Variation in the gene encoding the serotonin 2A receptor is associated with outcome of antidepressant treatment

Depressive disorders account for a large and increasing global burden of disease. Although the condition of many patients improves with medication, only a minority experience full remission, and patients whose condition responds to one medication may not have a response to others. Individual variation in antidepressant treatment outcome is, at present, unpredictable but may have a partial genetic basis. We searched for genetic predictors of treatment outcome in 1,953 patients with major depressive disorder who were treated with the antidepressant citalopram in the Sequenced Treatment Alternatives for Depression (STAR*D) study and were prospectively assessed. In a split-sample design, a selection of 68 candidate genes was genotyped, with 768 single-nucleotide-polymorphism markers chosen to detect common genetic variation. We detected significant and reproducible association between treatment outcome and a marker in HTR2A (P range 1 x 10(-6) to 3.7 x 10(-5) in the total sample). Other markers in HTR2A also showed evidence of association with treatment outcome in the total sample. HTR2A encodes the serotonin 2A receptor, which is downregulated by citalopram. Participants who were homozygous for the A allele had an 18% reduction in absolute risk of having no response to treatment, compared with those homozygous for the other allele. The A allele was over six times more frequent in white than in black participants, and treatment was less effective among black participants. The A allele may contribute to racial differences in outcomes of antidepressant treatment. Taken together with prior neurobiological findings, these new genetic data make a compelling case for a key role of HTR2A in the mechanism of antidepressant action.     

Genetic Predictors of Response to Serotonergic and Noradrenergic Antidepressants in Major Depressive Disorder: A Genome-Wide Analysis of Individual-Level Data and a Meta-Analysis

Background

It has been suggested that outcomes of antidepressant treatment for major depressive disorder could be significantly improved if treatment choice is informed by genetic data. This study aims to test the hypothesis that common genetic variants can predict response to antidepressants in a clinically meaningful way.

Methods and Findings

The NEWMEDS consortium, an academia–industry partnership, assembled a database of over 2,000 European-ancestry individuals with major depressive disorder, prospectively measured treatment outcomes with serotonin reuptake inhibiting or noradrenaline reuptake inhibiting antidepressants and available genetic samples from five studies (three randomized controlled trials, one part-randomized controlled trial, and one treatment cohort study). After quality control, a dataset of 1,790 individuals with high-quality genome-wide genotyping provided adequate power to test the hypotheses that antidepressant response or a clinically significant differential response to the two classes of antidepressants could be predicted from a single common genetic polymorphism. None of the more than half million genetic markers significantly predicted response to antidepressants overall, serotonin reuptake inhibitors, or noradrenaline reuptake inhibitors, or differential response to the two types of antidepressants (genome-wide significance p<5×10⁻⁸). No biological pathways were significantly overrepresented in the results. No significant associations (genome-wide significance p<5×10⁻⁸) were detected in a meta-analysis of NEWMEDS and another large sample (STAR*D), with 2,897 individuals in total. Polygenic scoring found no convergence among multiple associations in NEWMEDS and STAR*D.

Conclusions

No single common genetic variant was associated with antidepressant response at a clinically relevant level in a European-ancestry cohort. Effects specific to particular antidepressant drugs could not be investigated in the current study. Please see later in the article for the Editors'' Summary     

Behandlung depressiver Störungen bei Diabetes mellitus

Approximately 25% of all diabetes patients suffer from symptoms of clinical depression. This comorbidity of depression and diabetes is associated with hypoglycaemia, microvascular and microvascular complications and a clearly increased mortality. With regard to psychosocial outcome depression is related to impaired generic and diabetes-specific quality of life and poor treatment adherence. Despite this life endangering interaction depression is under-diagnosed and under-treated in diabetes patients. Therefore a screening for depression should be an integral part of routine care. Treatment for depression is aimed not only towards improvement of depression but should focus on physical aspects of diabetes as well. Depression can be treated with antidepressant medication, psychotherapy or a flexible combination of both. These approaches demonstrate relatively good results that are comparable to those patients with depression without diabetes. Up to now no single treatment that consistently leads to better medical outcome in patients with depression and diabetes could be identified. The management of diagnosis and treatment of comorbid depression in diabetes can be enhanced by following algorithms that are grounded on evidence-based treatment guidelines.     

