Current evidence on integrated treatment for serious mental disorder and substance misuse

Substance misuse in people with serious mental disorders is common and has a wideranging negative impact. The multiplicity of problems suggests that this comorbidity is better conceptualized as a type of complex disorder than by ‘dual diagnosis’. Problems with sequential and parallel treatments have led to the development of integrated approaches, with one practitioner or team addressing both the substance use and mental disorder. These treatments are typically characterized by motivation enhancement, minimizing treatment-related stress, emphasizing harm reduction as well as abstinence, and assertive outreach. A review of published randomized trials demonstrates that superior effects to controls are rarely consistent across treatment foci and over time. While motivational interventions assist engagement, more intervention is usually required for integrated treatment programs to improve long-term outcomes more than control conditions. More intensive case management does not consistently improve impact, but extended cognitive-behavioral therapies have promise. Suggestions for maximizing treatment effects and improving research evidence are provided.

Genome-wide association study of major depressive disorder: New results, meta-analysis, and lessons learned

Major depressive disorder (MDD) is a common complex disorder with a partly genetic etiology. We conducted a genome-wide association study of the MDD2000+ sample (2431 cases, 3673 screened controls and >1 M imputed single-nucleotide polymorphisms (SNPs)). No SNPs achieved genome-wide significance either in the MDD2000+ study, or in meta-analysis with two other studies totaling 5763 cases and 6901 controls. These results imply that common variants of intermediate or large effect do not have main effects in the genetic architecture of MDD. Suggestive but notable results were: (a) gene-based tests suggesting roles for adenylate cyclase 3 (ADCY3, 2p23.3) and galanin (GAL, 11q13.3); published functional evidence relates both of these to MDD and serotonergic signaling; (b) support for the bipolar disorder risk variant SNP rs1006737 in CACNA1C (P=0.020, odds ratio=1.10), and; (c) lack of support for rs2251219, a SNP identified in a meta-analysis of affective disorder studies (P=0.51). We estimate that sample sizes 1.8- to 2.4-fold greater are needed for association studies of MDD compared with those for schizophrenia to detect variants that explain the same proportion of total variance in liability. Larger study cohorts characterized for genetic and environmental risk factors accumulated prospectively are likely to be needed to dissect more fully the etiology of MDD.

Ryanodine receptor phosphorylation in human heart failure

Heart failure is a complex disorder, characterized by activation of the sympathetic nervous system, leading to dysregulated Ca2+ homeostasis in cardiac myocytes and tissue remodeling. In a variety of diseases, cardiac malfunction is associated with aberrant fluxes of Ca2+ across both the surface membrane and the internal Ca2+ store, the sarcoplasmic reticulum (SR). One prominent hypothesis residues is that in heart failure, the activity of the ryanodine receptor (RyR2) Ca2+ release channel in the SR is increased due to excess phosphorylation and that this contributes to excess SR Ca2+ leak in diastole, reduced SR Ca2+ load and decreased contractility (Huke & Bers, 2008). There is controversy over which serine residues in RyR2 are hyperphosphorylated in animal models of heart failure and whether this is via the CaMKII or the PKA-linked signaling pathway. S2808, S2814 and S2030 in RyR2 have been variously claimed to be hyperphosphorylated. Our aim was to examine the degree of phosphorylation of these residues in RyR2 from failing human hearts. The use of human tissue was approved by the Human Research Ethics Committee, The Prince Charles Hospital, EC28114. Left ventricular tissue samples were obtained from an explanted heart of a patient with endstage heart failure (Emery Dreifuss Muscular Dystrophy with cardiomyopathy) and non-failing tissue was from a patient with cystic fibrosis undergoing heart-lung transplantation with no history of heart disease. SR vesicles were prepared as described by Laver et al. (1995) and examined with SDS-Page and Western Blot. Transferred proteins were probed with antibodies to detect total protein phosphorylation, phosphorylation of RyR2 serine residues S2808, S2814, S2030 and for the key proteins calsequestrin, triadin, junctin and FKBP12.6. To avoid membrane stripping artifact, each membrane was exposed to one phosphorylation-specific antibody and signal densities quantified using Bio-Rad Quantity One software. We found no distinguishable difference between failing and healthy hearts in the protein expression levels of RyR2, triadin, junctin or calsequestrin. We found an expected upregulation of total RyR2 phosphorylation in the failing heart sample, compared to a matched amount of RyR2 (quantified using densiometry) in healthy heart. Probing with antibodies detecting only the phosphorylated form of the specific RyR2 residues showed that the increase in total RyR2 phosphorylation in the failing heart was due to hyperphosphorylation of S2808 and S2814. We found that S2030 phosphorylation levels were unchanged in human heart failure. Interestingly, we found that S2030 has a basal level of phosphorylation in the healthy human heart, different from the absence of basal phosphorylation recently reported in rodent heart (Huke & Bers, 2008). Finally, preliminary results indicate that less FKBP 12.6 is associated with RyR2 in the failing heart, possibly as a consequence of PKA activation. In conclusion, residues S2808 and S2814 are hyperphosphorylated in human heart failure, presumably due to upregulation of the CaMKII and/or PKA signaling pathway as a result of chronic activation of the sympathetic nervous system. Such changes in RyR2 phosphorylation are believed to contribute to the leaky RyR2 phenotype associated with heart failure, which increases the incidence of arrhythmia and contributes to the severely impaired contractile performance of the failing heart. Huke S & Bers DM. (2008). Ryanodine receptor phosphorylation at serine 2030, 2808 and 2814 in rat cardiomyocytes. Biochemical and Biophysical Research Communications 376, 80-85. Laver DR, Roden LD, Ahern GP, Eager KR, Junankar PR & Dulhunty AF. (1995). Cytoplasmic Ca2+ inhibits the ryanodine receptor from cardiac muscle. Journal of Membrane Biology 147, 7-22. Proceedings

