Childhood Trauma in Schizophrenia: Current Findings and Research Perspectives

1Schizophrenia is a severe neuropsychiatric disorder that affects about 1% of the population. It is particularly prevalent in young adults between 20 and 30 years of age and leads to disability in about half of the patients. The disorder is among the leading cause of years lived with disability worldwide, and, among all mental illnesses, schizophrenia is associated with the highest socioeconomic costs. This high disorder burden is due to the early onset of schizophrenia in late adolescence and early adulthood and the persistence of symptoms throughout adult life in over 90% of affected patients despite meeting remission criteria. Symptom improvement has been measured as “therapeutic response,” which was defined by, e.g., a 20% symptom reduction after 4 weeks of treatment. Subsequently, the term “remission” was introduced, requiring a simultaneous reduction of all diagnosis-specific core symptoms (positive and negative symptoms) to a level of “mild or less” on established questionnaires (Positive and Negative Syndrome Scale, Brief Psychiatric Rating Scale, Scale for the Assessment of Positive Symptoms, Scale for the Assessment of Negative Symptoms) for a minimum of 6 months. However, since only a small portion of schizophrenia patients can achieve this, the new definition of “recovery” was conceived, which takes into account not only a reduction of clinical symptoms, but also an improvement in occupational, social and adaptive functioning. However, only 20% of people with schizophrenia are able to work in the primary labor market, and only about 30% are able to maintain a stable relationship. The unfavorable disorder course is associated with multiple episodes and residual symptoms, mainly negative symptoms and cognitive deficits. Cognitive deficits as a core feature of the disorder are present in domains such as episodic memory, executive function, social cognition, and attention. These deficits may lead to memory decline, social withdrawal, and ultimately impaired social and role functioning as measured by the Global Assessment of Functioning (GAF) scale. Several studies have operationalized the term “recovery” by using the GAF scale to investigate the long-term outcome and its relevant influencing factors in psychosis patients. While childhood trauma has been repeatedly shown to negatively impact “recovery” among schizophrenia patients, some of these findings were only partially replicated, hereby leading to a rather heterogeneous body of evidence and consequently emphasizing the need for further research into the neurobiological underpinnings of this association.

2Twin studies found a heritability of about 60–80% for schizophrenia, and new genome-wide association studies (GWASs) revealed a total of 145 genetic risk loci, the single nucleotide polymorphisms (SNPs), each with only a weak effect. GWAS-based schizophrenia polygenic risk scores showed associations with social and cognitive impairments during early childhood, which were interpreted as being possible early manifestations of genetic liability. In schizophrenia, however, about 8,300 SNPs have been estimated to contribute to a common risk of only 32%, suggesting that—in addition to the genetic background—environmental factors may be the basis of pathophysiological processes.

3Schizophrenia has been regarded as a neurodevelopmental disorder in which defective genes and environmental factors interact and induce symptoms of the disorder. The neurodevelopmental hypothesis proposes that schizophrenia is related to adverse conditions, such as genetic background and environmental factors, which lead to abnormal brain development. Disorder onset and first symptoms occur in early adulthood, after synaptic pruning. In the two-hit model, a neurodevelopmental disturbance during the perinatal period may lead to dysfunction of neuronal circuits and vulnerability to stress during vulnerable brain periods, and later psychosocial stress or drug abuse, for example, may then trigger the disorder. Today, researchers propose that several hits in the form of genetic and environmental risk factors may interact in a complex way during key periods of neurodevelopment and cumulate in the expression of the disorder state (Figure 1); these risk factors are hypothesized to be common across neuropsychiatric disorders such as schizophrenia, bipolar disorder, and major depression. The neural diathesis-stress model proposes that psychosocial stress acts upon a pre-existing vulnerability and triggers the symptoms of schizophrenia. Specific stress factors have been identified that trigger or worsen symptoms of the disorder, such as perceived uncontrollable threats to important goals and socio-evaluative threats. In addition, schizophrenia patients are more emotionally reactive than non-psychiatric controls to stressors such as higher arousal and anxiety.

4Stress sensitization may play a role in schizophrenia by lowering the vulnerability threshold for the disorder. The neurobiological consequence of stress sensitization involves dysregulation of the hypothalamus-pituitary-adrenal (HPA) axis, which is the major stress neuroendocrine system of the body and is involved in the production of the stress hormone cortisol by the adrenal glands. A stress-induced activation of the HPA axis contributes to dopamine sensitization in mesolimbic areas and increases stress-induced striatal dopamine release. These effects are important because increased dopamine neurotransmission with overstimulation of the D2 receptors in several brain regions has been hypothesized in the pathophysiology of schizophrenia, a hypothesis that is supported by the antipsychotic effects of dopamine receptor antagonists.