Genotype-Based Ancestral Background Consistently Predicts Efficacy and Side Effects across Treatments in CATIE and STAR*D

Only a subset of patients will typically respond to any given prescribed drug. The time it takes clinicians to declare a treatment ineffective leaves the patient in an impaired state and at unnecessary risk for adverse drug effects. Thus, diagnostic tests robustly predicting the most effective and safe medication for each patient prior to starting pharmacotherapy would have tremendous clinical value. In this article, we evaluated the use of genetic markers to estimate ancestry as a predictive component of such diagnostic tests. We first estimated each patient’s unique mosaic of ancestral backgrounds using genome-wide SNP data collected in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) (n = 765) and the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) (n = 1892). Next, we performed multiple regression analyses to estimate the predictive power of these ancestral dimensions. For 136/89 treatment-outcome combinations tested in CATIE/STAR*D, results indicated 1.67/1.84 times higher median test statistics than expected under the null hypothesis assuming no predictive power (p<0.01, both samples). Thus, ancestry showed robust and pervasive correlations with drug efficacy and side effects in both CATIE and STAR*D. Comparison of the marginal predictive power of MDS ancestral dimensions and self-reported race indicated significant improvements to model fit with the inclusion of MDS dimensions, but mixed evidence for self-reported race. Knowledge of each patient’s unique mosaic of ancestral backgrounds provides a potent immediate starting point for developing algorithms identifying the most effective and safe medication for a wide variety of drug-treatment response combinations. As relatively few new psychiatric drugs are currently under development, such personalized medicine offers a promising approach toward optimizing pharmacotherapy for psychiatric conditions.     

Pindolol is a potent scavenger of reactive nitrogen species

Pindolol is an indolic drug that has been shown to enhance and/or accelerate selective serotonin specific reuptake inhibitors (SSRI)-induced antidepressant (AD) effect, even though the respective mechanism is still unclear. It has been demonstrated that inhibition of nitric oxide (*NO) synthesis in CNS produces anxiolytic and AD-like behavioural effects in a variety of animal paradigms. On the other hand, sustained high levels of *NO may be deleterious to CNS, predominantly due to the formation of peroxynitrite anion (ONOO-), which is generated via reaction of *NO with superoxide radical (O2*-). Therefore, the purpose of the present study was to characterize the putative pindolol scavenging effect on *NO, ONOO-, and O2*-, using in vitro non-cellular systems. The obtained results clearly show that pindolol is a potent scavenger of *NO (IC50 of 449+/-33 microM) and ONOO- (IC50 of 131+/-24 microM). Additionally, the scavenging effect of pindolol increased almost 8 times in the presence of 25 mM NaHCO3 (IC50 of 17+/-3 microM), which indicates that pindolol efficiently scavenges reactive species that are produced from the ONOO-/CO2 reaction such as the nitrogen dioxide radical (*NO2) and the carbonate radical anion (CO3*-). These effects may contribute for the reduction of SSRI antidepressant latency that has been attributed to pindolol and may also constitute an additional value for this drug when depression is associated with pro-oxidant neurodegenerative diseases.     

Altered editing of serotonin 2C receptor pre-mRNA in the prefrontal cortex of depressed suicide victims

Five adenosines within the coding sequence of the serotonin 2C receptor (5-HT2C) pre-mRNA are converted to inosines by RNA editing (named A, B, C' (E), C, and D sites). In human prefrontal cortex (PFC), the most abundant 5-HT2C mRNA sequences result from editing at the A site, or from the editing combinations AC'C, ABCD, and ABD. In suicide victims with a history of major depression, C' site editing is significantly increased, D site editing is significantly decreased, and the C site shows a trend toward increased editing. Treatment of mice with the antidepressant drug fluoxetine (Prozac) causes changes in C', C, and D site editing that are exactly opposite to those seen in suicide victims. Thus, one outcome of fluoxetine treatment may be to reverse the abnormalities in 5-HT2C pre-mRNA editing seen in depressed suicide victims.     

