Double Threat

Background: Substance use disorders (SUDs) are a great burden on adolescent patients and treatment of these patients is often not successful. One reason for this difficulty is the high rate of co-occurring disorders. One disorder that frequently accompanies SUDs in adolescence is a Post-Traumatic Stress Disorder (PTSD). In studies it has often been reported that a large number of patients fulfill diagnostic criteria for both disorders at the same time. Several explanations for this co-occurrence exist: i) A common etiological factor (genetic predisposition, similar neurobiological pathways) might underlie the development of both disorders. ii) Various lifestyle factors that go hand-in-hand with an adolescent SUD (risky sexual behavior, violent dark markets) might expose patients to circumstances that increase the rate of encountered traumatic experiences (TEs) and therefore PTSD. iii) The self-medication hypothesis, where it is posited that adolescents use drugs to medicate their PTSD symptoms, often in a very specific manner, such that particular substances are used to reduce explicit symptoms. One aim explored in this thesis is the relationship between SUD, TEs, and PTSD with regard to differences in SUD severity, patterns of substance use, the role of self-medication and the effects of SUD-specific treatment on PTSD symptomatology. Methods: Five studies are presented in chapters 2 to 6 of this thesis. Chapter 2 contains a study in which the Drug Use Disorder Identification Test (DUDIT) was evaluated for use in a psychiatric adolescent patient population. This was the first study in which the DUDIT in relation to DSM-5 criteria was evaluated, in order to try to establish cut-off scores for the presence of a SUD in adolescents. In chapter 3 an evaluation is presented of the differences in SUD severity between adolescents with a SUD (‘noTE’ group), adolescents with a SUD and a history of TE but not PTSD (‘TE’ group) and adolescents with SUD and co-occurring PTSD (‘PTSD’ group). In the study presented in chapter 4 an investigation of the differences in substance use patterns between the three groups was undertaken, along with an evaluation of the associations between PTSD symptoms and use of specific substances. In chapter 5, the role coping motives play in the relationship between substance and PTSD symptoms was established. Finally, in chapter 6 the results of a pragmatic clinical trial are presented, in which the effects of a group-based treatment manual (the DELTA program) on SUD symptoms, substance use frequency and PTSD symptoms are assessed. Results: Across all included studies in this dissertation, an instrument for the assessment of SUD in adolescents was evaluated. This was used with other instruments, to establish a link between adolescent SUD and increased rates of PTSD and substance use. Furthermore, the connection between SUD and PTSD in adolescence seems to be related to a self-medication motive. Additionally we established a treatment program that reduced SUD symptoms but failed to influence the PTSD symptoms, which indicates treatment specific to one disorder is unlikely to support reductions in the co-occurring disorder. More specifically, the results presented in chapter 2 showed that the DUDIT has excellent discriminant validity and is a valid tool for the assessment of SUD severity in a clinical adolescent population. In chapter 3, it was shown that the prevalence of TEs and PTSD in adolescents with SUD is higher than in the general adolescent population. Furthermore, the PTSD group showed a significantly higher level of SUD severity than the other two groups. In contrast to our expectations, the TE group did not differ significantly with regard to SUD severity from the noTE group. In addition, SUD severity correlated positively with the number of PTSD symptoms in each symptom cluster. The study presented in chapter 4 showed that past-month substance use frequency was nearly the same across groups and across substances, with only the use of methylenedioxymethamphetamine (MDMA) being significantly more frequent and more prominent in the PTSD group compared to the other two. Participants in the PTSD group also reported a significantly earlier age of first substance use compared to participants in the other two groups. Moreover, in this study it was shown that the presence of the avoidance symptom cluster of PTSD was related to a more frequent past-month MDMA use. The findings presented in chapter 5, confirmed the pattern detected for past-month substance use in chapter 4. The PTSD group showed a more frequent MDMA use over the past-year compared to the other two groups. Additionally, the PTSD group reported using substances more frequently for coping reasons, and the frequency of coping use motives was positively correlated with the frequency of past-year MDMA use. In this study, evidence was provided that the relationship between group membership (noTE, TE, PTSD) and MDMA use frequency is in part mediated by the relationship both variables have with coping use motives. In chapter 6 medium-sized but non-significant reductions were shown in SUD symptoms and substance use frequency as a result of the DELTA intervention. Additionally, there was no indication that the treatment program resulted in changes in PTSD symptomatology. Discussion: Several important conclusion can be derived from the studies presented in this thesis. First, a co-occurring PTSD is more prevalent in SUD patients than in the general adolescent population and is associated with higher SUD severity. Second, patients with co-occurring PTSD and SUD are distinguished from SUD patients without PTSD through their increased use of MDMA. Third, the relationship between PTSD and MDMA use is partially mediated by a coping motive, supporting the self-medication hypothesis. Finally, the treatment of co-occurring PTSD and SUD seems to require therapeutic interventions specific for each disorder. The result that PTSD symptoms are not reduced after SUD-specific treatment can be interpreted as support for the self-medication hypothesis as well, in the sense that the treatment of the consequence (SUD) does not affect the preceding factor (PTSD). However, while the above interpretation is consistent with the data presented in this thesis on substance use itself, the associated data on the occurrence of SUDs indicates, that more factors than just self-medication are relevant for the development of a SUD. Furthermore, the results of this thesis do not imply that substance use motivated by self-medication motives is harmless or even beneficial, since there was no way of assessing if self-reported, coping-motivated substance use is successful in reducing symptoms or acute psychopathology. Consequently, in future projects focus should be on developing longitudinal research designs, in order to assess if and how PTSD symptoms develop over time with regard to substance use and how substance use trajectories develop in relation to PTSD symptomatology

