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  • Integrated Exposure-Based Therapy for Co-occurring Posttraumatic Stress Disorder and Substance Dependence: A Randomized Controlled Trial
    (2012) Mills, Katherine; Teesson, Maree; Back, Sudie; Brady, Kathleen; Baker, Amanda; Hopwood, Sally; Sannibale, Claudia; Barrett, Emma; Merz, Sabine; Rosenfeld, Julia; Ewer, Philippa
    Journal Article
    Context: There is concern that exposure therapy, an evidence-based cognitive-behavioral treatment for posttraumatic stress disorder (PTSD), may be inappropriate for patients with co-occurring substance dependence (SD). Objective: To determine whether an integrated treatment for PTSD and SD, Concurrent Treatment of PTSD and Substance Use Disorders Using Prolonged Exposure (COPE), can achieve greater reductions in PTSD and SD symptom severity compared to treatment as usual (TAU) for SD. Design, Setting, and Patients: A randomized controlled trial of 103 participants who met DSM-IV-TR criteria for both PTSD and SD. Participants were recruited from 2007-2009 in Sydney, Australia, and randomized to one of two conditions. The treatment group received COPE plus TAU (COPE+TAU; n=55) and the control group received TAU alone (n=48). Outcomes were assessed at 9-months post-baseline, and interim measures collected at 6-weeks and 3-months post-baseline. Interventions: COPE consists of 13 individual 90-minute sessions (i.e., 19.5 hours) with a clinical psychologist. It represents an integration of existing evidence based manualized cognitive behavioral treatments for PTSD and SD, comprising psychoeducation, motivational enhancement, and cognitive behavioral therapy for PTSD and SD, including imaginal and in vivo exposure. Main outcome measures: Change in PTSD symptom severity as measured by the Clinician Administered PTSD Scale (CAPS; scale range 0-240), and change in severity of SD as measured by the number of dependence criteria met according to the Composite International Diagnostic Interview version 3.0 (CIDI; range 0-7), from baseline to 9-month follow-up. A change of 15 points on the CAPS scale and 1 dependence criteria on the CIDI were considered to be clinically significant. Results: From baseline to 9-month follow-up, significant reductions in PTSD symptom severity were found for both the treatment (mean difference -38.24, 95%CI: -47.93 - -28.54) and control group (mean difference -22.14, 95%CI: -30.33 - -13.95), however, the treatment group demonstrated a significantly greater reduction in PTSD symptom severity compared to the control group (mean difference -16.09, 95%CI: -29.00 to -3.19). No significant between group difference was found in relation to improvement in severity of SD (0.43 v 0.52; IRR 0.85, 95%CI: 0.60 - 1.21), nor were there any significant between group differences in relation to changes in substance use, depression or anxiety. Conclusions: Among patients with PTSD and SD, the combined use of COPE+TAU, compared with TAU alone, resulted in improvement in PTSD symptom severity without an increase in severity of SD. Trial registration: Registration number ISRCTN12908171; URL: http://www.controlled-trials.com/ISRCTN12908171/mills
  • DNA methylation of MAPT gene in Parkinson's disease cohorts and modulation by vitamin E In Vitro
    (2014) Coupland, Kirsten G; Mellick, George D; Silburn, Peter A; Huang, Yue; Halliday, Glenda; Hallup, Marianne; Woojin, S. Kim; Dobson-Stone, Carol; Kwok, John BJ; Mather, Karen; Armstrong, Nicola J; Sachdev, Perminder; Brodaty, Henry
    Journal Article
    Background: Parkinson's disease (PD) is a neurodegenerative disorder for which environmental factors influence disease risk and may act via an epigenetic mechanism. The microtubule-associated protein tau (MAPT) is a susceptibility gene for idiopathic PD. Methods: Methylation levels were determined by pyrosequencing of bisulfite treated DNA in a leukocyte cohort (358 PD and 1084 controls) and two brain cohorts (Brain1 comprising 69 cerebellum controls, Brain2 comprising 3 brain regions from 28 PD and 12 controls). In vitro assays involved the transfection of methylated promoter-luciferase constructs or treatment with an exogenous micronutrient. Results: In normal leukocytes, MAPT H1/H2 diplotype and gender were predictors of MAPT methylation. Haplotype-specific pyrosequencing confirmed H1 haplotype to have higher methylation than H2 in normal leukocyte and brain tissues. MAPT methylation was negatively associated with MAPT expression in Brain1 cohort and transfected cells. Methylation levels differed between three normal brain regions (Brain2, putamen > cerebellum > anterior cingulate cortex). In PD samples, age at onset was positively associated with MAPT methylation in leukocytes. Moreover, there was hypermethylation in the cerebellum and hypomethylation in the putamen of PD patients compared with controls (Brain2 cohort). Finally, leukocyte methylation status was positively associated with blood Vitamin E levels, the effect being more significant in H2 haplotype carriers; this result was confirmed in cells exposed to 100 μM Vitamin E. Conclusions: The significant effects of gender, diplotype and brain region suggest that hypermethylation of the MAPT is neuroprotective by reducing MAPT expression. Vitamin E effect on MAPT represents a possible gene-environment interaction.