Neurogenomic evidence for a shared mechanism of the antidepressant effects of exercise and chronic fluoxetine in mice

Several different interventions improve depressed mood, including medication and environmental factors such as regular physical exercise. The molecular pathways underlying these effects are still not fully understood. In this study, we sought to identify shared mechanisms underlying antidepressant interventions. We studied three groups of mice: mice treated with a widely used antidepressant drug--fluoxetine, mice engaged in voluntary exercise, and mice living in an enriched environment. The hippocampi of treated mice were investigated at the molecular and cellular levels. Mice treated with fluoxetine and mice who exercised daily showed, not only similar antidepressant behavior, but also similar changes in gene expression and hippocampal neurons. These changes were not observed in mice with environmental enrichment. An increase in neurogenesis and dendritic spine density was observed following four weeks of fluoxetine treatment and voluntary exercise. A weighted gene co-expression network analysis revealed four different modules of co-expressed genes that were correlated with the antidepressant effect. This network analysis enabled us to identify genes involved in the molecular pathways underlying the effects of fluoxetine and exercise. The existence of both neuronal and gene expression changes common to antidepressant drug and exercise suggests a shared mechanism underlying their effect. Further studies of these findings may be used to uncover the molecular mechanisms of depression, and to identify new avenues of therapy.     

Efficacy of light therapy for perinatal depression: a review

ABSTRACT: Perinatal depression is an important public health problem affecting 10-20% of childbearing women. Perinatal depression is associated with significant morbidity, and has enormous consequences for the well-being of the mother and child. Treatment of depression during the perinatal period poses a complex problem for both mother and clinician, as antidepressant treatment strategies must consider the welfare of both mother and child during pregnancy and lactation. Bright light therapy may be an attractive treatment for perinatal depression because it is low cost, home-based, and has a much lower side effect profile than pharmacotherapy. The antidepressant effects of bright light are well established, and there are several rationales for expecting that bright light might also be efficacious for perinatal depression. This review describes these rationales, summarizes the available evidence on the efficacy of bright light therapy for perinatal depression, and discusses future directions for investigation of bright light therapy as a treatment for perinatal depression.     

Repetitive transcranial magnetic stimulation induces kf-1 expression in the rat brain

Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive approach used for stimulating the brain, and has proven effective in the treatment of depression, however the mechanism of its antidepressant action is unknown. Recently, we have reported the induction of kf-1 in rat frontal cortex and hippocampus after chronic antidepressant treatment and repeated electroconvulsive treatment (ECT). In this study, we demonstrated the induction of kf-1 after rTMS in the rat frontal cortex and hippocampus, but not in hypothalamus. Our data suggest that kf-1 may be a common functional molecule that is increased after antidepressant treatment, ECT and rTMS. In conclusion, it is proposed that induction of kf-1 may be associated with the treatment induced adaptive neural plasticity in the brain, which is a long-term target for their antidepressant action.     

Effects of an exercise programme for chronically ill and mobility-restricted elderly with structured support by the general practitioner's practice (HOMEfit) - study protocol of a randomised controlled trial

Background

After more than half a century of modern psychopharmacology, with billions of dollars spent on antidepressants annually world-wide, we lack good evidence to guide our everyday decisions in conducting antidepressant treatment of patients with major depression. First we did not know which antidepressant to use as first line treatment. Second we do not know which dosage we should be aiming at with that antidepressant. Because more than half of the patients with major depression starting treatment do not remit after adequate trial with the first agent, they will need a second line treatment. Dose escalation, augmentation and switching are the three often recommended second line strategies but we do not know which is better than the others. Moreover, we do not know when to start considering this second line treatment. The recently published multiple-treatments meta-analysis of 12 new generation antidepressants has provided some partial answers to the first question. Starting with these findings, this proposed trial aims to establish the optimum 1st line and 2nd line antidepressant treatment strategy among adult patients with a non-psychotic unipolar major depressive episode.

