Genome-wide methylation analysis of treatment resistant schizophrenia.

Various studies have investigated the relationship between genetic polymorphisms of antipsychotic drug-metabolizing agents and drug response. DNA methylation is a form of epigenetic modification that regulates gene expression. Few studies have analyzed the relationship between genome-wide methylation patterns and treatment resistance schizophrenia. The primary aim of this pilot study is to investigate the association between treatment resistance status and genome-wide DNA methylation in schizophrenia patients. Treatment resistance status was determined for 109 patients with schizophrenia. Treatment resistance was the primary outcome variable in a model, including methylation status of white blood cells using the Illumina 450 array. The genome-wide DNA methylation levels in 109 Schizophrenia subjects did not show that DNA methylation sties were associated with resistance status. From our study, it is evident the importance of continuing to investigate the relationship between DNA methylation and antipsychotic response to personalize treatment in schizophrenia. Future studies require larger prescription databases to build on the results presented in this pilot study.

Epigenetics for Drug Discovery: Dissecting the Effect of High Antipsychotic Dosage and D2 Blockage on Peripheral DNA Methylation.

INTRODUCTION: The relationship between genetic polymorphisms of antipsychotic drug-metabolizing agents and drug receptors has been often investigated. DNA methylation is a form of epigenetic modification that regulates gene expression. Few studies have analyzed the relationship between genome-wide methylation patterns and antipsychotic dosage. The primary aim of this pilot study was to investigate the association between antipsychotic dosage and genome-wide DNA methylation in patients with schizophrenia (SCZ). METHODS: Current dosage of antipsychotic medications was assessed in 136 patients with SCZ. Dosage was standardized using three different methods: chlorpromazine equivalent dose (CPZe), defined daily dose (DDD), and percentage of Lexicomp maximum dose (PM%). DNA methylation was measured in white blood cells. Antipsychotic dosage was the primary outcome variable in a model, including genome-wide methylation status as the main predictor. RESULTS: This study did not show any association between DNA methylation and dosage variation for CPZe, PM%, and DDD. However, the probe cg271403389 was consistently associated with antipsychotic dosage across the three standardization methods. When looking at the genomic location of the most significant probes, we found that 15% were intergenic, 23% were in the distal promoter, 9% in the 3'untranslated region, 32% in the gene body, 3% in the 5' untranslated region, 15% in the proximal promoter, and 3% in the first exon. DISCUSSION: This study shows the importance of investigating the relationship between DNA methylation and optimal antipsychotic dosage to personalize treatment in SCZ. Future studies require larger prescription databases to build on the results of this analysis.

Estimating the effect of endogenous dopamine on baseline [(11) C]-(+)-PHNO binding in the human brain.

Endogenous dopamine (DA) levels at dopamine D2/3 receptors (D2/3 R) have been quantified in the living human brain using the agonist radiotracer [(11) C]-(+)-PHNO. As an agonist radiotracer, [(11) C]-(+)-PHNO is more sensitive to endogenous DA levels than antagonist radiotracers. We sought to determine the proportion of the variance in baseline [(11) C]-(+)-PHNO binding to D2/3 Rs which can be accounted for by variation in endogenous DA levels. This was done by computing the Pearson's coefficient for the correlation between baseline binding potential (BPND ) and the change in BPND after acute DA depletion, using previously published data. All correlations were inverse, and the proportion of the variance in baseline [(11) C]-(+)-PHNO BPND that can be accounted for by variation in endogenous DA levels across the striatal subregions ranged from 42-59%. These results indicate that lower baseline values of [(11) C]-(+)-PHNO BPND reflect greater stimulation by endogenous DA. To further validate this interpretation, we sought to examine whether these data could be used to estimate the dissociation constant (Kd) of DA at D2/3 R. In line with previous in vitro work, we estimated the in vivo Kd of DA to be around 20 nM. In summary, the agonist radiotracer [(11) C]-(+)-PHNO can detect the impact of endogenous DA levels at D2/3 R in the living human brain from a single baseline scan, and may be more sensitive to this impact than other commonly employed radiotracers.

Reduced insulin sensitivity is related to less endogenous dopamine at D2/3 receptors in the ventral striatum of healthy nonobese humans.

