Objective: To evaluate the association between childhood trauma (CT) and serum levels of brainderived neurotrophic factor (BDNF) and thiobarbituric acid-reactive substances (TBARS) during crackcocaine withdrawal. Method: Thirty-three male crack-cocaine users were recruited at admission to a public addiction treatment unit. Serum BDNF and TBARS levels were evaluated at intake and discharge. Information about drug use was assessed by the Addiction Severity Index-6th Version (ASI-6); CT was reported throughout the Childhood Trauma Questionnaire (CTQ). CTQ scores were calculated based on a latent analysis model that divided the sample into low-, medium-, and high-level trauma groups. Results: There was a significant increase in BDNF levels from admission to discharge, which did not differ across CT subgroups. For TBARS levels, we found a significant time vs. trauma interaction (F2,28 = 6.357, p = 0.005,Zp 2 = 0.312). In participants with low trauma level, TBARS decreased, while in those with a high trauma level, TBARS increased during early withdrawal. Conclusion: TBARS levels showed opposite patterns of change in crack-cocaine withdrawal according to baseline CT. These results suggest that CT could be associated with more severe neurological impairment during withdrawal

Aguiar, Bianca Wollenhaupt de

Diemen, Lisia von

Gubert, Carolina de Moura

Kapczinski, Flávio Pereira

Ornell, Felipe

Pechansky, Flavio

Pfaffenseller, Bianca

Salum Junior, Giovanni Abrahão

Schuch, Silvia Bassani

Sordi, Anne Orgler

Brazilian Journal of Psychiatry

English

Lume 5.8

BRIEF COMMUNICAITONEffects of childhood trauma on BDNF and TBARS duringcrack-cocaine withdrawalAnne O. Sordi,1 Lisia von Diemen,1,2 Felix H. Kessler,1,20000-0000-0000-0000 Silvia Schuch,1Felipe Ornell,1,20000-0000-0000-0000 Flávio Kapczinski,2,3,4,5 Bianca Pfaffenseller,4,6 Carolina Gubert,4,6Bianca Wollenhaupt-Aguiar,4,6 Giovanni A. Salum,2 Flavio Pechansky1,21Centro de Pesquisa em Álcool e Drogas (CPAD), Hospital de Clı́nicas de Porto Alegre (HCPA), Universidade Federal do Rio Grande do Sul(UFRGS), Porto Alegre, RS, Brazil. 2Programa de Pós-Graduação em Psiquiatria e Ciências do Comportamento, UFRGS, Porto Alegre, RS,Brazil. 3Instituto Nacional de Ciência e Tecnologia Translacional em Medicina (INCT-TM), HCPA, UFRGS, Porto Alegre, RS, Brazil. 4Laboratóriode Psiquiatria Molecular, HCPA, Porto Alegre, RS, Brazil. 5Departamento de Psiquiatria e Medicina Legal, UFRGS, Porto Alegre, RS, Brazil.6Programa de Pós-Graduação em Ciências Biológicas, Bioquı́mica, Departamento de Bioquı́mica, UFRGS, Porto Alegre, RS, Brazil.Objective: To evaluate the association between childhood trauma (CT) and serum levels of brain-derived neurotrophic factor (BDNF) and thiobarbituric acid-reactive substances (TBARS) during crack-cocaine withdrawal.Method: Thirty-three male crack-cocaine users were recruited at admission to a public addictiontreatment unit. Serum BDNF and TBARS levels were evaluated at intake and discharge. Informationabout drug use was assessed by the Addiction Severity Index-6th Version (ASI-6); CT was reportedthroughout the Childhood Trauma Questionnaire (CTQ). CTQ scores were calculated based on alatent analysis model that divided the sample into low-, medium-, and high-level trauma groups.Results: There was a significant increase in BDNF levels from admission to discharge, which did notdiffer across CT subgroups. For TBARS levels, we found a significant time vs. trauma interaction(F2,28 = 6.357, p = 0.005,Zp2 = 0.312). In participants with low trauma level, TBARS decreased, whilein those with a high trauma level, TBARS increased during early withdrawal.Conclusion: TBARS levels showed opposite patterns of change in crack-cocaine withdrawalaccording to baseline CT. These results suggest that CT could be associated with more severeneurological impairment during withdrawal.Keywords: Childhood trauma; cocaine; drug abuse; BDNF; oxidative stressIntroductionThere is a growing body of evidence implicating possibleneurobiological markers in the pathogenesis of substanceuse disorders (SUD).1 Whether this is related to early lifeexperiences or to drug use itself is still unknown. Persis-tently increased oxidative stress (OS), a marker of cellimpairment, is a consequence of childhood trauma (CT),and is also observed in SUD.2 One way of measuring OSis through quantitation of thiobarbituric acid-reactive sub-stance (TBARS) levels. Conversely, neurotrophins areimplicated in neuronal protection. Among the neurotro-phins, brain-derived neurotrophic factor (BDNF) has themost established evidence of influence on synaptic plasti-city, and might act directly on cocaine-induced neuro-adaptation.3 BDNF levels seem to increase duringcrack-cocaine withdrawal, and later return to normal, whichmay be an indicative of brain recovery.1,4 Brain plasti-city could also be mediated by early-life experiences,especially in the limbic system, and may be implicated inthe development of SUD.5Since crack-cocaine dependence is a subject of majorconcern worldwide, it is imperative to understand moreabout its underlying mechanisms. Therefore, the aim ofthis brief communication is to present some novel find-ings on how the intensity of CT may be associated withchanges in serum BDNF and TBARS levels during earlycrack-cocaine withdrawal.MethodsSample selection and proceduresThirty-three adult male crack-cocaine users (age X 18years) who screened positive for cocaine (Bioeasy®Cocaine-Test, Aleret) were recruited on the first day ofhospitalization at a public addiction treatment unit in PortoAlegre, Brazil. The exclusion criteria were: psychoticCorrespondence: Anne Orgler Sordi, Centro de Pesquisa em Álcoole Drogas (CPAD), Hospital de Clı́nicas de Porto Alegre, UnidadeAlvaro Alvim, Rua Prof. Alvaro Alvim, 400, CEP 90420-020, PortoAlegre, RS,Brazil.E-mail: asordi@hcpa.edu.brSubmitted Jan 09 2019, accepted Aug 28 2019, Epub Dec 05 2019.How to cite this article: Sordi AO, von Diemen L, Kessler FH,Schuch S, Ornell F, Kapczinski F, et al. Effects of childhood traumaon BDNF and TBARS during crack-cocaine withdrawal. Braz JPsychiatry. 2020;42:214-217. http://dx.doi.org/10.1590/1516-4446-2019-0532Braz J Psychiatry. 2020 Mar-Apr;42(2):214-217doi:10.1590/1516-4446-2019-0532Brazilian Psychiatric Association00000000-0002-7316-1185symptoms, intelligence quotient o 70, and refusal ofconsent. Interviews were conducted by trained graduatestudents in Psychology between the 5th and 7th day ofwithdrawal. Drug use information was assessed by theAddiction Severity Index – 6th Version (ASI-6).6 CT wasassessed by the Childhood Trauma Questionnaire (CTQ).7Blood collection and assayA 10-mL blood sample was collected from each participanton the first 24 hours of hospitalization, and again in the24 hours preceding hospital discharge. TBARS were mea-sured using a commercial assay kit (Cayman Chemical Com-pany, Ann Arbor, MI, USA). BDNF were measured using asandwich ELISA method with monoclonal antibodies specificfor BDNF from R&D Systems (Minneapolis, MN, USA).Statistical analysisSince there is no established cutoff point for traumascores, CTQ scores were calculated on the basis of a pre-vious report suggesting a new second-order structure forthe instrument.8 Factor scores for the five CTQ subscalesand a higher-order trauma factor were saved for ananalysis using mean- and variance-adjusted weightedleast squares (WLSMV) estimator, which presented properfit in the sample from which our subjects derive: root meansquare error of approximation (RMSEA) = 0.049; 90%confidence interval (90%CI) = 0.042-0.055; comparative fitindex (CFI) = 0.960; Tucker-Lewis index (TLI) = 0.956; andweighted root mean square residual (WRMR) = 1.058. Thefit indices and rules of thumb used were as follows: CFI,good fit if X 0.95; TLI, good fit if X 0.90; and RSMEA,good fit if o 0.06. CTQ total scores were then split into acategorical variable based on the sample tertile distribution(low, medium, and high). Differences in BDNF and TBARSfrom admission to discharge and among trauma groupswere tested using repeated-measures analysis of covar-iance (ANCOVA). Significant results were controlled forseverity