Prenatally traumatized mice reveal hippocampal methylation and expression changes of the stress-related genes Crhr1 and Fkbp5

In our previous study, we found that prenatal trauma exposure leads to an anxiety phenotype in mouse pups, characterized by increased corticosterone levels and increased anxiety-like behavior. In order to understand the mechanisms by which aversive in utero experience leads to these long-lasting behavioral and neuroendocrine changes, we investigated stress reactivity of prenatally traumatized (PT) mice, as well as the expression and methylation levels of several key regulatory genes of the stress axis in the dorsal hippocampus (dHPC) of the PT embryo and adult mice. We detected increased corticotropin-releasing hormone receptor 1 (Crhr1) and decreased FK506 binding protein 5 (Fkbp5) mRNA levels in the left dHPC of adult PT mice. These alterations were accompanied by a decreased methylation status of the Crhr1 promoter and an increased methylation status of the Fkbp5 promoter, respectively. Interestingly, the changes in Fkbp5 and Crhr1 mRNA levels were not detected in the embryonic dHPC of PT mice. Together, our findings provide evidence that prenatal trauma has a long-term impact on stress axis function and anxiety phenotype associated with altered Crhr1 and Fkbp5 transcripts and promoter methylation

Attenuated psychotic symptoms, substance use and self-reported PTSD in adolescence

Background: The occurrence of attenuated psychotic symptoms (APS) is a major concern in populations with substance use disorders (SUDs). However, APS also frequently develop in the course of Post-Traumatic Stress Disorder (PTSD). This study explores how the prevalence of APS differs between adolescent patients with only SUD, SUD with a history of traumatic experiences (TEs), and with SUD and self-reported PTSD.Methods: We recruited n = 120 treatment-seeking adolescents at a German outpatient clinic for adolescents with SUD. All participants filled out questionnaires assessing APS (PQ-16, YSR schizoid scale), trauma history, PTSD symptoms (both UCLA PTSD Index), and SUD severity (DUDIT) next to an extensive substance use interview. We performed a multivariate analysis of co-variance with the four PQ-16 scales and the YSR scale as outcomes and PTSD status as predictor. Additionally, we performed five linear regressions predicting each PQ-16 score and YSR score based on tobacco, alcohol, cannabis, ecstasy, amphetamine, and methamphetamine use.Results: Participants with co-occurring SUD and self-reported PTSD showed significantly higher APS prevalence rates (PQ-16 score, p = .00002), more disturbed thought content (p = .000004), more perceptual disturbances (p = .002), more negative symptoms (p = .004) and more thought problems (p = .001) compared to adolescents with SUD and a history of trauma and adolescents with only SUD. Past-year substance use was not predictive for APS prevalence (F(75) = 0.42; p = .86; R2 = .04).Conclusion: Our data suggests that the occurrence of APS in adolescents with SUD is better explained by co-occurring self-reported PTSD than by substance use frequency or substance class. This finding might indicate that APS might be reduced through treating PTSD or focusing on TEs in SUD therapy