BACKGROUND: Food addiction is a debated topic in neuroscience. Evidence suggests diabetes is related to reduced basal dopamine levels in the nucleus accumbens, similar to persons with drug addiction. It is unknown whether insulin sensitivity is related to endogenous dopamine levels in the ventral striatum of humans. We examined this using the agonist dopamine D2/3 receptor radiotracer [(11)C]-(+)-PHNO and an acute dopamine depletion challenge. In a separate sample of healthy persons, we examined whether dopamine depletion could alter insulin sensitivity. METHODS: Insulin sensitivity was estimated for each subject from fasting plasma glucose and insulin using the Homeostasis Model Assessment II. Eleven healthy nonobese and nondiabetic persons (3 female) provided a baseline [(11)C]-(+)-PHNO scan, 9 of which provided a scan under dopamine depletion, allowing estimates of endogenous dopamine at dopamine D2/3 receptor. Dopamine depletion was achieved via alpha-methyl-para-tyrosine (64mg/kg, P.O.). In 25 healthy persons (9 female), fasting plasma and glucose was acquired before and after dopamine depletion. RESULTS: Endogenous dopamine at ventral striatum dopamine D2/3 receptor was positively correlated with insulin sensitivity (r(7)=.84, P=.005) and negatively correlated with insulin levels (r(7)=-.85, P=.004). Glucose levels were not correlated with endogenous dopamine at ventral striatum dopamine D2/3 receptor (r(7)=-.49, P=.18). Consistently, acute dopamine depletion in healthy persons significantly decreased insulin sensitivity (t(24)=2.82, P=.01), increased insulin levels (t(24)=-2.62, P=.01), and did not change glucose levels (t(24)=-0.93, P=.36). CONCLUSION: In healthy individuals, diminished insulin sensitivity is related to less endogenous dopamine at dopamine D2/3 receptor in the ventral striatum. Moreover, acute dopamine depletion reduces insulin sensitivity. These findings may have important implications for neuropsychiatric populations with metabolic abnormalities.

Assessing past suicidal behaviour in schizophrenia spectrum disorders using the Columbia-Suicide Severity Rating Scale and the Beck Scale for Suicide Ideation: Analysis across the life-span.

Assessing the number of past suicide attempts is vital in clinical and research settings, as it is a significant variable in assessing suicide risk. This study sought to compare the accuracy of the C-SSRS and the BSS in reporting past suicide attempts in schizophrenia spectrum disorders . Six hundred participants were recruited from the Centre for Addiction and Mental Health in Toronto, and completed the BSS and C-SSRS. A medical chart review was performed to determine the number of past suicide attempts. In addition, receiver operating characteristic curves were generated to compare the accuracy of both tests under various stratifications. Based on our findings, there were no significant differences (P = 0.8977) between the BSS and CSSRS in detecting a history of past suicide attempts. The BSS exhibited a sensitivity of 0.847 and a specificity of 0.841, while the C-SSRS had a slightly lower sensitivity of 0.795 and a slightly higher specificity of 0.889. Additionally, repeating the analysis to determine the accuracy of detecting multiple past suicide attempts, the BSS demonstrated a sensitivity of 0.704 and a specificity of 0.959, whereas the C-SSRS had a sensitivity of 0.787 and a specificity of 0.927. We further contrasted the two scales, stratified by different demographic variables such as age and sex. The accuracy of both tools, which is defined as the ability to identify true positive cases while minimizing false positives, increased as age increased, but these differences were not statistically significant. Therefore, both tools show a high level of accuracy in reporting past suicide attempt history and should be utilized to fit the specific needs of the research or clinical teams. These findings can inform clinical practice and future research, highlighting the importance of selecting assessment tools that fit the population's needs and context.

Effect of personality traits, psychological resilience and life adversities on lifetime violence trajectories: A novel classification model in schizophrenia.

The risk of violence is higher in schizophrenia spectrum disorders (SSD) compared to the general population and it is a pressing and understudied issue. Several dispositional and environmental factors have been previously correlated with violence, however, there has been little success in assessing their ability to predict violence patterns across the life span. This study aims to assess violence prediction based on personality traits, psychological resilience, and life-course adversities in a non-forensic population of SSD patients. In a sample of 231 patients with SSD, we assessed violence using the Brown-Goodwin History of Lifetime Aggression Scale and conducted cross-sectional assessments of possible predictors such as childhood trauma, personality traits and resilience scores. We then utilized a logistic regression classification algorithm to predict different violence trajectories based on the proposed risk factors. Our model significantly predicted individuals with violence in both childhood and adulthood, as well as childhood-only violence (p < 0.001). However, the model did not show significance for adult-only violence (p = 0.604). In all given trajectories, female sex appeared to be protective against violence, while stressful life events appeared to contribute to it. These results suggest that distinct factors can better inform risk assessment of lifespan violence patterns for personalized interventions in SSD.