An analysis of clinical characteristics in genetically linked migraine-affected pedigrees

Migraine is a common complex disorder characterized by severe recurrent headache and usually accompanied by nausea and vomiting. Previous studies in our laboratory have utilized three large multigenerational Australian pedigrees affected with migraine to indicate that the disease is genetically heterogeneous, with linkage results implicating genomic susceptibility regions on both chromosomes 19p and Xq. The present study explores the possibility of a correlation between genetic and clinical heterogeneity in these affected pedigrees. Specifically, the clinical characteristics of migraine including subtype, age of onset, frequency, duration, and disease symptoms were compared between the migraine pedigrees, and gender differences were also assessed. Our exploratory analyses revealed no significant differences in any of the clinical characteristics tested between the chromosome 19-linked family and the two X-linked families. Also, we did not detect any differences in male vs. female clinical features for these pedigrees. In conclusion, migraine is considered to be a clinically and genetically heterogeneous disorder; however, our study provided no conclusive evidence that variation in genomic susceptibility region is related to heterogeneity at the clinical level in these migraine-affected pedigrees.

Molecular mechanisms of migraine

Migraine is a common complex disorder that affects a large portion of the population and thus incurs a substantial economic burden on society. The disorder is characterized by recurrent headaches that are unilateral and usually accompanied by nausea, vomiting, photophobia, and phonophobia. The range of clinical characteristics is broad and there is evidence of comorbidity with other neurological diseases, complicating both the diagnosis and management of the disorder. Although the class of drugs known as the triptans (serotonin 5-HT1B/1D agonists) has been shown to be effective in treating a significant number of patients with migraine, treatment may in the future be further enhanced by identifying drugs that selectively target molecular mechanisms causing susceptibility to the disease. Genetically, migraine is a complex familial disorder in which the severity and susceptibility of individuals is most likely governed by several genes that may be different among families. Identification of the genomic variants involved in genetic predisposition to migraine should facilitate the development of more effective diagnostic and therapeutic applications. Genetic profiling, combined with our knowledge of therapeutic response to drugs, should enable the development of specific, individually-tailored treatment.

