Showing papers in "Dialogues in Clinical Neuroscience in 2014"

Pathophysiology of depression and innovative treatments: remodeling glutamatergic synaptic connections.

Abstract: Despite the complexity and heterogeneity of mood disorders, basic and clinical research studies have begun to elucidate the pathophysiology of depression and to identify rapid, efficacious antidepressant agents. Stress and depression are associated with neuronal atrophy, characterized by loss of synaptic connections in key cortical and limbic brain regions implicated in depression. This is thought to occur in part via decreased expression and function of growth factors, such as brain-derived neurotrophic factor (BDNF), in the prefrontal cortex (PFC) and hippocampus. These structural alterations are difficult to reverse with typical antidepressants. However, recent studies demonstrate that ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist that produces rapid antidepressant actions in treatment-resistant depressed patients, rapidly increases spine synapses in the PFC and reverses the deficits caused by chronic stress. This is thought to occur by disinhibition of glutamate transmission, resulting in a rapid but transient burst of glutamate, followed by an increase in BDNF release and activation of downstream signaling pathways that stimulate synapse formation. Recent work demonstrates that the rapid-acting antidepressant effects of scopolamine, a muscarinic receptor antagonist, are also associated with increased glutamate transmission and synapse formation. These findings have resulted in testing and identification of additional targets and agents that influence glutamate transmission and have rapid antidepressant actions in rodent models and in clinical trials. Together these studies have created tremendous excitement and hope for a new generation of rapid, efficacious antidepressants.

Early life adversity and the epigenetic programming of hypothalamic-pituitary-adrenal function.

Abstract: We review studies with human and nonhuman species that examine the hypothesis that epigenetic mechanisms, particularly those affecting the expression of genes implicated in stress responses, mediate the association between early childhood adversity and later risk of depression The resulting studies provide evidence consistent with the idea that social adversity, particularly that involving parent-offspring interactions, alters the epigenetic state and expression of a wide range of genes, the products of which regulate hypothalamic-pituitary-adrenal function We also address the challenges for future studies, including that of the translation of epigenetic studies towards improvements in treatments

Clinical predictors of therapeutic response to antipsychotics in schizophrenia.

Abstract: The search for clinical outcome predictors for schizophrenia is as old as the field of psychiatry. However, despite a wealth of large, longitudinal studies into prognostic factors, only very few clinically useful outcome predictors have been identified. The goal of future treatment is to either affect modifiable risk factors, or use nonmodifiable factors to parse patients into therapeutically meaningful subgroups. Most clinical outcome predictors are nonspecific and/or nonmodifiable. Nonmodifiable predictors for poor odds of remission include male sex, younger age at disease onset, poor premorbid adjustment, and severe baseline psychopathology. Modifiable risk factors for poor therapeutic outcomes that clinicians can act upon include longer duration of untreated illness, nonadherence to antipsychotics, comorbidities (especially substance-use disorders), lack of early antipsychotic response, and lack of improvement with non-clozapine antipsychotics, predicting clozapine response. It is hoped that this limited capacity for prediction will improve as pathophysiological understanding increases and/or new treatments for specific aspects of schizophrenia become available.

Epigenetic signaling in psychiatric disorders: stress and depression.

Abstract: Psychiatric disorders are complex multifactorial disorders involving chronic alterations in neural circuit structure and function. While genetic factors play a role in the etiology of disorders such as depression, addiction, and schizophrenia, relatively high rates of discordance among identical twins clearly point to the importance of additional factors. Environmental factors, such as stress, play a major role in the psychiatric disorders by inducing stable changes in gene expression, neural circuit function, and ultimately behavior. Insults at the developmental stage and in adulthood appear to induce distinct maladaptations. Increasing evidence indicates that these sustained abnormalities are maintained by epigenetic modifications in specific brain regions. Indeed, transcriptional dysregulation and associated aberrant epigenetic regulation is a unifying theme in psychiatric disorders. Aspects of depression can be modeled in animals by inducing disease-like states through environmental manipulations, and these studies can provide a more general understanding of epigenetic mechanisms in psychiatric disorders. Understanding how environmental factors recruit the epigenetic machinery in animal models is providing new insights into disease mechanisms in humans.