Methods

SUN(^_^)D, the Strategic Use of New generation antidepressants for Depression, is an assessor-blinded, parallel-group, multi-centre randomised controlled trial. Step I is a cluster-randomised trial comparing titration up to the minimum vs maximum of the recommended dose range among patients starting with sertraline. The primary outcome is the change in the Patient Health Questionnaire (PHQ)-9 scores administered by a blinded rater via telephone at week 1 through 3. Step II is an individually randomised trial comparing staying on sertraline, augmentation of sertraline with mirtazapine, and switching to mirtazapine among patients who have not remitted on the first line treatment by week 3. The primary outcome is the change in the PHQ-9 scores at week 4 through 9. Step III represents a continuation phase to Steps I and II and aims to establish longer-term effectiveness and acceptability of the above-examined treatment strategies up to week 25. The trial is supported by the Grant-in-Aid by the Ministry of Health, Labour and Welfare, Japan.

Discussion

SUN(^_^)D promises to be a pragmatic large trial to answer important clinical questions that every clinician treating patients with major depression faces in his/her daily practices concerning its first- and second-line treatments.

Trial registration

ClinicalTrials.gov: NCT01109693     

Clinical implications of pharmacogenetics of cytochrome P450 drug metabolizing enzymes

For many drugs, pharmacogenetic polymorphisms are known affecting biotransformation and clinical outcome. The clinical importance of these variants depends on allele-frequency and the effect size of the clinical outcome parameters. Further, it depends on the therapeutic range of the drug which is affected, on predictability of drug response as well as on duration until onset of therapeutic efficacy. Consequences which arise from genotyping might be: adjustment of dose according to genotype, choice of therapeutic strategy or even choice of drug. In antidepressant drug treatment, most drugs are metabolized via the polymorphic cytochrome P450 enzyme CYP2D6. Huge differences in pharmacokinetic parameters have been consistently shown for many tricyclics, some SSRIs, and other antidepressant drugs whereas the effects on therapeutic efficacy and adverse events have been described controversially. In cardiovascular disease, oral anticoagulants, nonsteroidal anti-inflammatory drugs, oral hypoglycemic drugs and other drugs are affected by genetic polymorphisms of the cytochrome P450 drug metabolizing enzyme CYP2C9. Studies in patients or healthy volunteers revealed up to 10-fold differences in pharmacokinetic parameters due to genetic polymorphisms of CYP2C9. Pharmacogenetics based dose adjustments are one tool to individualize drug treatment according to genetic factors. They can be derived from pharmacokinetic data with the aim to obtain equal drug concentrations in each individual. Prospective validation of dose adjustments based on pharmacogenetics should be performed before routine application of such strategies. A controlled prospective clinical trial with one arm receiving genotype-based dose adjustments and the other arm receiving therapy as usual will elucidate the benefit of pharmacogenomics-based individualization of certain drug therapies.     

Childhood and adolescent depression: why do children and adults respond differently to antidepressant drugs?

Childhood and adolescent depression is an increasingly problematic diagnosis for young people due to a lack of effective treatments for this age group. The symptoms of adult depression can be treated effectively with multiple classes of antidepressant drugs which have been developed over the years using animal and human studies. But many of the antidepressants used to treat adult depression cannot be used for pediatric depression because of a lack of efficacy and/or side effects. The reason that children and adolescents respond differently to antidepressant treatment than adults is poorly understood. In order to better understand the etiology of pediatric depression and treatments that are effective for this age group, the differences between adults, children and adolescents needed to be elucidated. Much of the understanding of adult depression has come from studies using adult animals, therefore studies using juvenile animals would likely help us to better understand childhood and adolescent depression. Recent studies have shown both neurochemical and behavioral differences between adult and juvenile animals after antidepressant treatment. Juvenile animals have differences compared to adult animals in the maturation of the serotonergic and noradrenergic systems, and in dose of antidepressant drug needed to achieve similar brain levels. Differences after administration of antidepressant drug have also been reported for adrenergic receptor regulation, a physiologic hypothermic response, as well as behavioral differences in two animal models of depression. The differences between adults and juveniles not only in the human response to antidepressants but also with animals studies warrant a specific distinction between the study of pediatric and adult depression and the manner in which new treatments are pursued.     