Self-reported PTSD is associated with increased use of MDMA in adolescents with substance use disorders

Background Adolescent patients with a substance use disorder (SUD) often fulfil the criteria for a co-occurring post-traumatic stress disorder (PTSD). However, it is not clear if these dual-diagnosed adolescents present with unique levels of substance use and how their substance use relates to PTSD symptom clusters. Objective To investigate substance use in adolescents with co-occurring PTSD and SUD. Additionally, we explored how the use of specific substances is related to specific PTSD symptom clusters. Method We recruited n = 121 German adolescent SUD patients, in three groups: no history of traumatic events (TEs) (n = 35), TEs but not PTSD (n = 48), probable PTSD (n = 38). All groups were administered a trauma questionnaire and were asked to report their past-month substance use. Results Adolescents with probable PTSD and SUD report a higher frequency of MDMA use than adolescents with no PTSD and no TE (PTSD vs. noTE: U = 510.5, p = .016; PTSD vs. TE: U = 710.0, p = .010). The use of MDMA was more frequent in adolescents with avoidance symptoms (X2 (1) = 6.0, p = .014). Participants report using substances at a younger age (PTSD vs. noTE: U = 372.0, p = .001; PTSD vs. TE: U = 653.5, p = .022) and PTSD symptom onset was on average 2.2 years earlier than first MDMA use (t (26) = −2.89, p = .008). Conclusions Adolescent SUD patients with probable PTSD are more likely to use MDMA than SUD patients without PTSD. The use of MDMA was associated with reported avoidance symptoms. The first age of MDMA use is initiated after PTSD onset. It is unclear whether the association of MDMA use with avoidance symptoms is due to efforts to reduce these symptoms or a result of regular MDMA use

Coping motives mediate the relationship between PTSD and MDMA use in adolescents with substance use disorders

Background: Post-traumatic stress disorder (PTSD) and substance use disorders (SUDs) often co-occur in adolescent patients. Previous research has shown that these patients differ from SUD patients without PTSD in terms of their substance use patterns. In this study, we aimed to test whether substance use in this population is related to an attempt to self-medicate PTSD-related symptoms. - Methods: German adolescent patients (aged 13–18 years) at an outpatient clinic for SUD treatment, n = 111 (43% female), completed a self-designed questionnaire on use motives, a measure of PTSD-related experiences, and underwent a standardized psychiatric interview including structured substance use questions. Participants were subsequently classified as ‘no traumatic experiences (‘noTEs’ but SUD), ‘traumatic experiences but no current PTSD diagnosis’ (‘TEs’ with SUD), and ‘PTSD’ with SUD. After establishing a self-designed motive measurement through exploratory and confirmatory factor analyses, we calculated non-parametric group differences and a mediation analysis in a linear regression framework. - Results: The past-year frequency of MDMA use was highest in the PTSD group and lowest in the noTE group (H (2) = 7.2, p = .027, η² = .058), but no differences were found for frequencies of tobacco, alcohol, cannabis, or stimulant use (all H ≤ 4.9, p ≥ .085, η² ≤ .033). While controlling for sex, the three groups showed a similar pattern (highest in the PTSD group and lowest in the noTE group) for coping scores (F (103) = 5.77, p = .004, η² = .101). Finally, mediation analyses revealed an indirect effect of coping score (b = 0.61, 95% CI [0.29, 1.58], p = .145) on the association between group membership and MDMA use frequency. - Conclusions: In adolescent SUD patients, we found an association of current PTSD and lifetime traumatic experiences with higher MDMA use that could be partially explained by substance use being motivated by an attempt to cope with mental health symptoms. This indicates a coping process involved specifically in MDMA use compared to the use of other psychoactive substances, possibly due to unique psychoactive effects of MDMA