Epigenetic alterations in depression and antidepressant treatment.

Abstract: Epigenetic modifications control chromatin structure and function, and thus mediate changes in gene expression, ultimately influencing protein levels. Recent research indicates that environmental events can induce epigenetic changes and, by this, contribute to long-term changes in neural circuits and endocrine systems associated with altered risk for stress-related psychiatric disorders such as major depression. In this review, we describe recent approaches investigating epigenetic modifications associated with altered risk for major depression or response to antidepressant drugs, both on the candidate gene levels as well as the genome-wide level. In this review we focus on DNA methylation, as this is the most investigated epigenetic change in depression research.

Epigenetic mechanisms in schizophrenia

Abstract: Schizophrenia is a major psychiatric disorder that lacks a unifying neuropathology, while currently available pharmacological treatments provide only limited benefits to many patients. This review will discuss how the field of neuroepigenetics could contribute to advancements of the existing knowledge on the neurobiology and treatment of psychosis. Genome-scale mapping of DMA methylation, histone modifications and variants, and chromosomal loopings for promoter-enhancer interactions and other epigenetic determinants of genome organization and function are likely to provide important clues about mechanisms contributing to dysregulated expression of synaptic and metabolic genes in schizophrenia brain, including the potential links to the underlying genetic risk architecture and environmental exposures. In addition, studies in animal models are providing a rapidly increasing list of chromatin-regulatory mechanisms with significant effects on cognition and complex behaviors, thereby pointing to the therapeutic potential of epigenetic drug targets in the nervous system.

Emerging role of microRNAs in major depressive disorder: diagnosis and therapeutic implications.

Abstract: Major depressive disorder (MDD) is a major public health concern. Despite tremendous advances, the pathogenic mechanisms associated with MDD are still unclear. Moreover, a significant number of MDD subjects do not respond to the currently available medication. MicroRNAs (miRNAs) are a class of small noncoding RNAs that control gene expression by modulating translation, messenger RNA (mRNA) degradation, or stability of mRNA targets. The role of miRNAs in disease pathophysiology is emerging rapidly. Recent studies demonstrating the involvement of miRNAs in several aspects of neural plasticity, neurogenesis, and stress response, and more direct studies in human postmortem brain provide strong evidence that miRNAs can not only play a critical role in MDD pathogenesis, but can also open up new avenues for the development of therapeutic targets. Circulating miRNAs are now being considered as possible biomarkers in disease pathogenesis and in monitoring therapeutic responses because of the presence and/or release of miRNAs in blood cells as well as in other peripheral tissues. In this review, these aspects are discussed in a comprehensive and critical manner.

Developmental programming of brain and behavior by perinatal diet: focus on inflammatory mechanisms.

Abstract: Obesity is now epidemic worldwide. Beyond associated diseases such as diabetes, obesity is linked to neuropsychiatric disorders such as depression. Alarmingly maternal obesity and high-fat diet consumption during gestation/lactation may "program" offspring longterm for increased obesity themselves, along with increased vulnerability to mood disorders. We review the evidence that programming of brain and behavior by perinatal diet is propagated by inflammatory mechanisms, as obesity and high-fat diets are independently associated with exaggerated systemic levels of inflammatory mediators. Due to the recognized dual role of these immune molecules (eg, interleukin [IL]-6, 11-1β) in placental function and brain development, any disruption of their delicate balance with growth factors or neurotransmitters (eg, serotonin) by inflammation early in life can permanently alter the trajectory of fetal brain development. Finally, epigenetic regulation of inflammatory pathways is a likely candidate for persistent changes in metabolic and brain function as a consequence of the perinatal environment.