Evidence for an X-linked genetic component in familial typical migraine

Migraine is a common complex disorder that shows strong familial aggregation. There is a general increased prevalence of migraine in females compared with males, with recent studies indicating that migraine affects 18% of females compared with 6% of males. This preponderance of females among migraine sufferers coupled with evidence of an increased risk of migraine in first degree relatives of male probands but not in relatives of female probands suggests the possibility of an X-linked dominant gene. We report here the localization of a typical migraine susceptibility locus to the X chromosome. Of three large multigenerational migraine pedigrees two families showed significant excess allele sharing to Xq markers (P = 0.031 and P = 0.012). Overall analysis of data from all three pedigrees gave significant evidence in support of linkage and heterogeneity (HLOD = 3.1). These findings provide conclusive evidence that familial typical migraine is a heterogeneous disorder. We suggest that the localization of a migraine susceptibility locus to the X chromosome could in part explain the increased risk of migraine in relatives of male probands and may be involved in the increased female prevalence of this disorder.

An investigation of the 5-HT2C receptor gene as a migraine candidate gene

Migraine is a common complex disorder, currently classified into two main subtypes, migraine with aura (MA) and migraine without aura (MO). The strong preponderance of females to males suggests an X-linked genetic component. Recent studies have identified an X chromosomal susceptibility region (Xq24-q28) in two typical migraine pedigrees. This region harbours a potential candidate gene for the disorder, the serotonin receptor 2C (5-HT2C) gene. This study involved a linkage and association approach to investigate two single nucleotide variants in the 5-HT2C gene. In addition, exonic coding regions of the 5-HT2C gene were also sequenced for mutations in X-linked migraine pedigrees. Results of this study did not detect any linkage or association, and no disease causing mutations were identified. Hence, results for this study do not support a significant role of the 5-HT 2C gene in migraine predisposition. © 2003 Wiley-Liss, Inc.

Transdisciplinary collaboration in wound care research

The highly complex disorder of chronic wounds is a significant problem. Information is often lacking, dynamically changing, or contradictory and thus acts to impede the progression of research and its translation into clinical care. Transdisciplinary collaboration may play an important role in chronic wound research, permitting key stakeholders with a single, central goal to take a unified approach towards addressing the problem. While transdisciplinary collaboration is not a new concept, its implementation within chronic wound research is relatively new. This is because the research area is still largely dominated by single-discipline researchers or by multiple disciplines working in isolation. Transdisciplinary research is a transcending approach, requiring a greater level of understanding between disciplines and may represent the next leap forward in wound care research. This approach necessitates a deeper understanding by all team members of the co-disciplines involved; where key stakeholders are better equipped to respond to dynamic changes and problems that arise in chronic wound research. In this paper, we illustrate what a transdisciplinary approach in wound care research may entail, with the ultimate goal of such an undertaking to improve understanding of the complexities of wound care, which could lead to potential benefits in wound management.

Genomewide significant linkage to migrainous headache on chromosome 5q21

Familial typical migraine is a common, complex disorder that shows strong familial aggregation. Using latent-class analysis (LCA), we identified subgroups of people with migraine/severe headache in a community sample of 12,245 Australian twins (60% female), drawn from two cohorts of individuals aged 23-90 years who completed an interview based on International Headache Society criteria. We report results from genomewide linkage analyses involving 756 twin families containing a total of 790 independent sib pairs (130 affected concordant, 324 discordant, and 336 unaffected concordant for LCA-derived migraine). Quantitative-trait linkage analysis produced evidence of significant linkage on chromosome 5q21 and suggestive linkage on chromosomes 8, 10, and 13. In addition, we replicated previously reported typical-migraine susceptibility loci on chromosomes 6p12.2-p21.1 and 1q21-q23, the latter being within 3 cM of the rare autosomal dominant familial hemiplegic migraine gene (ATP1A2), a finding which potentially implicates ATP1A2 in familial typical migraine for the first time. Linkage analyses of individual migraine symptoms for our six most interesting chromosomes provide tantalizing hints of the phenotypic and genetic complexity of migraine. Specifically, the chromosome 1 locus is most associated with phonophobia; the chromosome 5 peak is predominantly associated with pulsating headache; the chromosome 6 locus is associated with activity-prohibiting headache and photophobia; the chromosome 8 locus is associated with nausea/vomiting and moderate/severe headache; the chromosome 10 peak is most associated with phonophobia and photophobia; and the chromosome 13 peak is completely due to association with photophobia. These results will prove to be invaluable in the design and analysis of future linkage and linkage disequilibrium studies of migraine.