Substanzkonsum, Störungen durch Substanzkonsum und begleitende psychische Störungen bei Jugendlichen: Zahlen aus einer Spezialambulanz für Suchterkrankungen

Fragestellung: Nur wenige Kliniken für Kinder- und Jugendpsychiatrie (KJP) bieten eine ambulante Behandlung von Jugendlichen mit Substanzkonsumstörungen (SUDs) an. Daher fehlen Angaben, welche Konsummuster, SUDs und begleitenden psychischen Störungen diese Jugendlichen aufweisen. Methodik:N = 201 Patient_innen einer universitären Spezialambulanz (12–19 Jahre alt) wurden bezüglich Konsummustern, SUDs und aktuellen psychischen Störungen mittels Interview untersucht. Es wurden diesbezüglich deskriptive Darstellungen zu Prävalenzzahlen der SUDs, Konsummustern und begleitenden psychischen Störungen aufgeteilt nach Geschlecht und aktuellem Alter erstellt. Ergebnisse: Tabak (88 %) und Cannabis (86 %) waren die verbreitetsten Substanzen. Bei 67 % aller Patient_innen wurde mehr als eine SUD festgestellt. SUDs bezogen sich am häufigsten auf Cannabis (84 %), gefolgt von Tabak (77 %). 72 % aller Patient_innen zeigten eine die SUD begleitende psychische Störung, insbesondere Störungen des Sozialverhaltens (40 %), hyperkinetische Störungen (21 %) und depressive Störungen (18 %). Schlussfolgerungen: Ambulant behandelte jugendliche KJP-Patient_innen mit SUDs präsentieren sich häufig mit begleitenden psychischen Störungen. Angebotene Behandlungsprogramme sollten in der Behandlung von SUDs insbesondere Störungen des Sozialverhaltens, Depressionen und hyperkinetische Störungen berücksichtigen.Objective: Only few clinics offer the outpatient treatment of substance use disorders (SUDs) among adolescents. Therefore, only limited data describe substance use patterns, SUDs, and co-occurring psychiatric disorders characteristic of adolescents who present in such outpatient clinics specialized in the treatment of SUDs. Method: Via interview we collected data from n = 201 patients between 12 and 19 years concerning their substance use, SUDs, and current co-occurring psychiatric disorders. We created descriptive presentation of data regarding use patterns, SUDs, and co-occurring disorders divided by sex and current age. Results: Tobacco (88 %) and cannabis (86 %) were the most frequently used substances. 67 % of all patients presented with more than one SUD, cannabis use disorder being the most prevalent one (84 %). 72 % presented with at least one co-occurring disorder, with conduct disorders (40 %), attention deficit (hyperactivity) disorders (21 %), and depressive disorders (18 %) being the most frequent ones. Conclusions: Adolescent SUD patients often present with co-occurring psychiatric disorders. Institutions for adolescent SUD treatment should also focus on treating co-occurring conduct disorders, depression, and attention deficit disorders

Comparing self-report and parental report of psychopathologies in adolescents with substance use disorders

Both internalizing and externalizing psychopathologies interfere with the treatment of substance use disorders (SUD) in adolescents. Self-reports of psychopathologies are likely biased and may be validated with parental reports. We compared N = 70 standardized self-reports of adolescents entering outpatient SUD treatment (13.2-18.6 years old, 43% female) to parental reports on the same psychopathologies, and explored biases due to gender, age, SUD diagnoses and SUD severity. Bivariate bootstrapped Pearson correlation coefficients revealed several small to moderate correlations between both reporting sources (r = 0.29-0.49, all

Verbal learning impairment in adolescents with methamphetamine use disorder: a cross-sectional study.