Neurofeedback and networks of depression

Abstract: Recent advances in imaging technology and in the understanding of neural circuits relevant to emotion, motivation, and depression have boosted interest and experimental work in neuromodulation for affective disorders. Real-time functional magnetic resonance imaging (fMRI) can be used to train patients in the self-regulation of these circuits, and thus complement existing neurofeedback technologies based on electroencephalography (EEG). EEG neurofeedback for depression has mainly been based on models of altered hemispheric asymmetry. fMRI-based neurofeedback (fMRI-NF) can utilize functional localizer scans that allow the dynamic adjustment of the target areas or networks for self-regulation training to individual patterns of emotion processing. An initial application of fMRI-NF in depression has produced promising clinical results, and further clinical trials are under way. Challenges lie in the design of appropriate control conditions for rigorous clinical trials, and in the transfer of neurofeedback protocols from the laboratory to mobile devices to enhance the sustainability of any clinical benefits.

Lifetime stress experience: transgenerational epigenetics and germ cell programming

Abstract: The transgenerational epigenetic programming involved in the passage of environmental exposures to stressful periods from one generation to the next has been examined in human populations, and mechanistically in animal models. Epidemiological studies suggest that gestational exposures to environmental factors including stress are strongly associated with an increased risk of neurodevelopmental disorders, including attention deficit-hyperactivity disorder, schizophrenia, and autism spectrum disorders. Both maternal and paternal life experiences with stress can be passed on to offspring directly during pregnancy or through epigenetic marks in the germ cell. Animal models of parental stress have examined relevant offspring phenotypes and transgenerational outcomes, and provided unique insight into the germ cell epigenetic changes associated with disruptions in neurodevelopment. Understanding germline susceptibility to exogenous signals during stress exposure and the identification of the types of epigenetic marks is critical for defining mechanisms underlying disease risk.

Neuroimaging-based biomarkers for treatment selection in major depressive disorder.

Abstract: The use of neuroimaging approaches to identify likely treatment outcomes in patients with major depressive disorder is developing rapidly. Emerging work suggests that resting state pretreatment metabolic activity in the fronto-insular cortex may distinguish between patients likely to respond to psychotherapy or medication and may function as a treatment-selection biomarker. In contrast, high metabolic activity in the subgenual anterior cingulate cortex may be predictive of poor outcomes to both medication and psychotherapy, suggesting that nonstandard treatments may be pursued earlier in the treatment course. Although these findings will require replication before clinical adoption, they provide preliminary support for the concept that brain states can be measured and applied to the selection of a specific treatment most likely to be beneficial for an individual patient.

The assessment of quality of life in clinical practice in patients with schizophrenia.

Abstract: The aim of the present article is to review QoL scales used in studies investigating patients with schizophrenia over the past 5 years, and to summarize the results of QoL assessment in clinical practice in these patients. Literature available from January 2009 to December 2013 was identified in a PubMed search using the key words “quality of life” and “schizophrenia” and in a cross-reference search for articles that were particularly relevant. A total of n=432 studies used 35 different standardized generic and specific QoL scales in patients with schizophrenia. Affective symptoms were major obstacles for QoL improvement in patients with schizophrenia. Though positive symptoms, negative symptoms, and cognitive functioning may be seen as largely independent parameters from subjective QoL, especially in cross-sectional trials, long-term studies confirmed a critical impact of early QoL improvement on long-term symptomatic and functional remission, as well as of early symptomatic response on long-term QoL. Results of the present review suggest that QoL is a valid and useful outcome criterion in patients with schizophrenia. As such, it should be consistently applied in clinical trials. Understanding the relationship between symptoms and functioning with QoL is important because interventions that focus on symptoms of psychosis or functioning alone may fail to improve subjective QoL to the same level. However, the lack of consensus on QoL scales hampers research on its predictive validity. Future research needs to find a consensus on the concept and measures of QoL and to test whether QoL predicts better outcomes with respect to remission and recovery under consideration of different treatment approaches in patients with schizophrenia.

Quality of life as patient-reported outcomes: principles of assessment.

Abstract: Assessing quality of life (QoL) as a patient-reported outcome in adult psychiatry poses challenges in terms of concepts, methods, and applications in research and practice This review will outline conceptually the construct of QoL, its dimensionality, and its representation across patient groups Methodological challenges are examined, along with principles of QoL instrument development and testing, as well as across cultures Application of instruments in epidemiological, clinical health economics, and health services research is reviewed based on pertinent literature Validated measures for depression, psychosis, and anxiety disorders are available in adult psychiatry, and are increasingly used in research Still, targeted measures are lacking for many mental health conditions and only rarely are tools applied in the practice context Progress has been made in the development of instruments that are now ready for implementation The information to be gained is valuable for identifying patient-reported needs for and benefits of treatment

Deep brain stimulation in the treatment of depression.