The role of ethnicity in treatment refractory schizophrenia.

OBJECTIVE: The goal of this research was to describe the relationship between treatment resistant schizophrenia, defined using the APA criteria and ethnic background in patients with schizophrenia spectrum disorders in a Canadian sample. A secondary goal was to analyze the number of antipsychotics failed due to side effects and number of antipsychotics failed due to non-response. METHOD: We included 497 patients diagnosed with schizophrenia spectrum disorders using the SCID. The medication history was extracted from the electronic health records. Data collection included demographics (sex, age, ethnicity), principal diagnosis according to SCID (Diagnostic and Statistical Manual of Mental Disorders, 4th edition), duration of mental illness, number of psychiatric admissions and treatment information. If patients were on clozapine or polypharmacy treatment, this was recorded at the time of the SCID interview. Additional data, including prior antipsychotic history, were collected from the health records. RESULTS: Thirty per cent of the patients were classified as resistant according to the APA criteria. There were significantly more white European subjects in the treatment resistant group (p=0.031). The duration of illness was significantly higher in the resistant group then in the non-resistant group (21.0 vs 15.1 years; p<0.001). Patients who were treatment resistant were more likely to be on polypharmacy compared with non-resistant patients (p=0.001; OR=2.424; 95%CI=1.446-4.065). When we considered the number of drug trials failed due to non response and drug trial failed because of side effects, we found a strong negative correlation in both white Europeans and non-white Europeans. CONCLUSIONS: White European ethnicity is associated with treatment resistant schizophrenia. In addition, patients with treatment-resistant schizophrenia were on polypharmacy at higher rate than non resistant patients.

Mediating effect of genome-wide DNA methylation on suicidal ideation induced by stressful events.

OBJECTIVE: Schizophrenia is a debilitating disease that is associated with higher rates of death by unnatural causes including suicide. Exposure to stressful events is an important risk factor for suicidal ideation (SI); however, the mechanisms that link stress, SI, and suicide remain unclear. Epigenetic processes are involved in both vulnerability to suicidal behavior and stress. Therefore, we sought to study the relationship between epigenetic modifications and suicidal behavior and stress. METHODS: This pilot study was conducted on 39 patients diagnosed with schizophrenia (54% men and age 45.5 ± 12.7). We analyzed the effects of (a) stress exposure and (b) the mediation of DNA methylation [via an epigenetic wide association study (EWAS) of more than 450 000 CpG sites across the genome] on SI severity. RESULTS: The top CpG site mediating the effect of global stress exposure on SI was cg27660192 located in an intergenic region on chromosome 11, exerting a facilitating effect on worsening SI through DNA hypomethylation. CONCLUSION: These preliminary results indicate that DNA methylation in peripheral tissues can shed light on the complex relationship between stress and SI in schizophrenia.

Analysis of treatment-resistant schizophrenia and 384 markers from candidate genes.

The treatment of patients with schizophrenia who fail to respond to antipsychotics is a major challenge and the proportion of treatment-resistant patients is estimated to be 20 to 40%. There are few genetic association studies that have compared resistant versus non-resistant schizophrenic patients; however, many genetic association studies focusing on antipsychotic response have been published. This contribution investigates the genetics of treatment-resistant schizophrenia, testing 384 candidate gene loci related to the neurobiology of the disease. First, we identified a subgroup of treatment-resistant patients in a sample of 240 schizophrenia patients using the American Psychiatric Association criteria and then we genotyped all patients using a custom Illumina Bead Chip comprising of 384 single nucleotide polymorphisms. We screened all markers for nominal significance and for statistical significance after multiple-testing correction. The most significant single nucleotide polymorphism was the rs2152324 marker in the NALCN gene (P=0.004); however, after the FDR correction, the P-value was not significant. Our analysis of 384 markers across candidate genes did not indicate any robust association with treatment-resistant schizophrenia. However, this phenotype can be assessed retrospectively in cross-sectional studies and these preliminary results point out the importance of choosing alternative phenotypes in psychiatric pharmacogenetics.