State and Trait Olfactory Markers of Major Depression

Nowadays, depression is a major issue in public health. Because of the partial overlap between the brain structures involved in depression, olfaction and emotion, the study of olfactory function could be a relevant way to find specific cognitive markers of depression. This study aims at determining whether the olfactory impairments are state or trait markers of major depressive episode (MDE) through the study of the olfactory parameters involving the central olfactory pathway. In a pilot study, we evaluated prospectively 18 depressed patients during acute episodes of depression and 6 weeks after antidepressant treatment (escitalopram) against 54 healthy volunteers, matched by age, gender and smoking status. We investigated the participants’ abilities to identify odors (single odors and in binary mixture), to evaluate and discriminate the odors’ intensity, and determine the hedonic valence of odors. The results revealed an “olfactory anhedonia” expressed by decrease of hedonic score for high emotional odorant as potential state marker of MDE. Moreover, these patients experienced an “olfactory negative alliesthesia”, during the odor intensity evaluation, and failed to identify correctly two odorants with opposite valences in a binary iso-mixture, which constitute potential trait markers of the disease. This study provides preliminary evidence for olfactory impairments associated with MDE (state marker) that are persistent after the clinical improvement of depressive symptoms (trait marker). These results could be explained by the chronicity of depression and/or by the impact of therapeutic means used (antidepressant treatment). They need to be confirmed particularly the ones obtained in complex olfactory environment which corresponds a more objective daily life situation.     

Hyperforin promotes mitochondrial function and development of oligodendrocytes

St. John's wort has been found to be an effective and safe herbal treatment for depression in several clinical trials. However, the underlying mechanism of its therapeutic effects is unclear. Recent studies show that the loss and malfunction of oligodendrocytes are closely related to the neuropathological changes in depression, which can be reversed by antidepressant treatment. In this study, we evaluated the effects of hyperforin, a major active component of St. John's wort, on the proliferation, development and mitochondrial function of oligodendrocytes. The study results revealed that hyperforin promotes maturation of oligodendrocytes and increases mitochondrial function without affecting proliferation of an oligodendrocyte progenitor cell line and neural stem/progenitor cells. Hyperforin also prevented mitochondrial toxin-induced cytotoxicity in an oligodendrocyte progenitor cell line. These findings suggest that hyperforin may stimulate the development and function of oligodendrocytes, which could be a mechanism of its effect in depression. Future in vitro and in vivo studies are required to further characterize the mechanisms of hyperforin.     

A Longitudinal Functional Neuroimaging Study in Medication-Na?ve Depression after Antidepressant Treatment

Recent studies have indicated the potential clinical use of near infrared spectroscopy (NIRS) as a tool in assisting the diagnosis of major depressive disorder (MDD); however, it is still unclear whether NIRS signal changes during cognitive task are state- or trait-dependent, and whether NIRS could be a neural predictor of treatment response. Therefore, we conducted a longitudinal study to explore frontal haemodynamic changes following antidepressant treatment in medication-naïve MDD using 52-channel NIRS. This study included 25 medication-naïve individuals with MDD and 62 healthy controls (HC). We performed NIRS scans before and after antidepressant treatment and measured changes of [oxy-Hb] activation during a verbal fluency task (VFT) following treatment. Individuals with MDD showed significantly decreased [oxy-Hb] values during a VFT compared with HC in the bilateral frontal and temporal cortices at baseline. There were no [oxy-Hb] changes between pre- and post-antidepressant treatment time points in the MDD cohort despite significant improvement in depressive symptoms. There was a significant association between mean [oxy-Hb] values during a VFT at baseline and improvement in depressive symptoms following treatment in the bilateral inferior frontal and middle temporal gyri in MDD. These findings suggest that hypofrontality response to a VFT may represent a potential trait marker for depression rather than a state marker. Moreover, the correlation analysis indicates that the NIRS signals before the initiation of treatment may be a biological marker to predict patient’s clinical response to antidepressant treatment. The present study provides further evidence to support a potential application of NIRS for the diagnosis and treatment of depression.     

