Journal of Affective Disorders 308 (2022) 76–88

Contents lists available at ScienceDirect

Journal of Affective Disorders

journal homepage: www.elsevier.com/locate/jad

Review article

Neurotrophic factors, childhood trauma and psychiatric disorders: A

systematic review of genetic, biochemical, cognitive and imaging studies to
identify potential biomarkers
Maria Grazia Di Benedetto a, b, 1, Catia Scassellati a, 1, Nadia Cattane a, Marco Andrea Riva a, b,
Annamaria Cattaneo a, b, *
a
Biological Psychiatry Unit, IRCCS Istituto Centro S. Giovanni di Dio Fatebenefratelli, Brescia, Italy
b
Department of Pharmacological and Biomolecular Sciences, University of Milan, Italy

A R T I C L E I N F O A B S T R A C T

Keywords: Background: Exposure to traumatic experience represents one of the key environmental factors influencing the
Childhood trauma risk for several psychiatric disorders, in particular when suffered during childhood, a critical period for brain
Neurotrophic factors development, characterized by a high level of neuroplasticity. Abnormalities affecting neurotrophic factors might
Brain Derived Neurotrophic Factor
play a fundamental role in the link between childhood trauma (CT) and early life stress (ELS) and psychiatric
Neuroplasticity
Psychiatric disorders
disorders.
Brain imaging Methods: A systematic review was conducted, considering genetic, biochemical and expression studies along with
cognitive and brain structure imaging investigations, based on PubMed and Web of Science databases (available
up until November 2021), to identify potential neuroplasticity related biomarkers associated both with CT/ELS
and psychiatric disorders. The search was followed by data abstraction and study quality assessment (Newcastle-
Ottawa Scale).
Results: 103 studies met our eligibility criteria. Among them, 65 were available for genetic, 30 for biochemical
and 3 for mRNA data; 45 findings were linked to specific symptomatology/pathologies, 16 with various cognitive
functions, 19 with different brain areas, 6 on methylation and 36 performed on control subjects for the Brain
Derived Neurotrophic Factor (BDNF); whereas 4 expression/biochemical studies covered Neurotrophin 4 (NT-4),
Vascular Endothelium Growth Factor (VEGF), Epidermal Growth Factor (EGF), Fibroblast Growth Factor (FGF),
and Transforming Growth Factor β1 (TGF-β1).
Limitations: Heterogeneity of assessments (biological, psychological, of symptomatology, and CT/ELS), age range
and ethnicity of samples for BDNF studies; limited studies for other neurotrophins.
Conclusions: Results support the key role of BDNF (in form of Met allele) as biomarker, both at genetic and
biochemical level, in mediating the effect of CT/ELS in psychiatric disorders, passing through specific cognitive
functions and specific brain region architecture.

1. Introduction as psychological abuse, as well as physical or emotional neglect

Childhood trauma (CT) represents a key vulnerability factor
increasing the risk for mental disorders, and affecting the severity, type
of symptoms, and frequency of comorbid conditions (Danese, 2019;
Stanton et al., 2020; Terr, 2013). CT is represented by the direct expo­
sure to, or witnessing of, actual or threatened death, serious injury, or
sexual violence during childhood, but it also includes experiences such
(American Psychiatric Association, 2013). These negative experiences
have a major impact on the vulnerable psyche of children (Arafat et al.,
2019; Terr, 2013), contributing to the development of a wide array of
emotional and/or cognitive dysfunctions (Dvir et al., 2014; Majer et al.,
2010), which can potentially outbreak in psychiatric disorders, such as
Major Depressive Disorder (MDD) (Poole et al., 2017), Post-traumatic
Stress Disorder (PTSD), Schizophrenia (SZ) (Varese et al., 2012) and

* Corresponding author at: IRCCS Istituto Centro S. Giovanni di Dio Fatebenefratelli, Via Pilastroni 4, 25125 Brescia, Italy.
E-mail addresses: acattaneo@fatebenefratelli.eu, annamaria.cattaneo@unimi.it (A. Cattaneo).
1
These authors contributed equally to this work.