5In animal models, acute or chronic stress decreased brain-derived neurotrophic factor (BDNF) levels in the hippocampus, which is involved in synaptogenesis. In accordance with these findings, stress was found to reduce hippocampal dendrites. Additionally, application of glucocorticoids reduced hippocampal BDNF levels, mimicking the stress reaction. Animal models have shown that chronic stress or repeated administration of glucocorticoids results in degeneration of hippocampal neurons, with decreased soma size and atrophy of dendrites. This stress-induced glucocorticoid neurotoxicity may contribute to a volume loss in vulnerable brain regions such as the hippocampus; hippocampal volume reduction has been reported for schizophrenia even in early disorder stages. Moreover, elevated glucocorticoids can suppress myelination and may affect calcium channels. Both mechanisms are related to the pathophysiology of schizophrenia and result in impaired macro- and microconnectivity.

6In rodents, juvenile social isolation and maternal separation are models of childhood stress, and these animal models have shown lasting effects on the HPA axis along with deficits in hippocampus-dependent learning and memory. The mouse model of juvenile social isolation builds on social isolation immediately after weaning: social isolation leads to schizophrenia-related behavior, such as deficits in prepulse inhibition of the acoustic startle response (PPI) and working memory and decreased social exploration. Furthermore, deficits in oligodendrocyte morphology, reduced myelin thickness, and decreased myelin basic protein and myelin-associated glycoprotein expression have been detected in brain regions and resemble the deficit of myelination and oligodendrocytes in schizophrenia. Importantly, in contrast with the effects of adult social isolation this early-induced phenotype cannot be rescued by later social re-integration, implicating impaired recovery, such as in schizophrenia (Table 1).

7An increased release of glucocorticoids has been proposed to play a role in the pathophysiology of schizophrenia, and the stress-diathesis model proposes that schizophrenia is associated with elevated baseline and challenge-induced HPA activity. In addition, cortisol treatment can induce psychotic symptoms. This model is supported by reports of increased levels of blood cortisol and a blunted cortisol response to stress; the latter was suggested to reflect impaired responsiveness of a desensitized system. Indeed, a meta-analysis on stress-moderating effects of baseline cortisol levels revealed that schizophrenia patients have lower cortisol levels than controls during anticipation of social stress and after exposure to it. A reduced ability of these patients to appropriately contextualize past experiences has been hypothesized to underlie the missing cortisol response in these experiments. A blunted cortisol stress reactivity in schizophrenia patients was again reported in a more recent meta-analysis by, who also pointed toward a possible publication bias as well as an overall small number of studies with properly standardized cortisol protocols as limiting factors for the interpretation of these findings. Moreover, treatment with antipsychotics may have influenced the results. However, the HPA axis response was also impaired in medication-naïve patients with first-episode schizophrenia, i.e., the cortisol response was flattened, indicating impairments in stress processing.

8According to the neurodevelopmental hypothesis, prodromal and psychotic symptoms occur for the first time in adolescence. In adolescents at ultra-high risk of psychosis (UHR), increased resting cortisol levels have been reported and associated with higher rates of critical statements from relatives and negative self-concept, indicating that a dysfunction of the HPA axis is related to environmental characteristics. The cortisol level after awakening, which reflects HPA regulation, was also increased in this patient group compared with healthy controls. Additionally, in UHR adolescents a reduced stress responsivity of the HPA axis was correlated with smaller gray matter volumes of the hippocampus and prefrontal, temporal, and parietal cortices, which may represent the neural components in the stress vulnerability model (Figure 1). Interestingly, those individuals who subsequently developed psychosis showed a significant blunting of the HPA stress response.

9In addition to effects on the hormone system, environmental factors, such as childhood trauma, may contribute to genome–environment interactions; these interactions are mediated by epigenetic processes, such as DNA methylation and histone modifications. Hypomethylation of DNA repetitive sequences has been detected in first-episode schizophrenia patients with a history of childhood trauma. Inhibitors of histone deacetylases (HDAC) have been suggested to improve cognitive function and ameliorate disorder pathogenesis in neuropsychiatric disorders such as schizophrenia. In schizophrenia patients, we found that the experience of childhood trauma was related to increased HDAC1 levels in blood samples. This corresponds with recent findings that HDAC1 levels are increased in the prefrontal cortex and hippocampus of patients with schizophrenia (Figure 1). Interestingly, in mice with early life stress as a model of childhood trauma HDAC1 expression is increased in the prefrontal cortex and hippocampus, and these mice display schizophrenia-like behavioral phenotypes, such as deficits in PPI, working memory, and synaptic plasticity (Table 1). The effects of childhood trauma on epigenetic mechanisms and the relationship with cognition and disorder symptoms should be investigated in more detail in larger studies in schizophrenia patients.