of crack-cocaine use and days of hospitalization.Significant time vs. trauma interactions were analyzedusing paired t-tests stratified by level of trauma. Effectsizes were defined in terms of % of explained variance; 1,9, and 25% were defined as small, medium, and largeeffects, corresponding to 0.01, 0.06, and 0.14 partial etasquare (Zp2) values, respectively.9 Severity of crack usewas estimated using a composite of age at first use,duration of use in years, and number of crack rocks consu-med in the preceding 30 days (as described elsewhere).4Ethics statementThe study was approved by the institutional review boardsand ethics committees of Hospital de Clı́nicas de PortoAlegre and Hospital São Pedro. All participants providedwritten informed consent.ResultsAll participants were male. Mean age was 27.06 (standarddeviation [SD] = 6.94) years, and the mean duration ofhospitalization was 18.97 (SD = 4.24) days. There was nosignificant difference in age, days of hospitalization, yearsof crack-cocaine use, or severity of crack-cocaine useamong the low, medium, and high CT groups (Table 1).For BDNF levels, we found significant time effects (F1,30 =8.45, p = 0.007, Zp2 = 0.22), but not trauma effects (F2,30 =2.15, p = 0.134, Zp2 = 0.125), nor time vs. trauma inter-actions (F2,30 = 0.954, p = 0.397, Zp2 = 0.06) in repeated-measures ANOVA. Controlling for the effects of potentialconfounders did not change our results for time (F1,28 =0.273, p = 0.605, Zp2 = 0.01), trauma (F2,28 = 2.0, p = 0.153,Table 1 Sample profile, stratified by trauma groupsLow (n=11) Medium (n=11) High (n=11) TotalAge (years) 29.64a (8.3) 26.09a (5.68) 25.45a (6.47) 27.06 (6.94)Length of hospital stay (days) 19.82a (4.33) 19.18a (4.17) 17.91a (4.39) 18.97 (4.24)Crack-cocaine use (years) 7.00a (3.5) 6.91a (3.51) 5.82a (2.64) 6.56 (3.17)Severity score 14.27a (3.93) 15.09a (4.66) 15.18a (4.77) 14.85 (4.35)Standardized trauma levelsPhysical neglect -0.033a (0.189) 0.273b (0.127) 0.383b (0.179) 0.208 (0.241)Emotional neglect -0.025a (0.307) -0.367a (0.518) -0.294a (0.179) -0.229 (0.382)Sexual abuse -0.005a (0.452) 0.523ab (0.590) 0.760b (0.549) 0.426 (0.610)Physical abuse -0.354a (0.275) 0.395b (0.299) 0.835c (0.409) 0.292 (0.594)Emotional abuse -0.177a (0.264) 0.386b (0.101) 0.710c (0.228) 0.306 (0.424)Total trauma scores -0.074a (0.106) 0.166b (0.045) 0.297c (0.096) 0.130 (0.177)BiomarkersBDNF (admission) 29.28a (11.62) 26.01a (13.08) 30.77a (8.13) 28.69 (10.97)BDNF (discharge) 32.48a (9.88) 33.86a (13.09) 42.99a (12.13) 36.44 (12.35)TBARS (admission) 20.24a (14.65) 11.67ab (3.64) 7.54b (2.27) 13.15 (10.08)TBARS (discharge) 9.83a (4.18) 12.57a (5.41) 13.93a (7.87) 12.11 (6.08)Ethnicity (Caucasian), n (%) 10a (90.90) 6a (54.50) 9a (81.80) 25 (75.80)Marital status (married), n (%) 1a (9.10) 5a (45.50) 2a (18.20) 8 (24.20)Data presented as mean (SD), unless otherwise specified.BDNF = brain-derived neurotrophic factor; SD = standard deviation; TBARS = thiobarbituric acid-reactive substances.Between-group differences were assessed using t-tests and z-tests. Different lowercase superscript letters denote significant differences.Braz J Psychiatry. 2020;42(2)Childhood trauma effects on BDNF and TBARS 215Zp2 = 0.125), or time vs. trauma interactions (F2,28 = 2.25,p = 0.124, Zp2 = 0.138). This analysis reveals a significantincrease in BDNF levels from admission to discharge (timeeffect), which did not differ among groups (Figure 1A).For TBARS levels, we found no time effects (F1,30 =0.307, p =0.584, Zp2 = 0.01) nor trauma effects (F2,30 =1.901, p = 0.167, Zp2 = 0.112), but we did find a significanttime vs. trauma interaction (F2,30 = 6.95, p = 0.003, Zp2 =0.317). Controlling for the effects of potential confoun-ders did not change our results for time (F1,28 = 0.006,p = 0.94, Zp2 = 0.03), trauma (F2,28 = 1.972, p = 0.158,Zp2 = 0.123), or time vs. trauma interaction (F2,28 = 6.357,p = 0.005, Zp2 = 0.312). This analysis revels that the levelof CT moderates changes in TBARS levels duringwithdrawal. To clarify time vs. trauma interactions forTBARS, we performed a stratified