https://doi.org/10.1016/j.jad.2022.03.071
Received 4 June 2021; Received in revised form 1 March 2022; Accepted 29 March 2022
Available online 2 April 2022
0165-0327/© 2022 Published by Elsevier B.V.
M.G. Di Benedetto et al.
Borderline-personality Disorder (BPD) (Cattane et al., 2017), at any
point during life. This increased clinical risk suggests an impairment in
the brain wiring and function, above all during the critical early stages of
neurodevelopment, when brain trajectories are shaping, causing bio­
logical alterations that lurk for years, until they erupt in clinically severe
manifestations (Andersen, 2003; Carrion et al., 2007; De Bellis and Zisk,
2014).
Early-life stress (ELS), such as childhood maltreatment, is a well-
known etiological factor in psychopathology, including psychosis
(DeRosse and Barber, 2021). A recent meta-analysis examining the
impact of various types of childhood stress exposures on risk for psy­
chotic disorders estimated that 33% of cases worldwide are attributable
to such exposures (Varese et al., 2012). In general, ELS encompasses a
range of stress exposures, including abuse, neglect, institutionalization,
poverty, parental psychopathology, and family dysfunction, occurring
during the delicate early years of life, when these events can have a huge
impact.
From this perspective, abnormalities related to neuroplasticity across
brain development might represent a biological model for explaining the
well documented structural brain alterations (Fannon et al., 2000; Liu
et al., 2017; Zhang et al., 2018), which contribute to the multifactorial
picture of major psychiatric disorders. Neurotrophic factors (NFs), like
Neurotrophin- (NT-)3, NT-4, Brain Derived Neurotrophic Factor
(BDNF), Neural Growth Factor (NGF) and Glial Derived Neurotrophic
Factor (GDNF), are important players for maturation and phenotypic
differentiation of different neuronal populations (Huang and Reichardt,
2001; Snider, 1994). Their role is particularly relevant during early
stages of development, when the brain is characterized by elevated
plasticity and is also highly sensitive to environmental stimuli (Brown
and Jernigan, 2012). Along this line of reasoning, altered expression or
function of specific neurotrophic molecules may contribute to the
development of psychiatric disorders. Indeed, alterations in the pe­
ripheral levels of NFs have been found in patients affected by several
neuropsychiatric disorders, such as SZ, Bipolar Disorder (BD), MDD,
Anxiety Disorders, Attention Deficit Hyperactivity Disorder (ADHD),
and Autism Spectrum Disorder (Bora, 2019; Di Carlo et al., 2019;
Fourrier et al., 2019; Galvez-Contreras et al., 2017; Molendijk et al.,
2014), which have been also confirmed by genetic studies (Penadés
et al., 2020). Therefore, NFs could represent important biomarkers to
predict a genetic-based susceptibility for mental health problems.
Specific gene–environment (G × E) interactions have been identified
as playing a crucial role in the etiopathology of major psychiatric dis­
orders (Zwicker et al., 2018). Of relevance, many studies have investi­
gated the role that the hypofunctional form of BDNF carrying the single
nucleotide polymorphism (SNP) rs6265, (causing Valine (Val) to
Methionine (Met) substitution at codon 66, Val66Met) (Egan et al.,
2003), exerts in moderating the impact of environmental risk factors in
the increased susceptibility for depression (Zhao et al., 2018). Other
genes involved in neuroplasticity and neurogenesis have also been
proposed in mediating G × E interactions for other psychiatric disorders,
such as SZ (Strat et al., 2009). These G × E interactions have emerged as
a novel research approach that might serve as a missing link in the
biological trajectories leading to the onset of psychiatric diseases. This
strategy can refer to two scenarios: the effects of environmental expo­
sures depend on a specific genotype; or the effects of some candidate
genes might be significant only when certain high risk environmental
factors, such as the exposure to CT, are considered (Ayhan et al., 2016;
Ottman, 1996; Van Os et al., 2008).
Overall, it is possible to infer that CT but also ELS, which are highly
prevalent in psychiatric patients, might also be associated with alter­
ations in NFs. Indeed, a plethora of studies has investigated whether
alterations of NFs levels observed in major psychiatric disorders may be
attributable to the effects of child suffering. The aim of our review was
thus to provide a detailed picture of these studies in order to improve our
understanding of the relationship among childhood adversity (in form of
CT, ELS), NFs and mental illnesses. We included in this research also
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Journal of Affective Disorders 308 (2022) 76–88
cognitive and brain structural imaging studies, with the aim to identify
potential biomarkers mediating and predicting the effects of childhood
adversities exposure in psychiatric disorders.
2. Methods
2.1. Search strategy and selection criteria
This systematic review summarizes the current knowledge linking
psychiatric disorders with NFs and CT/ELS, based on PubMed and Web
of Science database searches conducted according to the PRISMA
guidelines. We selected published articles until November 2021,
excluding preclinical studies, review articles, as well as articles not
published in the English language. There was no restriction on year of
publication. In PubMed, we used the following search terms/syntax:
((Neurotrophic factor) OR (Neurotrophin) OR (NT-3) OR (NT-4) OR
(NT-5) OR (NGF) OR (Nerve Growth Factor) OR (BDNF) OR (Brain
Derived Neurotrophic Factor) OR (GDNF) OR (Glial Derived Neuro­
trophic Factor) OR (Neurturin) OR (NTN) OR (Artemin) OR (ARTN) OR
(PSPN) OR (PSP) OR (Persephin) OR (EGF) OR (Epidermal Growth
Factor) OR (IGF) OR (IGF-1) OR (Insulin-like Growth Factor) OR (CNTF)
OR (Ciliary Neurotrophic Factor) OR (FGF) OR (Fibroblast Growth
Factor) OR (VEGF) OR (Vascular Endothelial Growth Factor) OR (TGF)
OR (Transforming Growth Factor) OR (Neuropoetin)) AND ((Childhood
trauma) OR (Early life trauma)).
2.2. Inclusion and exclusion criteria
We included articles that assessed diagnostic criteria for CT/ELS
together with NFs, both as genes (genetic and expression studies) and
proteins (biochemical studies). We included studies reporting sufficient
details on performance measures on cognitive tasks, imaging findings of
the brain, and clinical and subclinical neuropsychiatric symptoms. We
excluded: a) other molecules beside NFs; b) studies performed on animal
models; c) reviews, editorials, commentaries, letters or case reports on
the topic; and d) articles not published in the English language.
2.2.1. Data extraction
MGDB and CS independently extracted the following data: first
author and year of publication, study design (genetic, expression and
biochemical, cross-sectional, case-control and cohort longitudinal
study), nationality, sample size, age, CT/ELS assessment and type of
trauma, SNPs, biological source, NFs, pathology or healthy subjects,
symptomatology, cognitive performance, structural brain imaging and
key results from each study.
2.3. Quality assessment and strength of evidence
We used the Newcastle-Ottawa quality assessment scale to assess
methodological quality and risk of bias (Wells et al., 2012). In brief, each
study is rated on three broad criteria: selection of the study groups;
comparability of the groups; and the ascertainment of the exposure or
outcome of interest. A score of 7 or more for case-control and cohort
studies, and of 6 or more for cross-sectional studies, is indicative of
“good” quality and bias control. Two reviewers independently applied
the tool, and discrepancies were resolved through discussion with a
third reviewer. As this is an under-researched area, all studies were
included regardless of quality rating.
3. Results
Using the mentioned search terms, a total of 326 results appeared in
PubMed, whereas 237 results appeared using Web of Science. From
these lists, during the screening, we selected 103 studies that were
investigating NFs at genetic, expression and biochemical levels and
meeting our eligibility criteria. We selected articles in relation to specific
M.G. Di Benedetto et al. Journal of Affective Disorders 308 (2022) 76–88

NFs (Fig. 1, PRISMA flow chart).
To achieve the highest homogeneity among the studies, we struc­
tured this review describing genetic and biochemical and expression
studies. In each of these paragraphs, we reported subparagraphs
evidencing the data in relation to mood and psychotic disorders (MDD,
BD, SZ); anxiety-related disorders (post-traumatic stress disorder, PTSD;
obsessive-compulsive disorder, OCD), other diagnoses (self-harm
behaviour, substance abuse), studies on healthy subjects (HC). More­
over, we described findings related to cognitive functions and structural
brain features. Also studies on methylation pattern have been reported.
The further classifications were based on CT versus ELS assessments and
Caucasian versus Asian/South African/Latin American/mixed

Fig. 1. PRISMA flow chart that summarizes the criteria used for the selection of published articles.
Briefly, through PubMed and Web of Science database searches, we selected published articles until November 2021, excluding preclinical studies, review articles,
studies related to other molecules/genes besides neurotrophic factors, as well as articles not published in the English language.