10Childhood trauma can be assumed to be a severe form of stress that renders individuals more vulnerable to developing schizophrenia. In a meta-analysis of 18 case-control studies (including 2048 patients with psychosis and 1856 non-psychiatric controls), 10 prospective studies (including 41,803 participants), and 8 population-based cross-sectional studies (35,546 participants), found that adverse experiences in childhood significantly increased the risk to develop psychosis and schizophrenia. The group showed a significant association between childhood adversity, including trauma, and psychosis: the odds ratio was between 2.72 and 2.99, indicating a strong association between childhood adversity and psychosis, including schizophrenia. Epidemiological studies show that exposure to early stress in the form of abuse and neglect in childhood increases the risk to later develop schizophrenia. In schizophrenia patients, the most frequent subtype of trauma was emotional neglect, but rates of physical abuse and physical neglect were also significantly increased. Childhood abuse and neglect are known to have a negative influence on cognition in patients with schizophrenia and bipolar disorder. In first-episode schizophrenia patients, exposure to childhood neglect was a predictor for impairment in social cognition and poorer verbal learning, whereas abuse was not. A study in Chinese patients with schizophrenia reported that physical neglect was negatively correlated with delayed memory and attention and with the total cognition score. A large study assessed 406 patients with schizophrenia spectrum disorders with the Childhood Trauma Questionnaire and found that physical abuse, sexual abuse, and physical neglect were significantly associated with reduced scores in working memory, executive function, and verbal tasks. In another study, metacognitive capacity was lower in patients with childhood emotional abuse. Female patients who reported childhood physical abuse had more psychotic and depressive symptoms than both women without this history and men with or without a trauma history.

11UHR individuals more frequently had a history of childhood trauma, such as emotional and sexual abuse as well as emotional and physical neglect, while emotional neglect in particular was associated with paranoid symptoms. Even in UHR individuals, a history of childhood maltreatment predicted poorer functioning at follow-up in both those who had transitioned to psychosis and those who had not. Childhood trauma did not predict transition to psychosis, but after a 2-year follow-up UHR individuals with higher levels of childhood trauma had higher levels of attenuated positive symptoms, general symptoms, and depressive symptoms and lower levels of global functioning. In children born to parents with major psychoses, those who were exposed to abuse or neglect had lower IQ and GAF scores and displayed poorer cognitive performance in visual episodic memory end executive functions.

12Gene–environment interactions have been suggested to play a role in the pathophysiology of schizophrenia (Figure 1). In 429 patients with schizophrenia or schizoaffective disorder, the catechol-O-methyltransferase (COMT) genotype moderated the effects of childhood trauma on cognition and symptoms in methionine (met) carriers with a history of childhood physical abuse and more severe positive symptoms; Met carriers with a history of emotional neglect had more severe negative symptoms. In another study, a variant of the FK506 binding protein 5 (FKBP5) gene interacted with childhood trauma and affected attention in both schizophrenia patients and healthy controls. In patients with schizophrenia and affective disorders, an interaction between a variant in the serotonin transporter gene 5-HTTLPR and childhood trauma was observed in the California Verbal Learning Test. A variant of BDNF Val66Met polymorphism was shown to moderate the impact of childhood adversity on later expression of affective symptoms in schizophrenia patients. In 249 patients with schizophrenia spectrum disorder, carriers of the met allele of the BDNF gene exposed to high levels of childhood physical and emotional abuse demonstrated poorer cognitive functioning than monozygotic valine carriers. Moreover, Met carriers exposed to childhood sexual abuse showed reduced right hippocampus volume, suggesting negative effects on neuroplasticity in the brain. On an epigenetic level, a recent review concluded that childhood trauma was associated with global DNA hypomethylation and reduced BDNF gene-expression in first-episode psychosis subjects. However, the literature on gene–environment relationship in the etiology of psychosis is rather heterogeneous as the results from candidate gene studies could quite frequently not be replicated. Thus, epidemiological studies investigating the interplay between familial and environmental factors in the development of psychosis within large cohorts are another valuable resource for further insight. Using these epidemiological approaches, it was found that environmental risk factors, such as childhood adversity, and a family history of affective and psychotic disorders additively impact the psychosis risk across a multidimensional spectrum of positive, negative, cognitive and affective symptoms. Moreover, studies repeatedly showed that childhood adversity and familial liability increased the risk predominantly for positive symptoms of psychosis, such as delusions and hallucinations, as well as affective symptoms. Therefore, the connection between childhood trauma, familial liability and the onset of psychosis is increasingly being labeled as one of the key mechanisms of the proposed “affective pathway” to psychosis.