Tetrabenazine augmentation in treatment-resistant schizophrenia: a 12-week, double-blind, placebo-controlled trial.

Evidence linking schizophrenia to alterations in presynaptic dopamine (DA) grows, although treatments to date have largely focused on postsynaptic D2 receptor blockade. This study examined augmenting response in treatment-resistant schizophrenia through the addition of tetrabenazine (TBZ), a presynaptic vesicular monoamine transporter (VMAT2) inhibitor. Participants included 41 outpatients (mean age, 43.5 years) with treatment-refractory schizophrenia, stabilized on their present antipsychotic treatment (clozapine, 73%) for more than 3 months. Individuals were randomly assigned to TBZ augmentation (12.5-75 mg/d), titrated according to a fixed, flexible schedule, or placebo over 12 weeks. Twenty subjects received TBZ, and 21 received placebo; doses of 18 of the 20 TBZ-treated individuals were titrated up to the maximum of 75 mg/d, and 16 (80%) of them completed the trial. Tetrabenazine was well tolerated and not linked to increased adverse effects, including those that have been reported more frequently (eg, parkinsonism, depression, and sedation) with higher doses (>100 mg/d) used in the treatment of hyperkinetic movement disorders. However, there was no indication of clinical improvement as measured using the Brief Psychiatric Rating Scale, the Clinical Global Impression scale, and the Global Assessment of Functioning scale. In examining those receiving TBZ-clozapine specifically, there was no indication of drug-drug interactions or difference in response compared to the overall sample. Tetrabenazine was not effective, as used here, in augmenting clinical response in treatment-resistant schizophrenia. It may be premature, however, to discount the potential benefits of VMAT2 inhibitors in treating psychosis in light of what is presently understood regarding presynaptic DA's role and evidence that "endogenous sensitization" may occur over the course of the illness.

Childhood trauma exposure and personality traits in schizophrenia patients.

Childhood trauma in schizophrenia (SCZ) is associated with aberrant neurobiological downstream effects and cognitive deficits that markedly hinder patient outcome and functioning. However, the relationship between specific forms of childhood abuse and the tendency for certain personality traits in patients with SCZ has not been comprehensively studied yet. We recruited 374 SCZ patients and screened for history of physical abuse (PA), emotional abuse (EA), sexual abuse (SA), physical neglect (PN) and emotional neglect (EN) using the Childhood Trauma Questionnaire and measured personality traits using the NEO Five-Factor inventory. Using CTQ cut-off scores, the prevalence of EA, PA, SA, EN and PN was 60.7%, 42.0%, 37.7%, 64.2% and 54.3% respectively. Exposure to any form of childhood abuse was associated with increased neuroticism. Exposure to EA, SA, PN and EN was correlated with decreased agreeableness and conscientiousness scores. PN, EN and PA exposure was associated with decreased openness while EA, PN and EN exposure was associated with decreased extraversion. Furthermore, a positive correlation was found between all forms of childhood abuse and trait neuroticism whereas negative correlations were found between certain forms of childhood abuse and all other personality traits. Exposure to specific forms of childhood abuse was associated with specific personality traits in patients with SCZ.

The effects of acute dopamine depletion on resting-state functional connectivity in healthy humans.

Alpha-methyl-para-tyrosine (AMPT), a competitive inhibitor of tyrosine hydroxylase, can be used to deplete endogenous dopamine in humans. We examined how AMPT-induced dopamine depletion alters resting-state functional connectivity of the basal ganglia, and canonical resting-state networks, in healthy humans. Fourteen healthy participants (8 females; age [mean ± SD] = 27.93 ± 9.86) completed the study. Following dopamine depletion, the caudate showed reduced connectivity with the medial prefrontal cortex (mPFC) (Cohen's d = 1.89, p<.0001). Moreover, the caudate, putamen, globus pallidus, and midbrain all showed reduced connectivity with the occipital cortex (Cohen's d = 1.48-1.90; p<.0001-0.001). Notably, the dorsal caudate showed increased connectivity with the sensorimotor network (Cohen's d = 2.03, p=.002). AMPT significantly decreased self-reported motivation (t(13)=4.19, p=.001) and increased fatigue (t(13)=4.79, p=.0004). A greater increase in fatigue was associated with a greater reduction in connectivity between the substantia nigra and the mPFC (Cohen's d = 3.02, p<.00001), while decreased motivation was correlated with decreased connectivity between the VTA and left sensorimotor cortex (Cohen's d = 2.03, p=.00004). These findings help us to better understand the role of dopamine in basal ganglia function and may help us better understand neuropsychiatric diseases where abnormal dopamine levels are observed.