78
M.G. Di Benedetto et al.
populations. As most of the work was performed on BDNF, we described
in primis the studies on this neurotrophin.
3.1. Brain Derived Neurotrophic Factor (BDNF)
Ninety-nine studies met our eligibility criteria regarding analyses for
BDNF: 71 studies were available for genetic (single nucleotide poly­
morphisms, SNPs) and epigenetic (DNA methylation) data, and 33 for
biochemical and mRNA expression approaches (Fig. 1).
3.1.1. Study characteristics
The study characteristics were summarized in supplementary mate­
rial (Tables 3S–11S). These tables described each study evidencing
sample source, study design, sample size, age disease informant,
assessment, diagnostic criteria, exposure type, exposure informant,
exposure type of report, exposure measure, cognitive performance,
structural brain features, biological source, main results obtained. The
studies were included in two categories: 67 were from clinical and 36
from non-clinical samples. Clinical populations included patients diag­
nosed with mood and psychotic disorders (MDD, BD, SZ), anxiety-
related disorders (PTSD, OCD) and self-harm behaviour or substance
abuse (as other diagnoses). Of the included papers, 9 were cohort-
longitudinal studies in genetic investigations and 2 for biochemical
and expression investigations; 24 were case-control studies for genetic
investigations (of which 5 were case-only), and 19 for biochemical and
expression investigations (of which 2 were case-only); 38 were cross-
sectional studies in genetic investigations and 11 for biochemical and
expression investigations.
3.1.2. Quality and strength of evidence appraisal
A detailed description of the methodological quality of the studies as
measured on the Newcastle Ottawa Scale is presented in supplementary
material (Tables 1S, 2S). Among studies which met the criteria for
“good” quality, there are 34 cross-sectional, 14 case-control and 7
cohort-longitudinal studies for genetic findings; whereas, 14 case-
control, 10 cross sectional and 2 cohort-longitudinal studies for
biochemical findings. We identified some methodological limitations/
strengths of the included studies. In general, the cross-sectional nature
has the limitation to not allow causal associations to be tested robustly,
although a priori hypotheses were clearly defined and guided all ana­
lyses. Moreover, although some studies have found high reliability of
self-reports of childhood adversity, its retrospective measure may be
influenced by recall bias. All the cohort-longitudinal studies had good
follow-up rates. Most of studies utilized validated psychometric in­
struments and used methods of recruitment which did not limit the
generalizability.
3.1.3. Genetic studies
We performed subparagraphs considering: 1. different pathologies:
mood and psychotic disorders (N = 27, Table 3S); anxiety-related dis­
orders (N = 5, Table 4S); other diagnoses (self-harm behaviours and
substance abuse, N = 3, Table 5S); 2. healthy subjects (HC, N = 30,
Table 6S); 3. different trauma assessments (CT versus ELS); 4. cognitive
functions and assessment (memory, emotional regulation, and atten­
tion/executive functions with respective test batteries) (Tables 3S–11S);
and 5. structural and functional imaging in specific brain areas, mainly
hippocampus, amygdala, hypothalamus, anterior cingulate cortex
(ACC), fusiform gyrus, subcallosal area (Tables 3S–11S). Six studies
investigated the methylation status of the BDNF gene, with ELS (N = 3)
versus CT (N = 5) assessments (Table 7S). In the mood and psychotic
disorders section, there were 13 studies that used ELS assessments
whereas 17 used CT tests. In anxiety disorders, there were 5 using CT
and 1 ELS assessments. In self-harm behaviours and substance abuse, all
studies available investigated CT. Finally, in HC, there were 17 studies
that performed CT questionnaires, whereas 15 used different tests for
ELS. 6. We identified 55 studies with Caucasian subjects and 16 for
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Journal of Affective Disorders 308 (2022) 76–88
Asian/South African/Latin American/mixed populations.
In the following paragraphs, we described the different genetic
studies on the role of BDNF according to pathology/symptomatology
including the different diagnoses (pathology) and the studies performed
on HC (symptomatology). In the second part, we described the studies
which investigated the role of genetic BDNF alterations on cognitive
functions and structural brain features. The results related to all these
studies were summarized in Table 1. Finally, we described gene
methylation findings.
3.1.4. Pathology/symptomatology
Seventy-one findings assessed the role of BDNF genetic variants on
symptomatology and/or psychiatric diagnosis.
3.1.4.1. Mood and psychotic disorders. Twenty-seven studies examined
the impact of BDNF gene polymorphism in mediating the effect of CT/
ELS on MDD, BD and SZ (Table 3S). Twenty-one studies (77%) agreed to
show a G × E interaction with Met allele carriers modulating the CT/ELS
and mood and psychotic disorders outcome (Table 1). Six studies
(Cristóbal-Narváez et al., 2017; Hernaus et al., 2014; Molendijk et al.,
2012; Ramsay et al., 2013; Rimay et al., 2015; Serretti et al., 2013) did
not find association, whereas 1 reported the involvement of rs6265 ge­
notype (Bi et al., 2018) (Table 3S; Table 1). Most of the investigations
were performed in Caucasian populations (N = 23, 85%).
3.1.4.2. Anxiety-related disorders. Five studies investigated the Val66­
Met × CT/ELS effect on a spectrum of different clinical expressions of
anxiety disorders (Table 4S). Among these, one study (Hemmings et al.,
2013) identified the Met allele to significantly increase the susceptibil­
ity, due to CT exposure, of developing OCD; but this was not confirmed
by a second study (Breet et al., 2019). Met allele was also found to be
associated to mixed anxiety disorders; however, the sample size was too
small (McGregor et al., 2018). On the contrary, only 1 study recognized
those with a Val/Val genotype to show more severe PTSD symptoms, in
the context of CT/ELS, as compared to Met allele carriers, in a Korean
population (Jin et al., 2019). In addition, one study did not find signif­
icant G × CT/ELS effect on the cognitive-behavioural therapy outcome
in panic disorder patients (Santacana et al., 2016) (Table 4S; Table 1).
Most of the studies were conducted in non-Caucasian populations (N =
4).
3.1.4.3. Other diagnoses. Two studies investigated the role of BDNF
Val66Met polymorphism in predisposing those subjects with a history of
CT to develop self-destructive behaviours. Interestingly, both studies
identified the Val/Val genotype as a risk factor increasing the likelihood
of adult violent suicidal attempt in those sexually abused (Perroud et al.,
2008), and the prevalence of self-injurious behaviours in emotionally
maltreated individuals (Bresin et al., 2013) (Table 5S; Table 1). Third
research reported contrary results; however, this was performed on
autopsies of suicide victims (Pregelj et al., 2011).
3.1.4.4. Healthy subjects. Thirty studies were performed on HC
(Table 6S, Table 1). From samples of HC characterized by a history of
CT/ELS, with different ages from childhood to adulthood, developing
depressive symptomatology and psychotic experiences, we observed
that the presence of a Met allele represented a risk factor in 20 studies
(67%) (Table 6S, Table 1). In a group of healthy adolescents, sexual
abuse was found to be the type of trauma that significantly interacted
with the Val66Met genotype to alter levels of depressive symptoms
(Comasco et al., 2013). Seven studies (Caldwell et al., 2013; Chen et al.,
2012; de Castro-Catala et al., 2016; Jiang et al., 2013; Min et al., 2013;
Tian et al., 2021; van Velzen et al., 2016) reported the Val/Val genotype
as a risk factor for depressive symptoms and higher anxiety symptoms in
children/young adults/adults, on the exposure to CT/ELS. In one study,
conducted in two independent cohorts of nonclinical subjects, a
M.G. Di Benedetto et al. Journal of Affective Disorders 308 (2022) 76–88

Table 1 Table 1 (continued )