Abstract: Major depressive disorder is a worldwide disease with debilitating effects on a patient's life. Common treatments include pharmacotherapy, psychotherapy, and electroconvulsive therapy. Many patients do not respond to these treatments; this has led to the investigation of alternative therapeutic modalities. Deep brain stimulation (DBS) is one of these modalities. It was first used with success for treating movement disorders and has since been extended to the treatment of psychiatric disorders. Although DBS is still an emerging treatment, promising efficacy and safety have been demonstrated in preliminary trials in patients with treatment-resistant depression (TRD). Further, neuroimaging has played a pivotal role in identifying some DBS targets and remains an important tool for evaluating the mechanism of action of this novel intervention. Preclinical animal studies have broadened knowledge about the possible mechanisms of action of DBS for TRD, Given that DBS involves neurosurgery in patients with severe psychiatric impairment, ethical questions concerning capacity to consent arise; these issues must continue to be carefully considered.

Role of DNA methylation and the DNA methyltransferases in learning and memory

Abstract: Dynamic regulation of chromatin structure in postmitotic neurons plays an important role in learning and memory. Methylation of cytosine nucleotides has historically been considered the strongest and least modifiable of epigenetic marks. Accumulating recent data suggest that rapid and dynamic methylation and demethylation of specific genes in the brain may play a fundamental role in learning, memory formation, and behavioral plasticity. The current review focuses on the emergence of data that support the role of DNA methylation and demethylation, and its molecular mediators in memory formation.

Epigenetics, microRNA, and addiction.

Abstract: Drug addiction is characterized by uncontrolled drug consumption and high rates of relapse to drug taking during periods of attempted abstinence Addiction is now largely considered a disorder of experience-dependent neuroplasticity, driven by remodeling of synapses in reward and motivation relevant brain circuits in response to a history of prolonged drug intake Alterations in gene expression play a central role in addiction-relevant neuroplasticity, but the mechanisms by which additive drugs remodel brain motivation circuits remains unclear MicroRNAs (miRNAs) are a class of noncoding RNA that can regulate the expression of large numbers of protein-coding mRNA transcripts by binding to the 3' untranslated region (3' UTR) of target transcripts and blocking their translation into the encoded protein or triggering their destabilization and degradation Emerging evidence has implicated miRNAs in regulating addiction-relevant neuroplasticity in the brain, and in controlling the motivational properties of cocaine and other drugs of abuse Here, the role for miRNAs in regulating basic aspects of neuronal function is reviewed The involvement of miRNAs in controlling the motivational properties of addictive drugs is also summarized Finally, mechanisms by which miRNAs exert their actions on drug intake, when known, are considered

How to assess quality of life in child and adolescent psychiatry

Abstract: This article provides an overview of the conceptual foundations of measuring health-related quality of life (HRQoL) in children and adolescents in child and adolescent psychiatry, and of the current state of research in this field. The available procedures for determining quality of life are presented according to their areas of use and their psychometric characteristics. The internationally available generic instruments for measuring HRQoL in children are identified and assessed in terms of their strengths and weaknesses with regard to selected criteria. As a result, seven generic HRQoL instruments and two utility procedures have been identified which satisfy the following criteria: (i) psychometric quality; (ii) age-appropriate measurement; (iii) versions for self-reporting and external rating; and (iv) cross-cultural measurement. The identified instruments satisfy the individual criteria to different degrees. They are increasingly being used in health services research, treatment studies, and epidemiological research; however, they are not yet widely used as part of the clinical routine in child and adolescent psychiatrics.

Pharmacogenetics and outcome with antipsychotic drugs.