Evidence for an X-linked genetic component in familial typical migraine

Migraine is a common complex disorder that shows strong familial aggregation. There is a general increased prevalence of migraine in females compared with males, with recent studies indicating that migraine affects 18% of females compared with 6% of males. This preponderance of females among migraine sufferers coupled with evidence of an increased risk of migraine in first degree relatives of male probands but not in relatives of female probands suggests the possibility of an X-linked dominant gene. We report here the localization of a typical migraine susceptibility locus to the X chromosome. Of three large multigenerational migraine pedigrees two families showed significant excess allele sharing to Xq markers (P = 0.031 and P = 0.012). Overall analysis of data from all three pedigrees gave significant evidence in support of linkage and heterogeneity (HLOD = 3.1). These findings provide conclusive evidence that familial typical migraine is a heterogeneous disorder. We suggest that the localization of a migraine susceptibility locus to the X chromosome could in part explain the increased risk of migraine in relatives of male probands and may be involved in the increased female prevalence of this disorder.

Bayesian mixtures for modelling complex medical data : a case study in Parkinson’s disease

Mixture models are a flexible tool for unsupervised clustering that have found popularity in a vast array of research areas. In studies of medicine, the use of mixtures holds the potential to greatly enhance our understanding of patient responses through the identification of clinically meaningful clusters that, given the complexity of many data sources, may otherwise by intangible. Furthermore, when developed in the Bayesian framework, mixture models provide a natural means for capturing and propagating uncertainty in different aspects of a clustering solution, arguably resulting in richer analyses of the population under study. This thesis aims to investigate the use of Bayesian mixture models in analysing varied and detailed sources of patient information collected in the study of complex disease. The first aim of this thesis is to showcase the flexibility of mixture models in modelling markedly different types of data. In particular, we examine three common variants on the mixture model, namely, finite mixtures, Dirichlet Process mixtures and hidden Markov models. Beyond the development and application of these models to different sources of data, this thesis also focuses on modelling different aspects relating to uncertainty in clustering. Examples of clustering uncertainty considered are uncertainty in a patient’s true cluster membership and accounting for uncertainty in the true number of clusters present. Finally, this thesis aims to address and propose solutions to the task of comparing clustering solutions, whether this be comparing patients or observations assigned to different subgroups or comparing clustering solutions over multiple datasets. To address these aims, we consider a case study in Parkinson’s disease (PD), a complex and commonly diagnosed neurodegenerative disorder. In particular, two commonly collected sources of patient information are considered. The first source of data are on symptoms associated with PD, recorded using the Unified Parkinson’s Disease Rating Scale (UPDRS) and constitutes the first half of this thesis. The second half of this thesis is dedicated to the analysis of microelectrode recordings collected during Deep Brain Stimulation (DBS), a popular palliative treatment for advanced PD. Analysis of this second source of data centers on the problems of unsupervised detection and sorting of action potentials or "spikes" in recordings of multiple cell activity, providing valuable information on real time neural activity in the brain.

Epigenetics and migraine; complex mitochondrial interactions contributing to disease susceptibility

Migraine is a common neurological disorder classified by the World Health Organisation (WHO) as one of the top twenty most debilitating diseases in the developed world. Current therapies are only effective for a proportion of sufferers and new therapeutic targets are desperately needed to alleviate this burden. Recently the role of epigenetics in the development of many complex diseases including migraine has become an emerging topic. By understanding the importance of acetylation, methylation and other epigenetic modifications, it then follows that this modification process is a potential target to manipulate epigenetic status with the goal of treating disease. Bisulphite sequencing and methylated DNA immunoprecipitation have been used to demonstrate the presence of methylated cytosines in the human D-loop of mitochondrial DNA (mtDNA), proving that the mitochondrial genome is methylated. For the first time, it has been shown that there is a difference in mtDNA epigenetic status between healthy controls and those with disease, especially for neurodegenerative and age related conditions. Given co-morbidities with migraine and the suggestive link between mitochondrial dysfunction and the lowered threshold for triggering a migraine attack, mitochondrial methylation may be a new avenue to pursue. Creative thinking and new approaches are needed to solve complex problems and a systems biology approach, where multiple layers of information are integrated is becoming more important in complex disease modelling.