Epigenetic age dysregulation in individuals with bipolar disorder and schizophrenia.

Bipolar disorder (BD) and schizophrenia (SCZ) are debilitating disorders that are associated with significant burden and reduced quality of life. In this study, we leveraged microarray data derived from both the Illumina HumanMethylation450 platform to investigate the epigenetic age of individuals with SCZ (n = 40), BD (n = 40), and healthy controls (n = 38), across five epigenetic clocks. Various statistical metrics were used to identify discrepancies between epigenetic and chronological age across the three groups. We observed a significant increase in epigenetic age compared to chronological age in the BD group. Mean epigenetic age acceleration was also higher in individuals with bipolar disorder compared to healthy controls across four different epigenetic clocks (p<0.05). Despite the study's relatively small sample size, these findings suggest that both individuals with bipolar disorder and schizophrenia may have epigenetic markers associated with a premature aging phenotype, which could be suggestive of negative outcomes associated with the disease. In our future studies, we hope to elucidate this finding further by elucidating the precise link between epigenetic age, symptomatology and disease progression.

Antipsychotic nonadherence measured by electronic adherence monitoring in stabilized chronic schizophrenia: Clinical implications.

BACKGROUND: There have been a number of studies investigating antipsychotic adherence measured by electronic adherence monitoring (EAM) in patients with schizophrenia. However, no study has looked at overall adherence and both baseline and endpoint illness/symptom severity. METHODS: We performed a secondary analysis of our previous study to examine antipsychotic adherence, as measured by EAM, and illness/symptom severity at baseline and endpoint in patients with schizophrenia. Adherence rates were defined as the proportion of adherent days over 3 months. Adherent days were defined as the subject having taken the medication at the prescribed time, with 2 tolerance margins operationally defined i.e., ±3 h and ±12 h. In addition, a dichotomous version of adherence was defined i.e., if he/she was adherent greater than 80% of the days. Illness severity and symptom severity were assessed using the Brief Psychiatric Rating Scale (BPRS) total score and the Clinical Global Impression - Severity of illness (CGI-S) scale score, respectively. RESULTS: A total of 111 patients were enrolled in the study. Neither continuous or dichotomous adherence rates were significantly associated with baseline or endpoint illness/symptom severity (all Ps ≥ 0.05). The results remained unchanged when adjusting for clinico-demographic characteristics. CONCLUSION: Antipsychotic adherence, as measured by EAM, was not associated with illness/symptom severity at baseline and endpoint in patients with chronic schizophrenia, whose clinical status and adherence pattern were stabilized. This suggests that individuals may be able to achieve clinical stability in the face of maintenance antipsychotic treatment despite variations in adherence.

Early-life stressful events and suicide attempt in schizophrenia: Machine learning models.

Childhood abuse and neglect predicts suicide attempt. Furthermore, other early-life stressful events may predict lifetime suicide attempt in psychiatric disorders. We assessed 189 schizophrenics for suicide attempt and stressful life events. Early-life stressful events were used as predictors of lifetime suicide attempt in three machine learning models. In our sample, 38% of the schizophrenics had at least one suicide attempt lifetime. The machine learning models provided an overall significant prediction (accuracy range: 62-69%). Childhood sexual molestation and mental illness were important predictors of suicide attempt. Early-life stressful events should be included in models aiming at predicting suicide attempt in schizophrenia.

Patient versus rater evaluation of symptom severity in treatment resistant schizophrenia receiving clozapine.

Patient input as part of health care has taken on increased importance recently. To look at whether patients with treatment resistant schizophrenia (TRS) are able to provide a valid self-assessment of symptoms, the present study investigated patient versus rater evaluation of clinical symptoms. Ninety-three patients diagnosed with TRS and treated with clozapine were recruited. Both patients and raters completed the 7-point Clinical Global Impression - Schizophrenia Version (CGI-SCH) scale, thereby providing evaluations for positive, negative, depressive, and cognitive symptoms as well as overall illness severity. Patients rated their clinical symptoms significantly lower than raters. A positive correlation was found between patients and raters for all symptom domains, while the strength of correlation varied. Age, gender and years of education did not impact the relationship between patient and rater scores. The conclusion is that patients provided valid information in self-assessments of symptoms when compared to raters, and this was consistent over time. In addition, the greatest heterogeneity between rater and patient ratings occurred with regard to cognitive symptoms. Patient assessments may help further engage individuals in their care and permit clinicians to identify where discrepancies exist. Addressing these issues offers opportunities for improved therapeutic alliance, education, and shared decision-making within treatment.

