewed in
reference 16), this study examined from more than 15,000
pregnancies the influences of prenatal maternal bacterial
infections. Offspring were followed into adulthood to be-
tween ages 32 and 39, and findings demonstrated that lo-
calized maternal bacterial infections increased the odds of
developing a psychotic disorder by 1.6 times, whereas mul-
tisystemic infections increased the odds by 2.9 times. In-
terestingly, these effects appeared to be sex specific, with the
effect predominantly occurring in exposed male offspring. In
his editorial, Dr. Ken Kendler, a renowned expert in the
epidemiology and genetics of psychiatric disorders from
Virginia Commonwealth University, discusses issues related
to the interpretation of causality as well as the potential
importance of these findings for prevention (17).
Finally, Fornaro et al. (18) alert us to questions regarding
the effects of the medications we use for the treatment of
maternal psychiatric illness on the developing neonate. To
address safety issues related to the use of lithium during
pregnancy, the authors performed a meta-analysis and found
that the overall risk associated with lithium treatment was
present but low. The odds ratio for lithium to be associated
with any congenital abnormality was 1.81, and for cardiac
anomalies it was 1.86. Mothers with lower lithium levels (less
than 0.64 mEq/L) did not appear to have an increased risk
for producing offspring with cardiac malformations. Im-
portantly, this analysis confirmed that lithium treatment was
effective in preventing the postpartum relapse of bipolar
disorder. This article is a valuable in-depth review and
analysis, and the authors conclude by providing impor-
tant and practical recommendations for the use of lithium
treatment during pregnancy.
In conclusion, this issue of the Journal provides new and
important insights relating to the treatment of and the risk for
developing psychopathology. Ongoing molecular and neural
circuit–based work has the potential to more specifically
elucidate the mechanisms by which environmental events
affect the rapidly developing young brain in ways that in-
crease vulnerability. At the same time, the insights presented
in this issue regarding early-life environmental factors that
influence neonatal development have the potential to inform
intervention approaches that would increase resilience by
buffering the heritable genetic factors that confer disease
risk.
AUTHOR AND ARTICLE INFORMATION
Department of Psychiatry, University of Wisconsin School of Medicine
and Public Health, Madison.
Send correspondence to Dr. Kalin (nkalin@wisc.edu).
Am J Psychiatry 177:1, January 2020

Disclosures of Editors’ financial relationships appear in the April 2019
issue of the Journal.
Am J Psychiatry 2020; 177:1–3; doi: 10.1176/appi.ajp.2019.19111181
REFERENCES
1. Smoller JW: Psychiatric genetics begins to find its footing. Am J
Psychiatry 2019; 176:609–614
2. Weinberger DR: Thinking about schizophrenia in an era of genomic
medicine. Am J Psychiatry 2019; 176:12–20
3. Nestler EJ, Peña CJ, Kundakovic M, et al: Epigenetic basis of mental
illness. Neuroscientist 2016; 22:447–463
4. Meyer HC, Lee FS: Translating developmental neuroscience to
understand risk for psychiatric disorders. Am J Psychiatry 2019; 176:
179–185
5. Price AJ, Collado-Torres L, Ivanov NA, et al: Divergent neuronal
DNA methylation patterns across human cortical development re-
veal critical periods and a unique role of CpH methylation. Genome
Biol 2019; 20:196
6. Tierney AL, Nelson CA III: Brain development and the role of ex-
perience in the early years. Zero Three 2009; 30:9–13
7. Lippard ETC, Nemeroff CB: The devastating clinical consequences
of child abuse and neglect: increased disease vulnerability and poor
treatment response in mood disorders. Am J Psychiatry 2020; 177:
20–36
8. Maier A, Gieling C, Heinen-Ludwig L, et al: Association of
childhood maltreatment with interpersonal distance and social
touch preferences in adulthood. Am J Psychiatry 2020; 177:
37–46
9. Teicher MH: Childhood maltreatment hampers interpersonal dis-
tance and social touch in adulthood (editorial). Am J Psychiatry 2020;
177:4–6
Am J Psychiatry 177:1, January 2020
EDITOR’S NOTE
10. Esteves KC, Jones CW, Wade M, et al: Adverse childhood experi-
ences: implications for offspring telomere length and psychopa-
thology. Am J Psychiatry 2020; 177:47–57
11. Blackburn EH, Epel ES, Lin J: Human telomere biology: a con-
tributory and interactive factor in aging, disease risks, and protection.
Science 2015; 350:1193–1198
12. Epel ES: Can childhood adversity affect telomeres of the next gen-
eration? Possible mechanisms, implications, and next-generation
research (editorial). Am J Psychiatry 2020; 177:7–9
13. Michopoulos V, Beurel E, Gould F, et al: Association of prospective
risk for chronic PTSD symptoms with low TNFa and IFNg con-
centrations in the immediate aftermath of trauma exposure. Am J
Psychiatry 2020; 177:58–65
14. Heim C: Deficiency of inflammatory response to acute trauma ex-
posure as a neuroimmune mechanism driving the development of
chronic PTSD: another paradigmatic shift for the conceptualization
of stress-related disorders? (editorial). Am J Psychiatry 2020; 177:
10–13
15. Lee YH, Cherkerzian S, Seidman LJ, et al: Maternal bacterial in-
fection during pregnancy and offspring risk of psychotic disorders:
variation by severity of infection and offspring sex. Am J Psychiatry
2020; 177:66–75
16. Brown AS, Derkits EJ: Prenatal infection and schizophrenia: a review
of epidemiologic and translational studies. Am J Psychiatry 2010; 167:
261–280
17. Kendler KS: Maternal bacterial infection during pregnancy: a po-
tential causal risk factor for psychosis in offspring (editorial). Am J
Psychiatry 2020; 177:14–16
18. Fornaro M, Maritan E, Ferranti R, et al: Lithium exposure during
pregnancy and the postpartum period: a systematic review and meta-
analysis of safety and efficacy outcomes. Am J Psychiatry 2020; 177:
76–92
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