analysis for changes inTBARS levels from admission to discharge among thethree groups. We found that, for the low trauma levelgroup, TBARS showed a trend-level decrease acrosstime (mean difference = 10.4, SD = 16.12, 95%CI -0.4 to21.25, r = -0.230, t = 2.14, degrees of freedom [df] = 10,p = 0.058). It did not change for the medium trauma group(mean difference = -0.9, SD = 5.96, 95%CI -4.9 to 3.10,r = 0.178, t = -0.503, df = 10, p = 0.626), while it signi-ficantly increased for the high trauma group (meandifference = -6.38, SD = 7.25, 95%CI -11.3 to -1.51,r = 0.405, t = -2.919, df = 10, p = 0.015) (Figure 1B).DiscussionTo the best of our knowledge, this is the first study toshow opposite patterns of changes in TBARS levels incrack-cocaine users with high vs. low CT scores.Although evidence suggests that CT could decreaseBDNF levels in later life, we did not find a difference in thisparameter among groups. Previous studies that evalu-ated how CT might affect BDNF during crack-cocainewithdrawal are consistent with our results. Viola et al.demonstrated that CT did not have an impact on BDNFlevels during early withdrawal in a sample of femalecrack-cocaine users.10 Overall, BDNF levels increaseduring withdrawal, but this is related to craving, relapse,and severity of drug use.1,4,10 Therefore, we controlled forseverity of crack-cocaine use.When we investigated changes in TBARS during crack-cocaine withdrawal, we found a decrease in TBARSamong patients with low CT levels, but a sustainedincrease in TBARS among those with high CT levels. Thefirst finding is in accordance with the literature, whichshows that a decrease in OS occurs during abstinence.1Cocaine use rapidly increases the production and releaseof dopamine, and can increase OS because dopaminereuptake is due to self-oxidation.11 Furthermore, cocaineusers have impaired antioxidant defenses.12Different hypotheses might explain our results. Early-life stress could lead to a persistent increase in lipidperoxidation, and antioxidant defenses would ultima-tely become insufficient to overcome it.2 Individualswith a history of CT experience allostatic overload of thehypothalamus-pituitary-adrenal axis, which increasessymptoms of anxiety, leading to higher cortisol produc-tion – which consequently increases OS.13 In addition,drug use might represent a way to achieve immediaterelief of negative feelings.14 Abstinence would thencause the emergence of traumatic memories, thus increas-ing OS.Figure 1 BDNF and TBARS serum levels among trauma groups during withdrawal. A) BDNF levels from admission todischarge stratified by childhood trauma level. B) TBARS from admission to discharge stratified by childhood trauma level.BDNF = brain derived neurotrophic factor; MDA = malondialdehyde; TBARS = thiobarbituric acid reactive substances.Braz J Psychiatry. 2020;42(2)216 AO Sordi et al.Our findings must be interpreted in light of somelimitations. First, the history of CT was collected retro-spectively, which is always subject to recall bias. Never-theless, the CTQ is considered a reliable scientificinstrument. We also used a sophisticated latent-variablesmodel which takes into account that different types oftrauma contribute differently to overall trauma severity.8Second, our analysis was limited to 33 male subjects; ourfindings may not apply to women. However, the smallsample size did not prevent us from finding substantialassociations between biomarkers and trauma levels,which indicates sufficient power to detect the most impor-tant association under study. Third, we did not evaluatepsychiatric comorbidities. However, since CT is a majorrisk factor for the development of psychiatric disorders,it could be considered a mediator of the results. It isimportant to note that all patients attended the sametreatment program.Crack-cocaine dependence is a multifactorial disorderwhich involves biological as well as environmental factors,and causes great impact on the lives of users, theirfamilies, and wider society.15 Our study sheds light on howCT could interfere with specific biological markers