Childhood trauma predicts multiple, high lethality suicide attempts in patients with schizophrenia.

Childhood trauma has been shown to increase the risk of suicide attempts in individuals with schizophrenia. However, previous literature has been limited by considerable heterogeneity within the category of suicide attempters. Here we tested the predictive effect of childhood maltreatment on lifetime suicide attempt in a homogeneous sample of 650 patients with schizophrenia spectrum disorders. Childhood trauma was assessed using the Childhood Trauma Questionnaire-Short Form and suicide history was measured using subjective and objective validated scales as well as medical chart reviews. We refined our sample into two homogenous groups: 1) suicide attempters: patients who had attempted suicide multiple times, with highly lethal results (medical hospitalization required) (n = 24); and 2) non-ideators: patients who had no personal history of suicide attempt or ideation, or family history of attempt (n = 25). Binary logistic regression models revealed that total childhood trauma (ß = 0.002; OR: 1.07; 95% CI: 1.00-1.14) and emotional abuse (ß = 0.04; OR: 1.38; 95% CI: 1.08-1.77), but not other trauma subtypes, significantly predicted lifetime multiple, high lethality suicide attempts after adjusting for demographic and clinical covariates. Thus, childhood trauma is a weak, independent risk factor for extreme suicide attempts in patients with schizophrenia spectrum disorders.

Reduced insulin sensitivity may be related to less striatal glutamate: An 1H-MRS study in healthy non-obese humans.

Levels of striatal dopamine (DA) may be positively correlated with levels of striatal glutamate (Glu). While reduced insulin sensitivity (%S) has been associated with reduced striatal DA levels in healthy non-obese persons, whether reduced %S is also associated with reduced striatal Glu levels has not yet been established. Using 1H-MRS, we measured levels of several neurometabolites in the striatum and dorsolateral prefrontal cortex (DLPFC) of seventeen healthy non-obese persons (9 female, mean age: 28.35 ± 9.53). Insulin sensitivity was estimated for each subject from fasting plasma glucose and insulin using the Homeostasis Model Assessment II. We hypothesized that %S would be positively related with levels of Glu and Glu + glutamine (Glx) in the striatum. Exploratory analyses were also conducted between other fasting markers of metabolic health and neurometabolites measured with 1H-MRS. In the right striatum, %S was positively correlated with levels of Glu (r(15) = .49, p = .04) and Glx (r(15) = .50, p = .04). In the left striatum, there was a trend positive correlation between %S and Glu (r(15) = .46, p = .06), but not Glx levels (r(15) = .20, p = .44). The relationships between %S and striatal Glu levels remained after controlling for age, sex, and BMI (right: r(12) = .73, ß = .52, t = 2.55, p = .03; left: (r(12) = .63, ß = .53, t = 2.25, p = .04) These preliminary findings suggest that %S may be related to markers of glutamatergic functioning in the striatum of healthy non-obese persons. These findings warrant replication in larger samples and extension into neuropsychiatric populations where altered striatal DA, Glu, and %S are implicated.

GWAS analysis of treatment resistant schizophrenia: interaction effect of childhood trauma.

AIMS: In the current study, we aimed to compare the prevalence of adverse lifetime events in treatment resistant and non-treatment resistant schizophrenia in a genome-wide association study. MATERIALS & METHODS: Our sample consisted of 84 Caucasian participants with schizophrenia spectrum disorders, assessed cross-sectionally to collect information regarding drug effectiveness and childhood trauma. Using a genome-wide association analysis, we tested single-nucleotide polymorphisms for their association with resistance to antipsychotics defined according to American Psychiatric Association criteria. Two models were tested: a main model and an interaction model with the childhood trauma. RESULTS: Our analysis failed to demonstrate a significant relationship among 1,178,234 single-nucleotide polymorphisms and treatment-resistance in both the main model and in the childhood trauma interaction model. CONCLUSION: Even though we could not find any significant association, treatment resistance has clinical relevance and it may be determined by the interaction between biological and non biological factors.