Centre for Youth Mental Health - Research Publications

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    MGLU5 receptors are necessary for extinction of drug associated cues and contexts
    Perry, C ; Reed, F ; Luikinga, S ; Zbukvic, I ; Kim, JH ; Lawrence, A (Wiley, 2017-08-01)
    Drug-associated cues and contexts are strong predictors of relapse. We used complex behavioural preparations to examine whether extinction of such cues reduces their capacity to trigger drug-seeking. We also examined whether the mGlu5 receptor is necessary for extinction learning. In Experiment 1, rats were trained to lever press for cocaine. Once stable responding was established, the context was extinguished by replacing the rats in the chambers, but with no opportunity to respond (levers were retracted). Control group remained in their home cage. An mGlu5 receptor negative allosteric modulator (MTEP) or vehicle was administered immediately after context extinction sessions. During subsequent drug-induced reinstatement, rats responded less if they had received context extinction; however, this effect was attenuated where MTEP had been applied. In Experiment 2, rats were trained to lever press for cocaine, now paired with a cue light. To extinguish the cue, half of the rats were placed in the chambers and given non-reinforced presentations of the cue, but with the levers retracted. Control rats remained in home cage. All rats received either MTEP or vehicle 20 minutes prior. Cue-induced reinstatement was tested the following day by re-pairing the lever with the light. Rats gave fewer drug-seeking responses following cue extinction. This effect was attenuated by MTEP. Experiment 3 followed the same protocol as Experiment 2, except that a positive allosteric modulator CDPPB or vehicle was administered 20 minutes before CS extinction. At reinstatement, cue-elicited cocaine seeking was lower for the animals that had previously been administered CDPPB, regardless of extinction condition. This study highlights the important role cues and contexts play in driving drug-seeking behaviour during reinstatement. It also shows that mGlu 5 signalling is necessary for extinction of drug-cue associations, and that mGlu5 positive allosteric modulators are promising targets for treating cocaine addiction.
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    The impact of testicular cancer and its treatment on masculinity: A systematic review
    Dax, V ; Ftanou, M ; Tran, B ; Lewin, J ; Wallace, R ; Seidler, Z ; Wiley, JF (WILEY, 2022-09)
    OBJECTIVE: The purpose of this review was to synthesise the literature on the topic of masculinity and testicular cancer (TC) and investigate the relative impact of TC on men's view of their masculinity. METHODS: Searches were conducted across four databases (MEDline, PsycInfo, CINAHL Plus and Scopus) for articles published before April 2022 that included (1) TC and (2) masculinity. Two researchers independently rated studies for inclusion with a third resolving conflicts. Of the 6464 articles screened, 24 articles (10 quantitative and 14 qualitative) were included in the review. Articles were rated for quality and a narrative synthesis was performed. RESULTS: Overall, results indicated some men experience a shift in the way they relate to their sense of masculinity following diagnosis and treatment for TC. Being single and without children was related to the experience of negative masculinity-related outcomes, possibly due to a compounding lack of relational support and being unable to conform to protector, provider traditions. Men who described testicle loss as symbolic of their diminished masculinity were also negatively impacted. However, recent, high-quality literature on the topic using standardised masculinity measures was limited. CONCLUSION: Some men experience a reduced sense of masculinity after TC, however the impact of TC on masculinity remains person dependent. Further research using validated masculinity measures is required to uncover psycho-social variables that may account for whether and how meaning is made between TC and its treatment and any subsequent impact on perceived masculinity. Such factors may better support these men in life beyond cancer. SYSTEMATIC REVIEW REGISTRATION: PROSPERO. International Prospective Register of Systematic Reviews: CRD42020185649.
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    Brain Aging in Major Depressive Disorder: Results From the ENIGMA MDD Consortium
    Schmaal, L ; Han, L ; Dinga, R ; Thompson, P ; Veltman, D ; Penninx, B (ELSEVIER SCIENCE INC, 2018-05-01)
    Background: Major Depressive Disorder has been associated with accelerated biological aging. From a brain perspective, normal aging is associated with significant loss of grey matter and depression may have an accelerating effect on age-related brain atrophy. Here, data on brain aging in MDD from the ENIGMA MDD Working Group will be presented. Methods: A normative model of brain-based age was devel- oped in 4708 healthy controls by applying a Gaussian Process Regression analysis with 10-fold cross-validation to estimate chronological age from structural MRI scans, separately for males and females. This model was then applied to 2924 MDD individuals to predict their brain-based age. Accelerated brain aging was measured as the difference between predicted brain-based age and actual chronological age (brain age gap). Results: The brain age model explained 92% and 93% of the age variance in female and male healthy controls, respectively. The mean absolute error (MAE) was 6.79 years in females and 6.60 in males. Application of the model to MDD patients showed a mean brain age gap of 0.75 years in females (MAE¼6.82) and 0.64 in males (MAE¼6.68), which were significantly lower than brain age gap estimates in healthy controls in both females (F(1,4379)¼6.10,P¼0.01) and males (F(1,3166)¼4.07,P¼0.04). Our preliminary analysis also showed greater brain age gap associations with various clinical characteristics. Conclusions: We found preliminary evidence for accelerated brain aging in MDD, however, the brains of patients were estimated to be only <1 years older than healthy controls. The impact of different methods, feature selection and potential confounding effects will also be discussed.