Abstract: Antipsychotic medications are the gold-standard treatment for schizophrenia, and are often prescribed for other mental conditions However, the efficacy and side-effect profiles of these drugs are heterogeneous, with large interindividual variability As a result, treatment selection remains a largely trial-and-error process, with many failed treatment regimens endured before finding a tolerable balance between symptom management and side effects Much of the interindividual variability in response and side effects is due to genetic factors (heritability, h(2)~ 060-080) Pharmacogenetics is an emerging field that holds the potential to facilitate the selection of the best medication for a particular patient, based on his or her genetic information In this review we discuss the most promising genetic markers of antipsychotic treatment outcomes, and present current translational research efforts that aim to bring these pharmacogenetic findings to the clinic in the near future

Assessment of patient-reported symptoms of anxiety.

Abstract: Patient self-reported symptoms are of crucial importance to identify anxiety disorders, as well as to monitor their treatment in clinical practice and research. Thus, for evidence-based medicine, a precise, reliable, and valid (ie, “objective”) assessment of the patient's reported “subjective” symptoms is warranted. There is a plethora of instruments available, which can provide psychometrically sound assessments of anxiety, but there are several limitations of current tools that need to be carefully considered for their successful use. Nevertheless, the empirical assessment of mental health status is not as accepted in medicine as is the assessment of biomarkers. One reason for this may be that different instruments assessing the same psychological construct use different scales. In this paper we present some new developments that promise to provide one common metric for the assessment of anxiety, to facilitate the general acceptance of mental health assessments in the future.

A history of health-related quality of life outcomes in psychiatry.

Abstract: Health-related quality of life (HRQoL) is a multidimensional concept that includes subjective reports of symptoms, side effects, functioning in multiple life domains, and general perceptions of life satisfaction and quality. Rather than estimating it from external observations, interview, or clinical assessment, it is best measured by direct query. Due to a perception that respondents may not be reliable or credible, there has been some reluctance to use self-report outcomes in psychiatry. More recently, and increasingly, HRQoL assessment through direct patient query has become common when evaluating a range of psychiatric, psychological, and social therapies. With few exceptions, psychiatric patients are credible and reliable reporters of this information. This article summarizes studies that highlight the development, validation, and application of HRQoL measures in psychiatry. Thoughtful application of these tools in psychiatric research can provide a much-needed patient perspective in the future of comparative effectiveness research, patient-centered outcomes research, and clinical care.

Proteomics, metabolomics, and protein interactomics in the characterization of the molecular features of major depressive disorder.

Abstract: Omics technologies emerged as complementary strategies to genomics in the attempt to understand human illnesses In general, proteomics technologies emerged earlier than those of metabolomics for major depressive disorder (MDD) research, but both are driven by the identification of proteins and/or metabolites that can delineate a comprehensive characterization of MDD's molecular mechanisms, as well as lead to the identification of biomarker candidates of all types-prognosis, diagnosis, treatment, and patient stratification Also, one can explore protein and metabolite interactomes in order to pinpoint additional molecules associated with the disease that had not been picked up initially Here, results and methodological aspects of MDD research using proteomics, metabolomics, and protein interactomics are reviewed, focusing on human samples

Endogenous and exogenous electric fields as modifiers of brain activity: rational design of noninvasive brain stimulation with transcranial alternating current stimulation.

Abstract: Synchronized neuronal activity in the cortex generates weak electric fields that are routinely measured in humans and animal models by electroencephalography and local field potential recordings. Traditionally, these endogenous electric fields have been considered to be an epiphenomenon of brain activity. Recent work has demonstrated that active cortical networks are surprisingly susceptible to weak perturbations of the membrane voltage of a large number of neurons by electric fields. Simultaneously, noninvasive brain stimulation with weak, exogenous electric fields (transcranial current stimulation, TCS) has undergone a renaissance due to the broad scope of its possible applications in modulating brain activity for cognitive enhancement and treatment of brain disorders. This review aims to interface the recent developments in the study of both endogenous and exogenous electric fields, with a particular focus on rhythmic stimulation for the modulation of cortical oscillations. The main goal is to provide a starting point for the use of rational design for the development of novel mechanism-based TCS therapeutics based on transcranial alternating current stimulation, for the treatment of psychiatric illnesses.