13Emotional neglect in patients with schizophrenia was negatively associated with total gray matter volume and specifically with the density and volume of the dorsolateral prefrontal cortex, which in turn predicted disorganization. Interestingly, additive effects of childhood trauma and being a BDNF met carrier on volume loss in the hippocampal subregions cornu ammonis (CA)4/dentate gyrus and CA2/3 have been reported in schizophrenia. Childhood maltreatment has been associated with reduced hippocampal volume as well as amygdala hyperreactivity and was shown to predict poor treatment outcome. A functional magnetic resonance imaging study showed that childhood trauma exposure resulted in aberrant function of parietal areas involved in working memory and of visual cortical areas involved in attention. On the basis of these data, the authors hypothesized that childhood trauma in psychosis contributes to alterations in attention during performance of working memory tasks. During a theory-of-mind task that reflected social cognition, childhood trauma was associated with activation of the posterior cingulate gyrus, precuneus, and dorsomedial prefrontal cortex in patients with schizophrenia. In addition, decreased connectivity between the posterior cingulate/precuneus region and the amygdala was shown in patients with high levels of physical neglect and sexual abuse during childhood (Figure 1). Finally, an fMRI study showed an increased brain response to emotionally negative faces compared with the response to positive faces in patients with psychosis and high childhood trauma, as assessed by the Childhood Trauma questionnaire. Overall, findings from MRI, genetic, and large-scale gene expression and epigenetic studies often were not reproducible and need to be replicated in larger samples before final conclusions can be drawn.

14It must be noted that effects of childhood trauma are not specific for schizophrenia. In childhood-maltreatment related post-traumatic stress disorder (PTSD), a recent meta-analysis clearly showed bilateral reduction of hippocampal and amygdala volumes in the PTSD group compared to healthy controls. In addition, cognitive deficits in different domains such as general intelligence, language, information processing, learning and memory and executive skills have been observed in trauma-exposed children with PTSD compared to controls. Trauma-exposed children with PTSD had poorer general intelligence and visuospatial skills compared with trauma-exposed children who did not develop PTSD. Dysfunction of the HPA axis in PTSD has been reported, particularly hypersensitivity of the glucocorticoid receptor (GR). Single-nucleotide polymorphisms (SNPs) in the GR and FKBP5 gene were associated with PTSD risk and the FKBP5 gene SNP interacted with childhood adversity to moderate PTSD risk. Other neurochemical markers for PTSD include neurotrophic factors such as BDNF. Regarding epigenetic factors, DNA methylation is so far the best studied in PTSD and could be responsible for long-lasting effects of gene–environmental interactions. Furthermore, effects of parental trauma could be transmitted to the next generation by epigenetic marks.

15A meta-analysis showed that childhood psychological abuse and neglect were strongly associated with depression. Other factors of childhood maltreatment related to adult depression were emotional abuse, sexual abuse, domestic violence and physical abuse. Regarding genetic factors, the corticotropin-releasing hormone receptor 1 (CRHR1) gene may moderate the effects of childhood trauma on depression. BDNF gene methylation level was correlated with depression.

16In the field of childhood trauma research, it is not uncommon to investigate early stress by clinically assessing whether some form of maltreatment took place in the individual’s childhood without applying standardized trauma or maltreatment questionnaires. However, in the context of clinical studies and to further both the validity and the reliability of the observed effects in childhood trauma studies, standardized instruments should be used. Below, we present a representative selection of the most commonly used questionnaires because it would be beyond the scope of this article to include all the available ones.