Summary of the major results obtained from the studies included in the review N
between BDNF genetic, biochemical, expression, cognitive and structural brain
findings with childhood adversity and psychiatric disorders (N = number of Healthy subjects Higher levels 2
n=6 No association 2
studies/findings).
Childhood trauma 5
N Early life stress 2
Caucasian populations 4
Genetic studies
Asian/South African/Latin American/mixed 2
Major psychiatric Met allele carriers 21
populations
disorders (MDD, BD, SZ) rs6265 genotype 1
Cognitive functions/ Lower levels associated to immediate verbal 2
n = 27 No association 6
structural brain regions recall, reduced working memory/executive
Childhood trauma 17
n=7 function and general cognition
Early life stress 13
Lower levels associated to smaller hippocampal 2
Caucasian populations 23
volume
Asian/South African/Latin American/mixed 4
No association 3
populations
Anxiety-related disorders Met allele carriers (OCD) 1
(PTSD, OCD) No association (OCD) 1
n=5 Met allele carriers (mixed) 1 significant interaction was found between total CT, especially neglect,
Val/Val (PTSD) 1 and BDNF Val66Met on subclinical positive psychotic episodes. How­
No association 1 ever, the results for allele associated with the vulnerability were oppo­
Childhood trauma 5 site between the two included groups: in one cohort the Val allele
Early life stress 1
Caucasian populations 1
carriers were more at risk for psychotic experiences after CT, while in
Asian/South African/Latin American/mixed 4 the second cohort the Met carriers were the ones with the higher risk (de
populations Castro-Catala et al., 2016). Finally, four studies reported negative as­
Self-harm behaviours and Val/Val 2 sociations for psychological symptomatology (Agnafors et al., 2013;
substance abuse Childhood trauma 3
Martin et al., 2018; Nederhof et al., 2010; Tian et al., 2021), although
n=3 Caucasian populations 3
Healthy subjects Met allele carriers 20 Tian and colleagues (Tian et al., 2021) found an interaction between
n = 30 rs6265 genotype 1 Val/Val × CT on modulation of structural and functional connectivity in
Val/Val 7 an Asian population. Most of the studies were performed in Caucasian
No association 4 populations (N = 23, 77%) (Table 1).
Childhood trauma 17
Early life stress 15
From the remaining studies, only 1 identified the TT genotype at the
Caucasian populations 23 rs7103411 BDNF SNP as a risk factor for depressive symptoms in
Asian/South African/Latin American/mixed 7 African-American maltreated children (Cicchetti and Rogosch, 2014)
populations (Table 6S, Table 1).
Cognitive functions Met allele carriers in emotional processing and 4
n = 14 regulation
Met allele carriers in working memory, verbal 6 3.1.5. Cognitive functions
learning and visual recall memory, affective Fourteen studies regarded cognitive functions interacting with BDNF
memory, executive functions and CT/ELS (Tables 3S–7S).
Met allele carriers in cognitive flexibility 1
Met allele carriers in Perceptual Organization 1
Index 3.1.5.1. Emotional processing and regulation. In a population of remitted
No association 2 depressed adults, those carrying the Met allele and who had also a his­
Structural brain features Met allele carriers in hippocampus 5 tory of ELS, presented a significantly altered performance in the pro­
n = 14 No association (hippocampus) 3 cessing of positive emotions, detected by emotional n-back task (Vrijsen
Met allele carriers in other brain regions 6
Val/Val carriers in other brain regions 3
et al., 2014). Similarly, 2 studies investigated the reappraisal ability in
healthy young adults exposed to CT. Again, Met carriers with the higher
levels of CT performed worse in reappraisal ability tasks, conducted with
Biochemical and expression studies
Major psychiatric Lower levels 13
a very similar procedure (Bîlc et al., 2018; Miu et al., 2017). Finally, one
disorders (MDD, BD, SZ) No association 3 study conducted on healthy adult women, found that those carrying the
n = 18 Childhood trauma 14 Met allele and reporting an emotional abuse during childhood, exhibited
Early life stress 7 an increased attention bias variability to emotional information,
Caucasian populations 11
compared to those with Val/Val genotype, using the Dot-probe task
Asian/South African/Latin American/mixed 7
populations (Hori et al., 2021) (Table 1).
Anxiety-related disorders Lower levels (PTSD) 2
(PTSD, OCD) No association (PTSD) 1 3.1.5.2. Memory, attention and executive functions. Seven studies
n=6 Higher levels (OCD) 1
investigated the role of the BDNF Val66Met polymorphism in the asso­
Higher levels (Anxiety) 1
No association (Anxiety) 1 ciation between CT/ELS and various aspects of memory functions, using
Childhood trauma 3 different cognitive tasks (Table 1). In particular, Met allele was associ­
Early life stress 3 ated to impairments in working memory (evaluated using the Integ­
Caucasian populations 2
Neuro battery) (Gatt et al., 2009), in verbal learning and visual recall
Asian/South African/Latin American/mixed 4
populations
memory (assessed by a combined assessment of the Rey Auditory Verbal
Self-harm behaviours and Lower levels 1 Learning Test, RAVLT and Rey Complex Figure, RCF Test) (Savitz et al.,
substance abuse No association 2 2007), in affective memory (Self-referent encoding task, SRET) (van
n=3 Childhood trauma 3 Oostrom et al., 2012), and poorer working memory/executive function
Caucasian populations 1
and general cognition functioning evaluated with a standardized neu­
Asian/South African/Latin American/mixed 2
populations ropsychological test battery (Aas et al., 2013, 2014). Moreover, alter­
Lower levels 2 ation in BDNF promoter methylation was observed associated to
working and verbal learning memory (Hopkins Verbal Learning Test