Increased DNA methylation in the suicide brain.

Abstract: Clinical studies find that childhood adversity and stress-ful life events in adulthood increase the risk for major depression and for suicide. The predispositions to either major depression or suicide are thought to depend on genetic risk factors or epigenetic effects. We investigated DNA methylation signatures postmortem in brains of suicides with diagnosis of major depressive disorder. DNA methylation levels were determined at single C-phosphate-G (CpG) resolution sites within ventral prefrontal cortex of 53 suicides and nonpsychiatric controls, aged 16 to 89 years. We found that DNA methylation increases throughout the lifespan. Suicides showed an 8-fold greater number of methylated CpG sites relative to controls (P<2.2x10-16), with greater DNA methylation changes over and above the increased methylation observed in normal aging. This increased DNA methylation may be a significant contributor to the neuropathology and psychopathology underlying the risk of suicide in depression.

DNA methylation and demethylation as targets for antipsychotic therapy.

Abstract: Schizophrenia (SZ) and bipolar disorder (BPD) patients show a downregulation of GAD67, reelin (RELN), brain-derived neurotrophic factor (BDNF), and other genes expressed in telencephalic GABAergic and glutamatergic neurons. This downregulation is associated with the enrichment of 5-methylcytosine and 5-hydroxymethylcytosine proximally at gene regulatory domains at the respective genes. A pharmacological strategy to reduce promoter hypermethylation and to induce a more permissive chromatin conformation is to administer drugs, such as the histone deacetylase (HDAC) inhibitor valproate (VPA), that facilitate chromatin remodeling. Studies in mouse models of SZ indicate that clozapine induces DNA demethylation at relevant promoters, and that this action is potentiated by VPA. By activating DNA demethylation, clozapine or its derivatives with VPA or other more potent and selective HDAC inhibitors may be a promising treatment strategy to correct the gene expression deficits detected in postmortem brain of SZ and BPD patients.

Functional neuroimaging studies of the effects of psychotherapy.

Abstract: It has been long established that psychological interventions can markedly alter patients' thinking patterns, beliefs, attitudes, emotional states, and behaviors. Little was known about the neural mechanisms mediating such alterations before the advent of functional neuroimaging techniques. Since the turn of the new millenium, several functional neuroimaging studies have been conducted to tackle this important issue. Some of these studies have explored the neural impact of various forms of psychotherapy in individuals with major depressive disorder. Other neuroimaging studies have investigated the effects of psychological interventions for anxiety disorders. I review these studies in the present article, and discuss the putative neural mechanisms of change in psychotherapy. The findings of these studies suggest that mental and behavioral changes occurring during psychotherapeutic interventions can lead to a normalization of functional brain activity at a global level.

Serotonin-related pathways and developmental plasticity: relevance for psychiatric disorders.

Abstract: Risk for adult psychiatric disorders is partially determined by early-life alterations occurring during neural circuit formation and maturation. In this perspective, recent data show that the serotonin system regulates key cellular processes involved in the construction of cortical circuits. Translational data for rodents indicate that early-life serotonin dysregulation leads to a wide range of behavioral alterations, ranging from stress-related phenotypes to social deficits. Studies in humans have revealed that serotonin-related genetic variants interact with early-life stress to regulate stress-induced cortisol responsiveness and activate the neural circuits involved in mood and anxiety disorders. Emerging data demonstrate that early-life adversity induces epigenetic modifications in serotonin-related genes. Finally, recent findings reveal that selective serotonin reuptake inhibitors can reinstate juvenile-like forms of neural plasticity, thus allowing the erasure of long-lasting fear memories. These approaches are providing new insights on the biological mechanisms and clinical application of antidepressants.

Using biomarkers to predict treatment response in major depressive disorder: evidence from past and present studies.