17Overall, questionnaires on childhood trauma can be categorized into instruments to diagnose PTSD and more specialized assessment tools, whose goal is to assess childhood maltreatment in depth rather than to validate a DSM or ICD diagnosis. A vast number of PTSD-specific questionnaires are available, but we will give an overview of three structured interviews and one self-report measure. The Structured Clinical Interview for DSM-IV (SCID) and the Composite International Diagnostic Interview (CIDI) are structured interviews that cover the entire spectrum of mental disorders and can be applied by both trained professionals and trained lay interviewers. Both interviews have a specific section on PTSD, are frequently used in epidemiological studies and can be used to validate a suspected diagnosis of PTSD. Another instrument that has also been extensively reviewed and is regarded by some as the gold standard in diagnosing PTSD is the Clinician-Administered PTSD Scale (CAPS). The CAPS is a 30-item structured interview that should ideally be administered by clinicians and clinical researchers with a working knowledge of PTSD. In addition to these structured interviews, the PTSD Checklist for DSM-5 (PCL-5), a 20-item self-report measure that assesses the 20 DSM-5 symptoms of PTSD, can be used to solidify a PTSD diagnosis.

18Besides these PTSD-specific diagnostic instruments, a large group of questionnaires focuses on distinct types of childhood maltreatment that do not automatically have to fulfill the PTSD criteria. Childhood maltreatment is usually assessed along the domains of abuse (physical, sexual, emotional/psychological) and neglect (emotional/psychological, physical). The most commonly used childhood maltreatment self-reports and semi-structured interviews are described here. The Childhood Trauma Questionnaire (CTQ, ) is one of the most frequently used self-reports in the current literature. It has a total of 28 items and measures the above mentioned five types of maltreatment, i.e., emotional, physical, and sexual abuse, and emotional and physical neglect. It also includes a three-item minimization/denial scale to assess the potential underreporting of maltreatment. Another common self-report tool is the Personal Safety Questionnaire (PSQ), which is based on the Conflicts Tactics Scales. The PSQ queries the occurrence of specific incidents and mainly focuses on physical or sexual abuse; it can be used to sequentially assess incidents that occur in childhood, adolescence, or adulthood. This feature allows researchers to examine both the type (physical or sexual) and timing of abuse over life periods. A questionnaire that specifically focuses on sexual abuse in childhood is the Child Sexual Assaults Scale (CSAS, ). This instrument assesses sexual abuse along five subscales: demographic variables subscale, PTSD symptom subscale, center for epidemiologic studies depression subscale, traumatic events questionnaire, and childhood sexual experiences subscale. An advantage of the CSAS is that it not only assesses possible traumatizing sexual events, but it also checks for PTSD and affective symptoms, therefore mirroring the complex nature of this kind of childhood trauma. Because large multi-center studies have become more important in today’s psychiatry, the Early Trauma Inventory Self Report (ETI-SR) represents a powerful assessment tool that has the advantage of being validated many languages (German, French, Chinese, Spanish, Portuguese, ). The ETI-SR is a 56-item inventory that assesses the presence of childhood trauma with a series of “yes or no” questions and includes specific items for physical (9 items), emotional (7 items), and sexual abuse (15 items) and general trauma (31 items). It also assesses the frequency of trauma, age at trauma, perpetrator, and other variables before age 18. The Traumatic Life Events Questionnaire (TLEQ) can be a viable alternative if a broader perspective on possible traumatic or adverse life events is desired. This tool assesses exposure to 16 types of potentially traumatic events, including natural disasters, exposure to warfare, unexpected death of a loved one, severe physical assault, different forms of sexual abuse, and experiences of stalking, and also accounts for the frequency and severity of the named traumatic experiences. A rather brief self-report questionnaire is the Adverse Childhood Experiences (ACE) questionnaire. In a total of 17 questions, this questionnaire assesses childhood abuse within the domains of psychological, physical, and sexual abuse. Additionally, it sets itself apart from many other self-reports because it also includes four categories of childhood exposure to household dysfunction, i.e., substance abuse, mental illness, violent treatment of mother or stepmother, and criminal behavior in the household.

19With regards to semi-structured interviews, two more questionnaires are of interest because they both have specific advantages and can be useful in clinical studies: The Early Trauma Inventory and the Children’s Life Events Scale (CLES). The former instrument is a semi-structured interview that assesses four domains of traumatic experiences (physical, emotional, and sexual abuse and general traumatic experience) and then addresses the most serious trauma in an additional question. This additional question can be very useful in clinical settings because of the potential need for an extended conversation about the most burdensome issue. The CLES, which is an expansion of The Source of Stress Inventory, is a checklist composed of 50 moderate-to-major stressful childhood events that covers categories such as negative emotional feedback, family deaths, maltreatment, failure in school, and family dysfunction.