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M.G. Di Benedetto et al.
Revised TM, HVLT-R; Brief Visuospatial Memory Test Revised TM,
BVMTR, the Rey Complex Figure Test, RCFT) (Ferrer et al., 2019).
However, in 2 further studies, in healthy individuals and in psychotic
patients, investigating verbal learning functions with similar tests
(Hernaus et al., 2014; Tian et al., 2021), as well as spatial memory using
block design task (Hernaus et al., 2014), no significant effect was found
(Table 1).
Additional studies regarded the association between Met allele car­
riers × CT and cognitive flexibility assessed by Wisconsin Card Sorting
Task (WCST) (Gabrys et al., 2017), as well as with Perceptual Organi­
zation Index assessed by Wechsler Adult Intelligence Scale, 3rd Edition
(WAIS-III) (Veras et al., 2019).
3.1.6. Structural brain features
Fourteen studies investigated alterations in structural brain features
related with interacting effect of BDNF and CT/ELS (Tables 3S–7S,
Table 1).
3.1.6.1. Hippocampus. Five studies assessed potential hippocampal al­
terations due to CT/ELS exposure, on the basis of the differential BDNF
genotypes. Four of these studies showed that adults affected by mood
and psychotic disorders (MDD, BD, SZ), with a history of CT/ELS and
carrying the Met allele, showed smaller hippocampal volumes (Aas
et al., 2013, 2014; Carballedo et al., 2013; Frodl et al., 2014), and these
data were confirmed also in an independent cohort of adult healthy
subjects (Gatt et al., 2009).
On the other hand, 3 studies did not find any significant alterations at
the hippocampal level, when they looked at BDNF × CT interaction
(Gerritsen et al., 2012; Hernaus et al., 2014; Molendijk et al., 2012)
(Table 1).
3.1.6.2. Other brain regions. Two studies reported reduced gray matter
and amygdala volumes in BDNF Met carriers with a CT/ELS history (Gatt
et al., 2009; van Velzen et al., 2016). However, subregion-specific re­
sults were collected for the ACC: in one study, the Met allele was asso­
ciated with reduced gray matter in the subgenual ACC (Gerritsen et al.,
2012), whereas a second study reported that Val/Val carriers with CT
history had thinner rostral ACC (van Velzen et al., 2016). Moreover,
when investigating the functionality of the hypothalamus, Juhasz and
colleagues observed a greater hypothalamic reactivity to sad faces
stimuli in healthy Met carriers reporting a history of CT/ELS (Juhasz
et al., 2011). Furthermore, the condition of Met carriers with CT was
found to be associated with significantly lower subcallosal gray matter
in healthy individuals (Marusak et al., 2016) and to reductions in white
matter integrity in MDD patients (Tatham et al., 2016).
In addition, 1 study investigated the interaction between BDNF ge­
notype and CT history looking at the thickness of temporal lobe sub­
regions in adults affected by PTSD: Val/Val carriers with higher levels of
CT/ELS showed thinner left fusiform and left transverse temporal gyri,
compared to individuals with lower levels of trauma (Jin et al., 2019).
Finally, 1 study investigated, in healthy subjects, the Val66Met × CT
interaction on connectivity in different cortical structures. In Val/Val
homozygotes the CT severity was inversely associated with nodal simi­
larity of the left precentral gyrus and the right middle temporal gyrus,
and positively associated with nodal similarity of the right parsorbitalis.
However, when investigating functional connectivity between net­
works, Val/Val carriers with CT history had reduced connectivity be­
tween the dorsal attention network and the salience network (Tian et al.,
2021) (Table 1).
3.1.7. Gene methylation. We found 6 studies investigating the role of
methylation across the BDNF gene in mediating the effect of CT (N = 5)/
ELS (N = 3) (Table 7S) on mental disorders and cognitive performances.
For instance, Thaler and colleagues analysed the methylation of BDNF
gene in women affected by bulimic eating syndrome. They reported that
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Journal of Affective Disorders 308 (2022) 76–88
women with bulimia nervosa, who had been exposed to sexual abuse at
childhood, had a significantly higher percentage of methylation at the
specific CpGs site 19, of the exon IV promoter region of this gene,
compared to healthy controls. Conversely, bulimic women, without CT,
had a greater percentage of DNA methylation at sites 2, 17, 19 and 25 of
the same region, as compared to controls (Thaler et al., 2014).
A second study, performed by Ferrer and collaborators, reported that
a combination of higher methylation levels at multiple sites in both
promoters I and IV of BDNF gene and a more severe history of CT were
associated with poorer cognitive functioning in attention, executive
function, visual and verbal memory (Ferrer et al., 2019). Finally, 4
remaining studies, performed in adults and children, respectively,
demonstrated that individuals who had been maltreated in childhood
had significantly different methylation levels at multiple sites within the
BDNF gene when compared to non-maltreated subjects (Hossack et al.,
2020; Peng et al., 2018; Perroud et al., 2013; Weder et al., 2014) and in 3
of these studies the methylation × CT/ELS was associated with psy­
chopathology (Hossack et al., 2020; Peng et al., 2018; Perroud et al.,
2013).
3.1.8. Biochemical and gene expression studies
Thirty biochemical and 3 gene expression studies investigated the
associations between protein and/or mRNA levels of BDNF with CT/ELS
and mood and psychotic disorders (N = 16 for biochemical and 2 for
expression approaches, 14 performed for CT and 7 for ELS assessments;
Table 8S); anxiety-related disorders (N = 6, 3 performed for CT and 3 for
ELS assessments Table 9S); other diagnoses (N = 3 on CT assessment,
Table 10S) and in HC (N = 5 biochemical studies, N = 1 expression
studies, 5 performed for CT and 2 for ELS assessments; Table 11S)
(Table 1).
In patients affected by mood and psychotic disorders, BDNF levels in
serum/plasma seemed to follow the same direction, with CT/ELS being
associated with a decrease in the protein levels in 13 studies (72%)
(Table 8S; Table 1). Three studies reported negative results (Counotte
et al., 2019; Jeon et al., 2012; Perroud et al., 2013). One study (Dimi­
triadis et al., 2019) reported higher BDNF serum levels, but detected in
traumatized depressed patients without SSRI usage and in non-
traumatized depressed patients who used SSRIs. In addition, in
another study conducted in forensic patients with mixed diagnosis those
who experienced sexual abuse during childhood reported higher levels
of serum BDNF (Dotta-Panichi et al., 2015). Most of the studies were
conducted in Caucasian populations (N = 11, 61%) (Table 1).
In PTSD patients, 2 studies detected lower peripheral levels of BDNF
(Angelucci et al., 2014; Hauck et al., 2010), whereas a further one
(Dell'Osso et al., 2009) did not observe any alterations in relation to ELS
interaction (Table 9S; Table 1). In OCD patients with CT, Li and col­
leagues reported higher plasma levels of BDNF (Li et al., 2021). In
anxiety disorders, two studies were contrasting: (Bortoluzzi et al., 2014)
reported higher serum levels, whereas (de Baumont et al., 2019) no
alterations (Table 9S; Table 1).
In other diagnoses, we found 2 negative studies in crack cocaine
dependent patients (Sordi et al., 2020; Viola et al., 2014), whereas one
study showed lower serum levels of BDNF in the interaction between
self-harm behaviour and CT (Kavurma et al., 2017) (Table 10S; Table 1).
In healthy subjects, two studies found lower peripheral BDNF levels
(Do Prado et al., 2017; Simsek et al., 2015), whereas two others (Bücker
et al., 2015; Watt et al., 2020) found higher levels, associated with CT/
ELS (Table 11S; Table 1). One study did not observe any alterations (van
Velzen et al., 2016). When assessing the correlation between CT/ELS
and BDNF gene expression in peripheral blood, 2 studies showed similar
results. Indeed, in psychotic patients, CT/ELS was associated with lower
BDNF mRNA levels, and, also with smaller hippocampal subfields vol­
ume, especially in those subjects which were BDNF Met carriers (Aas
et al., 2014; Mondelli et al., 2011). Conversely, no difference was
observed in a study performed by van Velzen and colleagues, where
BDNF mRNA levels were not significantly altered by a history of
M.G. Di Benedetto et al. Journal of Affective Disorders 308 (2022) 76–88