Progress towards understanding the genetics of posttraumatic stress disorder

Posttraumatic stress disorder (PTSD) is a complex syndrome that occurs following exposure to a potentially life threatening traumatic event. This review summarises the literature on the genetics of PTSD including gene–environment interactions (GxE), epigenetics and genetics of treatment response. Numerous genes have been shown to be associated with PTSD using candidate gene approaches. Genome-wide association studies have been limited due to the large sample size required to reach statistical power. Studies have shown that GxE interactions are important for PTSD susceptibility. Epigenetics plays an important role in PTSD susceptibility and some of the most promising studies show stress and child abuse trigger epigenetic changes. Much of the molecular genetics of PTSD remains to be elucidated. However, it is clear that identifying genetic markers and environmental triggers has the potential to advance early PTSD diagnosis and therapeutic interventions and ultimately ease the personal and financial burden of this debilitating disorder.

Subcortical brain alterations in major depressive disorder: findings from the ENIGMA Major Depressive Disorder working group

The pattern of structural brain alterations associated with major depressive disorder (MDD) remains unresolved. This is in part due to small sample sizes of neuroimaging studies resulting in limited statistical power, disease heterogeneity and the complex interactions between clinical characteristics and brain morphology. To address this, we meta-analyzed three-dimensional brain magnetic resonance imaging data from 1728 MDD patients and 7199 controls from 15 research samples worldwide, to identify subcortical brain volumes that robustly discriminate MDD patients from healthy controls. Relative to controls, patients had significantly lower hippocampal volumes (Cohen’s d=−0.14, % difference=−1.24). This effect was driven by patients with recurrent MDD (Cohen’s d=−0.17, % difference=−1.44), and we detected no differences between first episode patients and controls. Age of onset ⩽21 was associated with a smaller hippocampus (Cohen’s d=−0.20, % difference=−1.85) and a trend toward smaller amygdala (Cohen’s d=−0.11, % difference=−1.23) and larger lateral ventricles (Cohen’s d=0.12, % difference=5.11). Symptom severity at study inclusion was not associated with any regional brain volumes. Sample characteristics such as mean age, proportion of antidepressant users and proportion of remitted patients, and methodological characteristics did not significantly moderate alterations in brain volumes in MDD. Samples with a higher proportion of antipsychotic medication users showed larger caudate volumes in MDD patients compared with controls. This currently largest worldwide effort to identify subcortical brain alterations showed robust smaller hippocampal volumes in MDD patients, moderated by age of onset and first episode versus recurrent episode status.

A mega-analysis of genome-wide association studies for major depressive disorder

Prior genome-wide association studies (GWAS) of major depressive disorder (MDD) have met with limited success. We sought to increase statistical power to detect disease loci by conducting a GWAS mega-analysis for MDD. In the MDD discovery phase, we analyzed more than 1.2 million autosomal and X chromosome single-nucleotide polymorphisms (SNPs) in 18 759 independent and unrelated subjects of recent European ancestry (9240 MDD cases and 9519 controls). In the MDD replication phase, we evaluated 554 SNPs in independent samples (6783 MDD cases and 50 695 controls). We also conducted a cross-disorder meta-analysis using 819 autosomal SNPs with P<0.0001 for either MDD or the Psychiatric GWAS Consortium bipolar disorder (BIP) mega-analysis (9238 MDD cases/8039 controls and 6998 BIP cases/7775 controls). No SNPs achieved genome-wide significance in the MDD discovery phase, the MDD replication phase or in pre-planned secondary analyses (by sex, recurrent MDD, recurrent early-onset MDD, age of onset, pre-pubertal onset MDD or typical-like MDD from a latent class analyses of the MDD criteria). In the MDD-bipolar cross-disorder analysis, 15 SNPs exceeded genome-wide significance (P<5 x 10(-8)), and all were in a 248 kb interval of high LD on 3p21.1 (chr3:52 425 083-53 822 102, minimum P=5.9 x 10(-9) at rs2535629). Although this is the largest genome-wide analysis of MDD yet conducted, its high prevalence means that the sample is still underpowered to detect genetic effects typical for complex traits. Therefore, we were unable to identify robust and replicable findings. We discuss what this means for genetic research for MDD. The 3p21.1 MDD-BIP finding should be interpreted with caution as the most significant SNP did not replicate in MDD samples, and genotyping in independent samples will be needed to resolve its status.