20When selecting a questionnaire, equally important to the frequency of use is the analysis of the resulting dataset. Therefore, in the next section we critically discuss current analysis methods and give an outlook on advanced mathematical analysis methods.

21Childhood trauma poses several challenges when it comes to data integration and data analysis, mainly with regards to the temporal resolution and the reciprocity and interdependency of the observed phenotypes. The temporal problem arises because most adverse events, which presumably occurred in childhood, can only be assessed retrospectively and are therefore prone to a certain recollection bias. Furthermore, the sequence in which adverse events in childhood were experienced and psychiatric symptoms developed is often unclear. Another issue lies in the reductionist steps that most studies take during “preprocessing” of the data on adverse experiences or events. In the first step, the data are categorized into specific overarching domains, such as physical or emotional abuse, which removes a great amount of the detailed information given by the individual. The next quite common reductionist step is to build sum scores for these domains or, in some cases, a total score for all domains. In this second step, information given by patients is summarized into nominal or ordinal categories, for example “childhood trauma present” versus “childhood trauma absent” or “high childhood trauma,” “medium childhood trauma,” and “low childhood trauma”. This step removes a great amount of variance and heterogeneity within the dataset that could be important for future analyses. Overall, these preprocessing steps take the interdependency and reciprocity of these adversary factors and their association with the observed psychopathology out of the equation. The possible interactive effects between various kinds of adverse experiences, psychopathological symptoms, and organic features (i.e., structural and functional MRI, DNA variants, gene expression, or epigenetic mechanisms) of the affected individual are largely removed. Thus, most current studies in the field of childhood trauma research are trying to investigate a highly dynamic phenomenon, in which various risk and protective factors interact with each other and produce complex clinical and organic phenotypes, with simplified models that use ordinal and nominal grouping and univariate statistics (Figure 2). At the same time, age and sex are mostly controlled for, even though age- and sex-specific effects are found in various psychiatric disorders. Based on these methodological issues, the potential advantage of using unbiased and explorative machine learning and multivariate analysis techniques becomes evident. While supervised learning algorithms such as neural networks, tree-based algorithms and vector machines can deliver insights into psychiatric disorders through classification and regression of labeled training data, unsupervised learning algorithms are able to complement this by uncovering latent structures within an unlabeled training dataset (Figure 3). Hence, latent variable models based on factor analysis or singular value decomposition (i.e., principal component analysis, non-negative matrix factorization, partial least squares) might be used to explore associative effects between variables of interest. In this context, these associative effects could then be used to further explore causal links between different kinds of childhood adversity, psychopathology, and organic features, e.g., MRI images or DNA expression profiles. Other unsupervised techniques like hierarchical clustering or self-organizing maps could be employed to find mathematically sound clusters of adverse childhood effects or certain phenotypical or organic patterns of childhood trauma, that would be lost if one kept to the overly restrictive approach of using DMS diagnoses or categorical/nominal grouping of childhood trauma loading. Another interesting topic for analysis with multivariate tools is the timeline of each individual, which is defined by specific childhood trauma experiences and onset and development of certain symptoms.

22The effect of childhood trauma on psychopathology and organic variables, such as brain structure and DNA variants (see above), cannot be reduced to a static observation, and we need to consider longitudinal data, the course of disorder, and the biography of each individual. Therefore, mixture models involving (Hidden) Markov Models, Directed Graphical Models, and Bayesian Networks, would help to model, predict and consequently explain the connection and evolution of childhood trauma, psychopathology, and, if desired, its organic correlates. Some of these approaches have already been undertaken in the field of PTSD research; however, to our knowledge in the field of childhood trauma and psychosis research no studies have yet been published on machine learning techniques (Figure 1). Therefore, this still unexplored field of unbiased, data-driven childhood trauma research has exciting potential and should be one of the priorities for future research.

23PF, BM, AS, and DP designed this manuscript. DP, AS, LK, FS, SP, BM, AF, TS, NK, and PF managed the literature searches, interpreted the data, and prepared the manuscript. All authors contributed to and approved the final manuscript and reviewed it critically for important intellectual content.

24PF has been an honorary speaker for AstraZeneca, Bristol Myers Squibb, Lilly, Essex, GE Healthcare, GlaxoSmithKline, Janssen Cilag, Lundbeck, Otsuka, Pfizer, Servier, and Takeda and has been a member of the advisory boards of Janssen-Cilag, AstraZeneca, Lilly, and Lundbeck. AS was honorary speaker for TAD Pharma and Roche and a member of Roche advisory boards. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling Editor declared a past co-authorship with one of the authors PF.