childhood maltreatment in adults affected by MDD/anxiety (van Velzen
et al., 2016). Five studies were performed in Caucasian populations
(Table 1).
Furthermore, some studies showed that lower BDNF plasma levels
were associated to impairment on immediate verbal recall using logical
memory test (Wechsler Memory Scale-Revised, WMS-R) (Grassi-Oliveira
et al., 2008), as well as to poorer working memory/executive function
and general cognition functioning, by evaluation with a standardized
neuropsychological test battery (Aas et al., 2014). However, no associ­
ation was observed with cognitive measures using different tests, in one
study (Theleritis et al., 2014) (Table 11S; Table 1).
3.2. Other neurotrophic factors
In addition to BDNF, further studies have investigated other NFs in
association with CT and the development of psychiatric disorders. The
investigated NFs were represented by the NT-4, the Vascular Endothe­
lium Growth Factor (VEGF), the Epidermal Growth Factor (EGF), the
Fibroblast Growth Factor (FGF) and the Transforming Growth Factor β1
(TGF-β1) (Fig. 1). The literature research produced four studies: 3 re­
ported biochemical data, and only 1 genetic data (Table 2).
In first episode psychosis, decreased levels of serum VEGF were
observed in patients with a history of CT, in comparison with patients
without trauma, whereas no significant alterations in EGF levels were
found (Di Nicola et al., 2013). Conversely, when assessing NFs levels in
MDD, depressed individuals with CT were more likely to show higher
levels of NT-4 and FGF in plasma than non-traumatized ones (Lu et al.,
2013) (Table 2). Additionally, a G × E interaction was found between 4
SNPs within TGF-β1 gene with sexual abuse, and 1 SNP with emotional
abuse, on depressive symptoms (Cattaneo et al., 2018) (Table 2). Pe­
ripheral higher levels of this growth factor were observed in a small
sample of MDD patients and controls with CT (Jovanovic et al., 2021).
To our knowledge, no studies on NFs other than BDNF are available
in relation to cognitive tasks and brain structure features.
4. Discussion
The current work represents the first systematic review of studies
investigating the relationship among CT/ELS, neuroplasticity molecules
and psychiatric disorders, with the aim to improve our understanding of
how adverse and traumatic events, especially when experienced early in
life, could mediate the vulnerability for psychiatric disorders via alter­
ations of molecules involved in neuroplasticity, in particular NFs. The
results indicate that, among the different NFs analysed, BDNF was the
most studied and consequently could represent a candidate biomarker
for the development of different phenotypes/endophenotypes such as
psychiatric symptomatology, cognitive functions and brain structure, as
well as to be a potential moderator in the relationship between child­
hood adversity and pathologies linked to psychiatry field. On the other
hand, the low numbers of available studies on other NFs did not allow us
to clearly define further potential biomarkers in this field.
BDNF is a member of the neurotrophins family, involved in brain
plasticity, including neuronal genesis, maturation and maintenance
(Begni et al., 2017; Gomez Palacio Schjetnan and Escobar, 2013). Be­
sides playing an important role in neurodevelopmental processes (Lu
et al., 2014), this NF also mediates neuronal survival during adult life,
strongly influencing cognitive functions (Kowiański et al., 2018).
Moreover, BDNF is highly expressed in both cerebral cortex and limbic
areas, where it participates in memory and learning functions (Cunha
et al., 2010). Aberrant BDNF signaling has been associated to several
neuropsychiatric conditions such as BD, MDD, SZ, ADHD, and anxiety
disorders (Autry and Monteggia, 2012; Miranda et al., 2019). Therefore,
alterations in the expression and function of BDNF may represent a
putative mechanism underlying the etiopathogenesis of these mental
health disorders.
To further support these findings, preclinical studies demonstrated
that exposure to ELS is associated with altered levels of BDNF (Bondar
and Merkulova, 2016), suggesting that the experience of these events
has a negative impact on neuronal plasticity. Interestingly, some studies
(Luoni et al., 2014) including a meta-analysis (Zhou et al., 2017) found
that pharmacological intervention during critical time windows may
prove effective in preventing neuroplastic dysfunction, leading to long-
term beneficial effects on brain function, through the increase of BDNF
expression. These findings further corroborate the role of BDNF as a
valid biomarker, due to its ability to reflect alterations occurring in the
brain and body, in the context of stress or pharmacological treatment,
which is likely dependent on its genetic and epigenetic regulation
(Cattaneo et al., 2016).
From this perspective, genetic studies reported that BDNF activity
could be influenced by the common functional rs6265 SNP within the
gene, which causes a Valine to Methionine substitution at codon 66
(Val66Met) (Egan et al., 2003). Val66Met polymorphism has been
associated with reduced trafficking of BNDF mRNA to dendrites as well
as decreased packaging and secretion of the neurotrophin (Baj et al.,
2013). Indeed, the extracellular levels of BDNF strictly depend on its
activity-dependent release, which is impaired in Met carriers (Egan
et al., 2003). This impairment has been related to the presence of the
Met allele in the pro-BDNF amino acid sequence which could impact its
ability to be packed from Golgi apparatus into secretory vesicles and to
be afterwards released into synapses (Egan et al., 2003).
This pattern of hypo-activity of BDNF in the Met form represents an
example of genetic vulnerability that could significantly mediate the
impact of environmental risk factors, including childhood adversity,
toward the development of mental health illnesses. Indeed, a

Table 2
Summary of studies included in the systematic review regarding Neurotrophin 4 (NT-4), Vascular Endothelium Growth Factor (VEGF), Epidermal Growth Factor
(EGF), Fibroblast Growth Factor (FGF), Transforming Growth Factor β1 (TGF-β1) levels and childhood trauma in psychiatric disorders.
Article Age (mean, Sample size NFs Childhood Trauma type Biological Pathology/ Results
(authors, year) years) trauma source healthy subjects
assessment

Di Nicola 28 24 VEGF CECA Serum FEP LOWER × CT

et al., 2013 EGF CECA Serum FEP NO
Lu et al., 2013 31 65 NT-4 CTQ Plasma MDD HIGHER × CT
FGF CTQ Plasma MDD HIGHER × CT
Cattaneo et al., 40 4791 (Grady TGF- CTQ Emotional, Blood Healthy subjects 4 SNPs × sexual abuse, 1 SNP ×
2018 Trauma cohort) β1 physical, sexual emotional abuse × depressive
61 1620 (Helsinki abuse symptoms
birth cohort)
Jovanovic 43 55 MDD TGF-β CTQ Plasma MDD vs Healthy HIGHER × CT
et al., 2021 45 healthy subjects
subjects

NFs: neurotrophic factors; CT: childhood trauma; CECA: Childhood Experience of Care and Abuse; CTQ: Childhood Trauma Questionnaire; FEP: first episode psychosis;
MDD: Major Depressive Disorder; SNP: single nucleotide polymorphism.