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    METHYLOME-WIDE ASSOCIATION STUDIES FOR MAJOR DEPRESSIVE DISORDER IN BLOOD OVERLAP WITH METHYLATION RESULTS FROM BRAIN AND LARGE-SCALE GWAS
    Aberg, K ; Dean, B ; Shabalin, A ; Zhao, M ; Chan, R ; Hattab, M ; van Grootheest, G ; Han, L ; Aghajani, M ; Milaneschi, Y ; Jansen, R ; Xie, L ; Clark, S ; Penninx, B ; van den Oord, E (ELSEVIER SCIENCE BV, 2019-01-01)
    Background: Epigenetic modifications such as DNA methy- lation provide stability and diversity to the cellular phenotype and aberrant methylation has been implicated in processes underlying psychiatric disorders. Therefore, studies combining DNA methylation and genotype information provide a promis- ing approach to study disorders where genotype information alone has failed to reveal the full etiology. Methods: We applied an optimized MBD-seq protocol to assay the complete CpG methylome in cases with Major Depressive Disorder (MDD) and controls using blood samples (N=1,132) from Netherlands Study of Depression and Anxiety and brain samples (N=64) from the Victorian Brain Bank Network. Data were analyzed with RaMWAS, a novel Biocon- ductor package specifically designed for Methylome-Wide Association Studies (MWAS). To study the overlap between top MWAS findings in blood and brain, we used a permutation based enrichment test (shiftR) that accounted for the depen- dency between adjacent CpG sites. Furthermore, we utilized the methylation data in combination with existing genotype information from the same individuals in a MWAS of CpGs created or destroyed by SNPs. Next, we tested whether top results from this CpG-SNP MWAS overlapped with recent large- scale GWAS to identify robust associations with genomic loci of importance for MDD etiology Results: The MWAS in blood identified five methylome- wide significant sites (P o 5 10-8) from three distinct loci and 472 nominally significant (P o 1 10-5) CpG sites. To study the robustness of the overall MWAS signal, we used an “in-sample” replication based on k-fold cross validation. Results showed that the findings replicated (P = 4.0 10- 10). When we compared blood and brain we found that top blood MWAS findings were significantly enriched for top CpGs in the brain MWAS (P = 5.4 10-3). The MWAS of CpG-SNPs identified 32 nominally significant sites and in- sample replication showed that the signal replicated (P = 2.2 10-8). Finally, the top CpG-SNP MWAS showed a consistent trend towards enrichment in all tested large- scale GWAS, with the most significant enrichment observed for the 23andMe study (P = 4.9 10-3). This overlap involved 55 genes that were overrepresented (P o 0.01) in 12 level-5 gene ontology terms, of which a major portion was related to neuronal regulation, function and development. Discussion: This work involves the largest MWAS for MDD performed to date. Our integrated analysis with brain tissue, genotype information and GWAS results highlighted biological functions of potential value for MDD etiology. Part of the associated methylation marks in blood overlapped with MWAS finding in brain. As blood can easily be collected in a clinical setting, these loci may be of direct value as potential diagnostic biomarkers for MDD.
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    Deviations From Normative Age-Brain Associations in Over 3,000 Individuals With Major Depressive Disorder
    Schmaal, L ; Han, L ; Bayer, J ; Marquand, A ; Dinga, R ; Cole, J ; Hahn, T ; Penninx, B ; Veltman, D ; Thompson, P (ELSEVIER SCIENCE INC, 2019-05-15)
    Background: Major depressive disorder (MDD) is a complex heterogeneous disorder. Identifying brain alterations as indi- vidual deviations from normative patterns of brain-age asso- ciations, instead of patient group mean differences, can provide important insights into heterogeneous patterns of brain abnormalities observed in MDD. Methods: We estimated normative models of (1) age pre- dicting individual structural brain measures, and (2) structural brain measures predicting age (Brain Age model) using ma- chine learning in healthy individuals (N¼2,515) from the ENIGMA MDD consortium. We applied model parameters to independent samples of healthy individuals (N¼2,513) and MDD patients (N¼3,433) to obtain predicted values of brain structure (model 1) and age (model 2). Z-scores quantifying differences between predictive and true values were calcu- lated, representing individual deviations from the normative range. Results: The estimated normative models showed good model fit in the training sample; e.g. a correlation of R¼0.86 between actual and predicted age for the Brain Age Model, and good generalization to independent healthy and MDD samples. We identified heterogeneous patterns of brain deviations in MDD patients (model 1). Patients with more extreme deviations showed different clinical characteristics compared to patients residing within the normative range. Additionally, patients were estimated on average w1 year older than controls (model 2), but we also observed large between-person variation in brain age gaps. Further ana- lyses showed associations between brain age gap and clinical symptoms. Conclusions: Our work shows substantial heterogeneity in deviations from normal age-related variation in brain structure in individuals with MDD. The impact of and solutions for con- founding effects of scan site will also be discussed.