The clinical characterization of the adult patient with depression aimed at personalization of management

Depression is widely acknowledged to be a heterogeneous entity, and the need to further characterize the individual patient who has received this diagnosis in order to personalize the management plan has been repeatedly emphasized. However, the research evidence that should guide this personalization is at present fragmentary, and the selection of treatment is usually based on the clinician's and/or the patient's preference and on safety issues, in a trial‐and‐error fashion, paying little attention to the particular features of the specific case. This may be one of the reasons why the majority of patients with a diagnosis of depression do not achieve remission with the first treatment they receive. The predominant pessimism about the actual feasibility of the personalization of treatment of depression in routine clinical practice has recently been tempered by some secondary analyses of databases from clinical trials, using approaches such as individual patient data meta‐analysis and machine learning, which indicate that some variables may indeed contribute to the identification of patients who are likely to respond differently to various antidepressant drugs or to antidepressant medication vs. specific psychotherapies. The need to develop decision support tools guiding the personalization of treatment of depression has been recently reaffirmed, and the point made that these tools should be developed through large observational studies using a comprehensive battery of self‐report and clinical measures. The present paper aims to describe systematically the salient domains that should be considered in this effort to personalize depression treatment. For each domain, the available research evidence is summarized, and the relevant assessment instruments are reviewed, with special attention to their suitability for use in routine clinical practice, also in view of their possible inclusion in the above‐mentioned comprehensive battery of measures. The main unmet needs that research should address in this area are emphasized. Where the available evidence allows providing the clinician with specific advice that can already be used today to make the management of depression more personalized, this advice is highlighted. Indeed, some sections of the paper, such as those on neurocognition and on physical comorbidities, indicate that the modern management of depression is becoming increasingly complex, with several components other than simply the choice of an antidepressant and/or a psychotherapy, some of which can already be reliably personalized.     

Towards translational rodent models of depression

Rodent models of depression have been developed in an effort to identify novel antidepressant compounds and to further our understanding of the pathophysiology of depression. Various rodent models of depression and antidepressant-like behaviour are currently used but, clearly, none of these current models fully recapitulate all features of depression. Moreover, these models have not resulted in the development of novel non-monoaminergic-based antidepressants with clinical efficacy. Thus, a refinement of the current models of depression is required. The present review outlines the most commonly used models of depression and antidepressant drug-like activity and suggests several factors that should be considered when refining these models.     

Abandoning personalization to get to precision in the pharmacotherapy of depression

Effectiveness studies and analyses of naturalistic cohorts demonstrate that many patients with major depressive disorder do not experience symptomatic remission with antidepressant treatments. In an effort to better match patients with effective treatments, numerous investigations of predictors or moderators of treatment response have been reported over the past five decades, including clinical features as well as biological measures. However, none of these have entered routine clinical practice; instead, clinicians typically personalize treatment on the basis of patient preferences as well as their own. Here, we review the reasons why it has been challenging to identify and deploy treatment‐specific predictors of response, and suggest strategies that may be required to achieve true precision in the pharmacotherapy of depression. We emphasize the need for changes in how depression care is delivered, measured, and used to inform future practice.     

The present Pyrenean population of bearded vulture (Gypaetus barbatus): Its genetic characteristics

The Pyrenean population of the endangered bearded vulture (Gypaetus barbatus) is the largest natural population in Europe. In this study, its current genetic variability was assessed using 110 animals of the recent population in order to know what the present situation. Sex identification by DNA methodology in the 110 bearded vultures, mitochondrial DNA (mtDNA) and eight microsatellite markers in 87 bearded vultures have been analysed. Our results for sex identification present a number of 49 males and 61 females; no significant differences for number of males and females in this population have been observed. mtDNA studies indicate that nucleotide and haplotype diversities and number of variable sites were low. Tajima's D test and Fu and Li's D* and F* tests suggest that mutations are selectively neutral and the population is expanding. A mean number of alleles per locus and a mean observed heterozygosity have been obtained by microsatellite analysis. FIS is not high, and inbreeding depression could be discarded in the near future. The results suggest that the Pyrenean population of bearded vultures have to be controlled in order to avoid the loss of genetic variability. This data should be taken into account when considering conservation plans for the species.