82
M.G. Di Benedetto et al.
disadvantaged genetic background in genes related to neuroplasticity
might shape the vulnerability in some individuals, due to a loss of
adaptive behaviours of resilience after exposure to an adverse environ­
ment, potentially explaining how not every child develops mental dis­
orders as a consequence of traumatizing experiences.
In this scenario, we have identified several studies investigating the
role of the Val66Met SNP in mediating the vulnerability for mental
disorders in individuals exposed to childhood adversity. The most recent
meta-analysis that was performed on this SNP, life stress and depression
dated back to 2018 (Zhao et al., 2018). The authors highlighted that Met
allele significantly moderated the relationship between stress and
depression, supporting the hypothesis of the impact of BDNF G × E in
depression; hypothesis that was for the first time supported in 2006 by
Kaufman and colleagues (Kaufman et al., 2006). They found the same
results both stratifying for ELS versus CT, for study design (cross-
sectional versus case-control/cohort studies) and for ancestry of popu­
lation (Caucasian versus Asian populations). As compared to 31 in­
vestigations reported in Zhao et al., 2018, in which the authors meta-
analysed studies from both MDD patients and HC with depressive
symptomatology, we detected a total number of 57 studies. A high
percentage in which Met allele was implicated in CT/ELS interaction
was found of 77% in mood/psychotic disorders and 63% in depressive/
psychotic subclinical symptomatology (Table 1). Most of them were
performed in Caucasian populations (85%) (Table 1). These findings
support the notion that adverse stressful events during childhood play
an important role in mood and psychotic disorders and that BDNF ge­
netic variants (the presence of the Met allele) represent a genetic
vulnerability factor that can mediate the effect of an adverse environ­
ment on the development of these mental illnesses.
On a further note, when analysing the collected results in view of the
age range of studies' participants, it is interesting to look at those studies
conducted in children and adolescents, who are potentially character­
ized by a higher neuroplasticity, but might also be more vulnerable to
the effects of traumatic events. In this perspective, 5 studies reported an
impact of 66Met allele × CT/ELS on the development of depressive
symptoms in childhood samples (Cruz-Fuentes et al., 2014; Dalton et al.,
2014; Kaufman et al., 2006; La Greca et al., 2013; Marusak et al., 2016),
whereas 4 studies did not find any association (Martin et al., 2018;
Nederhof et al., 2010; Ramsay et al., 2013; Rimay et al., 2015). Inter­
estingly, one study investigating the impact of increasing severity of
family discord, in the context of genetic vulnerability, on depressive
symptomatology at different ages, reported an association for increased
symptoms at 15 years old, which was not maintained at 20 or 22–25
years old (Dalton et al., 2014). Furthermore, at age 15, genetically
susceptible subjects exhibited fewer depressive symptoms under con­
ditions of positive family environment and more symptoms in adverse
environment, compared to non-genetically-susceptible peers. On the
other hand, at older ages, they appeared sensitive only to negative
environment, and unaffected by positive stimuli. This might indicate
that genetic susceptibility to positive stimuli diminishes over time,
potentially together with the reduction of the neuroplasticity across
ages, whereas in adulthood the impact of negative stimuli remains
without a positive counterbalance, and this might explain why results
collected in young people are not so strong, whereas the direction of the
Met × CT interacting effect on mental health problems is so much more
evident in studies conducted in adults.
To all this, we add the data that come from cognitive and imaging
assessments. In particular, an important concordant finding is the role of
the Met allele in mediating the effect of CT/ELS on cognitive perfor­
mances. In details, 12 studies observed that Met carriers with severe
exposure to CT/ELS showed impairments in emotional processing and
regulation, reappraisal ability (Bîlc et al., 2018; Hori et al., 2021; Miu
et al., 2017; Vrijsen et al., 2014), memory and executive functions,
cognitive flexibility and Perceptual Organization Index (Aas et al., 2013,
2014; Ferrer et al., 2019; Gabrys et al., 2017; Gatt et al., 2009; Savitz
et al., 2007; van Oostrom et al., 2012; Veras et al., 2019), with only two
83
Journal of Affective Disorders 308 (2022) 76–88
negative findings (Hernaus et al., 2014; Tian et al., 2021). These results
are in line with previous studies showing that CT/ELS can impair
cognitive functions, including working memory, either in healthy sub­
jects or psychiatric patients, even years after the traumatic experience
(Dodaj et al., 2017; Shannon et al., 2011).
As further support to these conclusions, 6 studies reported the evi­
dence that Met carriers showed smaller hippocampal volumes in genetic
and expression studies (Aas et al., 2013, 2014; Carballedo et al., 2013;
Frodl et al., 2014; Gatt et al., 2009; Mondelli et al., 2011). The hippo­
campus is a fundamental brain region implicated in cognitive functions,
including those related to the memory domains and to emotion regu­
lation and processing that are impaired in Met carriers with a CT history
(Opitz, 2014; Zhu et al., 2019). As a matter of facts, the hippocampal
structure significantly develops, both in volume and complexity of
subregions, during childhood (Brown and Jernigan, 2012; Gómez and
Edgin, 2016; Tamnes et al., 2018), a period that is characterized by a
high level of neuronal plasticity and during which these complex
cognitive abilities begin being developed (Herba et al., 2006; Schneider
and Ornstein, 2015). For these reasons, exposure to trauma during these
critical years increases the risk for structural and functional alterations
of regions that are not completely developed (Gould et al., 2012; Majer
et al., 2010; Malhi et al., 2019), in a way that has been found to be
specific for the different subtypes of CT (Cassiers et al., 2018). For
example, it has been suggested that sexual abuse affects more severely
the reward circuit and the hippocampal volume, whereas emotional
maltreatment has been more related to alterations in the fronto-limbic
socioemotional networks (Cassiers et al., 2018).
In relation to other brain regions, most of the studies reported the
involvement of Met allele, whereas others, even though in minority,
showed evidence for a role of Val/Val genotype. In particular, 6 studies
found increased stress reactivity by smaller amygdala volumes and less
gray matter among Met allele carriers exposed to ELS and childhood
adversity (Gatt et al., 2009; Gerritsen et al., 2012; Juhasz et al., 2011;
Marusak et al., 2016; Tatham et al., 2016; van Velzen et al., 2016),
whereas other studies reported the implication of the Val/Val genotype
(Jin et al., 2019; Tian et al., 2021; van Velzen et al., 2016).
From the peripheral point of view, most of biochemical and
expression studies agreed with lower peripheral levels of BDNF, asso­
ciated with CT/ELS, observed in patients affected by mood and psy­
chotic disorders (72%), prevalently of Caucasian origin. Importantly,
lower levels were associated to impairments in immediate verbal recall,
reduced working memory/executive function and general cognition, as
well as to smaller left hippocampal volume (Aas et al., 2014; Grassi-
Oliveira et al., 2008; Mondelli et al., 2011). Thus, these findings
strengthen the evidence that Met allele and lower BDNF levels, with
impairments in specific cognitive functions and specific brain areas
(mainly hippocampus volume) could be considered as potential bio­
markers for mood and psychotic disorders in Caucasian populations. It is
also important to underline that these data are also supported by 6
studies on BDNF promoter methylation pattern.
Although CT/ELS is generally accepted as an important risk factor for
brain impairment and mental disorders (Opel et al., 2019; Vythilingam
et al., 2002), not all children who experience traumatic events ulti­
mately develop them, but many apparently remain resilient during their
life; therefore, the genetic background plays a key role in mediating this
diverse vulnerability. In this regard, in order to give a better perspective