Abstract: Major depressive disorder (MDD) is a heterogeneous condition with a variable response to a wide range of treatments. Despite intensive efforts, no biomarker has been identified to date that can reliably predict response or non-response to any form of treatment, nor has one been identified that can be used to identify those at high risk of developing treatment-resistant depression (ie, non-response to a sequence of treatments delivered for adequate duration and intensity). This manuscript reviews some past areas of research that have proved informative, such as studies using indexes of hypercortisolism or sleep disturbance, and more recent research findings using measures of inflammation and different indicators of regional cortical activation to predict treatment response. It is concluded that, although no method has yet been demonstrated to be sufficiently accurate to be applied in clinical practice, progress has been made. It thus seems likely that--at some point in the not-too-distant future--it will be possible to prospectively identify, at least for some MDD patients, the likelihood of response or non-response to cognitive therapy or various antidepressant medications.

Prediction of treatment outcomes in psychiatry--where do we stand ?

Abstract: Psychiatric treatment relies on a solid armamentarium of pharmacologic and nonpharmacologic treatment modalities that perform reasonably well for many patients but leave others in a state of chronic disability or troubled by problematic side effects. Treatment planning in psychiatry remains an art that depends on considerable trial and error. Thus, there is an urgent need for better tools that will provide a means for matching individual patients with the most effective treatments while minimizing the risk of adverse events. This review will consider the current state of the science in predicting treatment outcomes in psychiatry. Genetic and other biomarkers will be considered alongside clinical diagnostic, and family history data. Problems inherent in prediction medicine will also be discussed, along with recent developments that support the hope that psychiatry can do a better job in quickly identifying the best treatments for each patient.

The epigenetic dimension of Alzheimer's disease: causal, consequence, or curiosity?

Abstract: Early-onset, familial Alzheimer's disease (AD) is rare and may be attributed to disease-causinq mutations. By contrast, late onset, sporadic (non-Mendelian) AD is far more prevalent and reflects the interaction of multiple genetic and environmental risk factors, together with the disruption of epigenetic mechanisms controlling gene expression. Accordingly, abnormal patterns of histone acetylation and methylation, as well as anomalies in global and promoter-specific DNA methylation, have been documented in AD patients, together with a deregulation of noncoding RNA. In transgenic mouse models for AD, epigenetic dysfunction is likewise apparent in cerebral tissue, and it has been directly linked to cognitive and behavioral deficits in functional studies. Importantly, epigenetic deregulation interfaces with core pathophysiological processes underlying AD: excess production of Aβ42, aberrant post-translational modification of tau, deficient neurotoxic protein clearance, axonal-synaptic dysfunction, mitochondrial-dependent apoptosis, and cell cycle re-entry. Reciprocally, DNA methylation, histone marks and the levels of diverse species of microRNA are modulated by Aβ42, oxidative stress and neuroinflammation. In conclusion, epigenetic mechanisms are broadly deregulated in AD mainly upstream, but also downstream, of key pathophysiological processes. While some epigenetic shifts oppose the evolution of AD, most appear to drive its progression. Epigenetic changes are of irrefutable importance for AD, but they await further elucidation from the perspectives of pathogenesis, biomarkers and potential treatment.

Patient-reported outcomes before and after treatment of major depressive disorder

Abstract: Patient reported outcomes (PROs) of quality of life (QoL), functioning, and depressive symptom severity are important in assessing the burden of illness of major depressive disorder (MDD) and to evaluate the impact of treatment. We sought to provide a detailed analysis of PROs before and after treatment of MDD from the large Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. This analysis examines PROs before and after treatment in the second level of STAR*D. The complete data on QoL, functioning, and depressive symptom severity, were analyzed for each STAR*D level 2 treatment. PROs of QoL, functioning, and depressive symptom severity showed substantial impairments after failing a selective serotonin reuptake inhibitor trial using citalopram (level 1). The seven therapeutic options in level 2 had positive statistically (P values) and clinically (Cohen's standardized differences [Cohen's d]) significant impact on QoL, functioning, depressive symptom severity, and reduction in calculated burden of illness. There were no statistically significant differences between the interventions. However, a substantial proportion of patients still suffered from patient-reported QoL and functioning impairment after treatment, an effect that was more pronounced in nonremitters. PROs are crucial in understanding the impact of MDD and in examining the effects of treatment interventions, both in research and clinical settings.