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    Meta-Analysis of Hippocampal Subfields: Results From the ENIGMA-MDD Working Group
    Saemann, P ; Czisch, M ; Jahanshad, N ; Whelan, CD ; van Velzen, L ; Hibar, D ; Han, L ; Veer, IM ; Walter, H ; Veltman, D ; Schmaal, L (ELSEVIER SCIENCE INC, 2019-05-15)
    Background Hippocampal volume reductions in major depressive disorder (MDD) represent a robust finding in retrospective meta-analyses. Subregional specificity of this finding has been suspected from several smaller previous studies. Given the complex role of the hippocampus both for stress response regulation and its vulnerability to chronic disease, we aim at finer mapping of this result using FreeSurfer based, automated subfield segmentation. Methods Twenty-three centers with MDD/control samples contributed. Results reported here stem from 2522 patients and 4244 controls. After segmentation and standardized QC, local statistical were run for 25 models in total. Key models were: Cases vs. controls (covarying for age, age squared, sex-by-age, sex-by-age-squared, ICV and scanner/site); recurrent vs. controls, first episode vs. controls, early onset (EO, <22 years) vs. controls, late onset (LO) vs. controls. Eventually, inverse variance-weighted random-effect meta-analysis model in R (metafor package) with FDR correction for 14 phenotypes was performed. Results Regional specificity of volume deficits were detected in MDD as a whole (2522 patients, 4244 controls) (CA3>whole>CA1>GC.ML.DG>CA4>molecular layer). No robust effects were found in first episode patients (743 patients, 3812 controls) except for nominal effects. In recurrent MDD, only CA1 effects were robust. EO depression showed unexpectedly strong effects (836 patients, 3472 controls). Similarly, patients with current AD treatment showed strong effects, similarly distributed as in MDD except for CA1. No correlation with depression severity was detected. Conclusions Hippocampal structural changes in MDD show subregion specificity. While first episode status seems less critical and first/recurrent episode patients are similar, early onset appears as key predictor of structural abnormalities.
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    Personality disorder among youth with first episode psychotic mania: An important target for specific treatment?
    Hasty, MK ; Macneil, CA ; Cotton, SM ; Berk, M ; Kader, L ; Ratheesh, A ; Ramain, J ; Chanen, AM ; Conus, P (WILEY, 2022-03)
    AIM: Personality disorder is a common co-occurrence ('comorbidity') among patients with bipolar disorder and appears to affect outcome negatively. However, there is little knowledge about the impact of this comorbidity in the early phases of bipolar disorder. We examined the prevalence and effect of personality disorder co-occurrence on outcome in a cohort of youth with first episode mania with psychotic features. METHODS: Seventy-one first episode mania patients, aged 15-29, were assessed at baseline, 6, 12, and 18 months as part of a randomized controlled trial of olanzapine and chlorpromazine as add-on to lithium in first episode mania with psychotic features. The current study involved secondary analysis of trial data. RESULTS: A co-occurring clinical personality disorder diagnosis was present in 16.9% of patients. Antisocial and narcissistic personality disorders were the most common diagnoses. Patients with co-occurring personality disorder had higher rates of readmission to hospital, lower rates of symptomatic recovery and poorer functional levels at 6 months, but these differences disappeared after 12 and 18 months. CONCLUSIONS: In the early phase of bipolar disorder, patients with personality disorder comorbidity display delayed symptomatic and functional recovery and increased likelihood to need hospital readmissions. These observations suggest that routine assessment for personality disorder and specific interventions are important in order to improve short-term treatment efficacy in this subgroup.
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    Brain structural correlates of insomnia severity in 1053 individuals with major depressive disorder: results from the ENIGMA MDD working group
    Leerssen, J ; Blanken, TF ; Pozzi, E ; Jahanshad, N ; Aftanas, L ; Andreassen, OA ; Baune, BT ; Ching, CRK ; Dannlowski, U ; Frodl, T ; Godlewska, BR ; Gotlib, IH ; Grotegerd, D ; Gruber, O ; Hatton, SN ; Hickie, IB ; Jaworska, N ; Kircher, T ; Krug, A ; Lagopoulos, J ; Li, M ; MacMaster, FP ; McIntosh, AM ; Mwangi, B ; Osipov, E ; Portella, MJ ; Sacchet, MD ; Samann, PG ; Simulionyte, E ; Soares, JC ; Walter, M ; Whalley, HC ; Veltman, DJ ; Thompson, PM ; Schmaal, L ; Van Someren, EJW (WILEY, 2020-09)