of Met-allele vulnerability in the context of CT/ELS, we provide a
comprehensive graphical representation of collected results, explaining
how this interaction can influence the risk to develop psychiatric dis­
orders, impact cognitive domains and alter brain morphological struc­
tures and functioning (Fig. 2).
On the other hand, controversial data as well as inconclusive results
are mostly present in anxiety-related disorders and in self-harm behav­
iours and substance abuse, both in genetic and in biochemical/expres­
sion studies (Table 1). For OCD, one study reported the involvement of
Met allele (Hemmings et al., 2013), and higher BDNF levels (Li et al.,
M.G. Di Benedetto et al.
Fig. 2. Graphical representation, based on collected results, of the interaction between BDNF 66Met allele genetic background and exposure to childhood adversities.
The reduced BDNF bioavailability due to the presence of the 66Met allele, combined with the exposure to traumatic experiences during childhood can potentially
determine altered neuroplasticity and therefore affect brain development. These, in turn, can explain the observed brain structural and functional alterations,
cognitive functions impairment, as well as psychiatric symptomatology.
2021), whereas another showed negative results (Breet et al., 2019). For
PTSD, one study reported the involvement of Val allele (Jin et al., 2019),
2 studies with BDNF lower levels (Angelucci et al., 2014; Hauck et al.,
2010), and 1 showing no alterations (Dell'Osso et al., 2009). On the same
line, when we considered self-harm behaviours and substance abuse, the
available studies and collected results are not enough to reach consistent
conclusions. Although these inconclusive results, it is interesting to
underline that some authors agreed on the role of Val/Val genotype
when considered the interaction with childhood maltreatment and
higher anxiety development, considering also the important evidence
that Val allele is a potential risk factor for anxiety disorders suscepti­
bility (Gatt et al., 2009; Jin et al., 2019; Min et al., 2013).
5. Limitations
The studies reported in this systematic review suffer from some
important limitations. For instance, we included studies characterized
by small sample sizes with a lower statistic power as evidenced in the
Newcastle-Ottawa quality assessment (Caldwell et al., 2013; Carver
et al., 2011; Hernaus et al., 2014; Hori et al., 2021; Kaufman et al., 2006;
La Greca et al., 2013; Min et al., 2013; Quinn et al., 2012), by different
age range (from childhood to adulthood), and by different tests and
methodologies applied for the valuation of CT/ELS, symptomatology,
cognitive and structural brain functions. Although most of studies uti­
lized validated psychometric instruments and used methods of recruit­
ment which did not limit the generalizability, as obtained from the
Newcastle-Ottawa quality assessment, phenotypes were heterogeneous
84
Journal of Affective Disorders 308 (2022) 76–88
mainly in relation to anxiety-related disorders and in self-harm behav­
iour and substance abuse.
Moreover, the Met allele has a different frequency across general
population and ranges from 0.55% for Sub-Saharan African individuals
to 19.9% and 43.6% for European and Asian subjects, respectively
(Petryshen et al., 2010). Caucasians appear to be more susceptible to the
effects of the 66Met, suggesting an ethnicity-specific effect of this
variant (Notaras et al., 2015). Besides, cultural differences between
Asian and Caucasians suggest that the interaction effect between BDNF
Val66Met SNP and childhood adversity in psychiatry may differ across
cultural contexts.
As for the difference in results between longitudinal and cross-
sectional group, retrospective assessment of exposure in cross-
sectional studies was often used in mental health research, because
many important exposure factors occur years before the disorder ap­
pears (e.g. childhood sexual abuse); however, the several dangers of
retrospective data are well known: normal forgetting, revisionist recall
and the best antidote to ills of retrospective data is collecting data
prospectively in a longitudinal study where repeated prospective mea­
surement of environmental pathogens and mental health status en­
hances the reliability and precision of measurement and augments
scientific inference.
Stress assessment methods used in studies are also an important
factor influencing the results. Specifically, genetic moderation was
stronger in studies using in-person interviews or objective measures
(such as trained investigators to assess stress) compared to studies which
used self-reported methods (Verhagen et al., 2010).
M.G. Di Benedetto et al.
The year of the publication is similarly a further important factor.
This implicates to have available an enough large sample size to perform
genetic studies (specific cohorts in longitudinal studies), more precise
methodology for high throughput genotyping and for peripheral and
mRNA expression detection, more precise instruments for imaging brain
regions recognition, and more accuracy in the clinical and neuropsy­
chological assessments with huge availability of specific battery tests.
Furthermore, it is extremely important to note that we are not
reporting information regarding pharmacological treatment that
mentally ill subjects might be undergoing, since in many of the included
studies there was no clear description of the effect of this variable on the
outcomes we took in consideration.
Finally, results about NFs different from BDNF, such as NT-4, VEGF,
EGF, FGF, TGF-β1, are more limited, or inconsistent, and do not allow us
to properly address the role of these molecules in the vulnerability of
developing psychiatric disorders as a consequence of CT/ELS exposure.
6. Conclusion
The causal relationship between CT/ELS and the vulnerability for
psychiatric disorders remains still unclear, however multiple biological
mechanisms concur to shape such susceptibility, including abnormal­
ities in neuroplasticity. The studies discussed in this review identify a
distinct BDNF × environment interaction in predicting mood disorders,
associated to specific cognitive (phenotype) and imaging (endopheno­
type) features.
Other neurotrophic factors, including NT-4, VEGF, EGF, FGF and
TGF-β1, are also known to play a fundamental role in both a proper
functioning of neurons and development of brain circuits, and their
alteration has been observed in many psychiatric disorders (Amoli et al.,
2019; Dmitrzak-Weglarz et al., 2013; Lee et al., 2015; Lim et al., 2016;
Turner et al., 2016). However, given few evidence collected, further
studies on larger cohorts are needed to establish the possible contribu­
tion of these important NFs and their relationship with the effects of CT
in mood disorders.
In conclusion, we suggest that BDNF plays a key role in CT/ELS,
mood, psychotic and anxiety disorders passing through cognitive func­
tions and hippocampal architecture. Thus, BDNF could represent a po­
tential biomarker mediating the impact of CT/ELS on these pathologies.
In order to uncover the complexity of the involved biological mecha­
nisms, future studies should characterize in detail the recruited clinical
sample, including ethnicity, age, sex, type and time of trauma. More­
over, there is a need for more consistency in the symptomatology
assessment, as well as for the inclusion of brain imaging studies,
biochemical and gene expression assessments, in order to obtain a full
picture of what happens in traumatized individuals at higher risk to
develop psychiatric disorders, with regard to their neuroplasticity.
Role of the funding source
Funding: MGDB, AC, NC, CS received funding from Ricerca Corrente
(Ministry of Health).
CRediT authorship contribution statement
Maria Grazia Di Benedetto: Investigation, Writing – original draft,
Validation. Catia Scassellati: Investigation, Writing – original draft,
Validation. Nadia Cattane: Writing – review & editing, Validation.
Marco A. Riva: Writing – review & editing, Validation. Annamaria
Cattaneo: Writing – review & editing, Validation.
Declaration of competing interest
All the authors declare no conflicts of interest.
85
Journal of Affective Disorders 308 (2022) 76–88
Acknowledgments
The manuscript was supported by Ricerca Corrente (Italian Ministry
of Health).
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.jad.2022.03.071.
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