BACKGROUND: Methamphetamine (MA) use has been shown to be associated with deficits in impulsivity, verbal learning, and working memory. Additionally, methamphetamine use disorder (MUD) is related to various brain changes, especially in adolescent users who might be more vulnerable to detrimental effects on brain development. However, little is known about the relationship between adolescent MA use and cognitive impairment. This cross-sectional study aims to explore how the presence of a MUD in adolescents is related to impairments of verbal memory, inhibition, and alertness. METHODS: N = 18 psychiatric outpatients with MUD were matched in terms of depressivity, age, and gender to n = 18 adolescents with other substance use disorders (SUDs), as well as n = 18 controls without SUDs. We compared these three groups on the Verbal Learning and Memory Task (VLMT), and the alertness and go/noGo subtests of the Test of Attentional Performance (TAP). Additionally, Spearman's rank order correlation coefficients were calculated to investigate whether cognitive functioning was directly associated with frequency of past year MA use. RESULTS: The three groups differed significantly in their verbal learning performance (H (2) = 11.7, p = .003, η = .19), but not in short-term memory, inhibition, cued recall, or alertness. Post hoc tests revealed significant differences in verbal learning between the MA using group and the control group without a SUD (U = 56.5, p = .001, η = .31). Frequency of past year MA use correlated negatively with short-term memory (ρ = -.25, p < .01) and verbal learning (ρ = -.41, p < .01). No other cognitive variables correlated significantly with MA use frequency. Significant p-values were considered significant after Bonferroni correction. CONCLUSIONS: Adolescent MUD outpatients with regular MA use show specific impairment in verbal learning performance, but not in other basal cognitive functions when compared to adolescents without a MUD. Verbal learning and short-term memory performance is negatively associated with the frequency of MA use. Future research should apply longitudinal designs to investigate long-term effects of methamphetamine and reversibility of these effects on cognitive functioning

DNA methylation changes associated with cannabis use and verbal learning performance in adolescents: an exploratory whole genome methylation study

The association between extent of chronic cannabis use (CCU-extent) and cognitive impairment among adolescents has been the subject of controversial debate. Linking DNA methylation to CCU-extent could help to understand cannabis associated changes in cognitive performance. We analyzed cognitive task performances, CpG methylation in peripheral whole-blood samples and self-reported past-year CCU-extent of n = 18 adolescents (n = 9 psychiatric outpatients with chronic cannabis use (CCU), n = 9 without) who were matched for age, gender and psychiatric disorders. Patients with CCU were at least 24 h abstinent when cognitive tasks were performed. A Principal Component Analysis (PCA) was carried out to identify group differences in whole genome DNA methylation. Mediation analyses were performed between CCU-extent associated CpG sites and CCU-extent associated variables of cognitive tasks. PCA results indicated large differences in whole genome DNA methylation levels between the groups that did not reach statistical significance. Six CpG sites revealed reduced methylation associated with CCU-extent. Furthermore, CCU-extent was associated with lower scores in verbal learning. All six CpG sites mediated the effects between CCU-extent and verbal learning free recall. Our results indicate that CCU is associated with certain patterns in the methylome. Furthermore, CCU-extent associated impairments in memory function are mediated via differential methylation of the six CCU-associated CpG sits. Six identified CpG are located in genes previously described in the context of neurodegeneration, hippocampus-dependent learning and neurogenesis. However, these results have to be carefully interpreted due to a small sample size. Replication studies are warranted

Prenatally traumatized mice reveal hippocampal methylation and expression changes of the stress-related genes Crhr1 and Fkbp5

In our previous study, we found that prenatal trauma exposure leads to an anxiety phenotype in mouse pups, characterized by increased corticosterone levels and increased anxiety-like behavior. In order to understand the mechanisms by which aversive in utero experience leads to these long-lasting behavioral and neuroendocrine changes, we investigated stress reactivity of prenatally traumatized (PT) mice, as well as the expression and methylation levels of several key regulatory genes of the stress axis in the dorsal hippocampus (dHPC) of the PT embryo and adult mice. We detected increased corticotropin-releasing hormone receptor 1 (Crhr1) and decreased FK506 binding protein 5 (Fkbp5) mRNA levels in the left dHPC of adult PT mice. These alterations were accompanied by a decreased methylation status of the Crhr1 promoter and an increased methylation status of the Fkbp5 promoter, respectively. Interestingly, the changes in Fkbp5 and Crhr1 mRNA levels were not detected in the embryonic dHPC of PT mice. Together, our findings provide evidence that prenatal trauma has a long-term impact on stress axis function and anxiety phenotype associated with altered Crhr1 and Fkbp5 transcripts and promoter methylation