thatseem to be involved in the pathogenesis of crack-cocainedependence. Understanding these underlying mechan-isms can help design different targeted treatment optionswhich take patients’ early-life experiences into account.In conclusion, childhood abuse or neglect can influencehow the brain of a crack-cocaine user behaves during thewithdrawal process, increasing oxidative stress in thosewith a higher level of trauma.AcknowledgementsFunding was provided by Secretaria Nacional de Polı́ti-cas sobre Drogas (SENAD) and Fundo de Incentivo àPesquisa e Eventos (FIPE).DisclosureThe authors report no conflicts of interest.References1 Sordi AO, Pechansky F, Kessler FH, Kapczinski F, Pfaffenseller B,Gubert C, et al. Oxidative stress and BDNF as possible markers forthe severity of crack cocaine use in early withdrawal. Psycho-pharmacology (Berl). 2014;231:4031-9.2 Schiavone S, Jaquet V, Trabace L, Krause KH. Severe life stress andoxidative stress in the brain: from animal models to human pathology.Antioxid Redox Signal. 2013;18:1475-90.3 Fumagalli F, Di Pasquale L, Caffino L, Racagni G, Riva MA. Repe-ated exposure to cocaine differently modulates BDNF mRNA andprotein levels in rat striatum and prefrontal cortex. Eur J Neurosci.2007;26:2756-63.4 von Diemen L, Kapczinski F, Sordi AO, de Magalhães Narvaez JC,Guimarães LS, Kessler FH, et al. Increase in brain-derived neuro-trophic factor expression in early crack cocaine withdrawal. Int JNeuropsychopharmacol. 2014;17:33-40.5 Cirulli F, Francia N, Berry A, Aloe L, Alleva E, Suomi SJ. Early lifestress as a risk factor for mental health: role of neurotrophins fromrodents to non-human primates. Neurosci Biobehav Rev. 2009;33:573-85.6 Kessler F, Cacciola J, Alterman A, Faller S, Souza-Formigoni ML,Cruz MS, et al. Psychometric properties of the sixth version of theAddiction Severity Index (ASI-6) in Brazil. Braz J Psychiatry. 2012;34:24-33.7 Grassi-Oliveira R, Stein LM, Pezzi JC. [Translation and contentvalidation of the Childhood Trauma Questionnaire into Portugueselanguage]. Rev Saude Publica. 2006;40:249-55.8 Grassi-Oliveira R, Cogo-Moreira H, Salum GA, Brietzke E, Viola TW,Manfro GG, et al. Childhood Trauma Questionnaire (CTQ) in Brazi-lian samples of different age groups: findings from confirmatory factoranalysis. PloS One. 2014;9:e87118.9 Cohen J. Statistical power analysis for the behavioral sciences. 2o ed.Abingdon: Routledge; 1988.10 Viola TW, Tractenberg SG, Levandowski ML, Pezzi JC, Bauer ME,Teixeira AL, et al. Neurotrophic factors in women with crack cocainedependence during early abstinence: the role of early life stress.J Psychiatry Neurosci. 2014;39:206-14.11 Dietrich JB, Mangeol A, Revel MO, Burgun C, Aunis D, Zwiller J.Acute or repeated cocaine administration generates reactive oxygenspecies and induces antioxidant enzyme activity in dopaminergic ratbrain structures. Neuropharmacology. 2005;48:965-74.12 Walker J, Winhusen T, Storkson JM, Lewis D, Pariza MW, SomozaE, et al. Total antioxidant capacity is significantly lower in cocaine-dependent and methamphetamine-dependent patients relative tonormal controls: results from a preliminary study. Hum Psycho-pharmacol. 2014;29:537-43.13 Badanes LS, Watamura SE, Hankin BL. Hypocortisolism as apotential marker of allostatic load in children: associations with fam-ily risk and internalizing disorders. Dev Psychopathol. 2011;23:881-96.14 Ramos Sde P. What can we learn from psychoanalysis and pro-spective studies about chemically dependent patients? Int J Psy-choanal. 2004;85:467-87.15 Kessler F, Woody G, De Boni R, Von Diemen L, Benzano D, Faller S,et al. Evaluation of psychiatric symptoms in cocaine users in theBrazilian public health system: need for data and structure. PublicHealth. 2008;122:1349-55.Braz J Psychiatry. 2020;42(2)Childhood trauma effects on BDNF and TBARS 217

Effects of childhood trauma on BDNF and TBARS during crack-cocaine withdrawal

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Effects of childhood trauma on BDNF and TBARS during crack-cocaine withdrawal

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