Genome-wide association analysis accounting for environmental factors through propensity-score matching: application to stressful live events in major depressive disorder.

Stressful life events are an established trigger for depression and may contribute to the heterogeneity within genome-wide association analyses. With depression cases showing an excess of exposure to stressful events compared to controls, there is difficulty in distinguishing between "true" cases and a "normal" response to a stressful environment. This potential contamination of cases, and that from genetically at risk controls that have not yet experienced environmental triggers for onset, may reduce the power of studies to detect causal variants. In the RADIANT sample of 3,690 European individuals, we used propensity score matching to pair cases and controls on exposure to stressful life events. In 805 case-control pairs matched on stressful life event, we tested the influence of 457,670 common genetic variants on the propensity to depression under comparable level of adversity with a sign test. While this analysis produced no significant findings after genome-wide correction for multiple testing, we outline a novel methodology and perspective for providing environmental context in genetic studies. We recommend contextualizing depression by incorporating environmental exposure into genome-wide analyses as a complementary approach to testing gene-environment interactions. Possible explanations for negative findings include a lack of statistical power due to small sample size and conditional effects, resulting from the low rate of adequate matching. Our findings underscore the importance of collecting information on environmental risk factors in studies of depression and other complex phenotypes, so that sufficient sample sizes are available to investigate their effect in genome-wide association analysis.

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.

Self-report and clinician-rated measures of depression severity: can one replace the other?

BACKGROUND: It has been suggested that clinician-rated scales and self-report questionnaires may be interchangeable in the measurement of depression severity, but it has not been tested whether clinically significant information is lost when assessment is restricted to either clinician-rated or self-report instruments. The aim of this study is to test whether self-report provides information relevant to short-term treatment outcomes that is not captured by clinician-rating and vice versa. METHODS: In genome-based drugs for depression (GENDEP), 811 patients with major depressive disorder treated with escitalopram or nortriptyline were assessed with the clinician-rated Montgomery-Åsberg Depression Rating Scale (MADRS), Hamilton Rating Scale for Depression (HRSD), and the self-report Beck Depression Inventory (BDI). In sequenced treatment alternatives to relieve depression (STAR*D), 4,041 patients treated with citalopram were assessed with the clinician-rated and self-report versions of the Quick Inventory of Depressive Symptomatology (QIDS-C and QIDS-SR) in addition to HRSD. RESULTS: In GENDEP, baseline BDI significantly predicted outcome on MADRS/HRSD after adjusting for baseline MADRS/HRSD, explaining additional 3 to 4% of variation in the clinician-rated outcomes (both P < .001). Likewise, each clinician-rated scale significantly predicted outcome on BDI after adjusting for baseline BDI and explained additional 1% of variance in the self-reported outcome (both P < .001). The results were confirmed in STAR*D, where self-report and clinician-rated versions of the same instrument each uniquely contributed to the prediction of treatment outcome. CONCLUSIONS: Complete assessment of depression should include both clinician-rated scales and self-reported measures.

Dissecting the genetic heterogeneity of depression through age at onset.

Genome-wide studies in major depression have identified few replicated associations, potentially due to heterogeneity within the disorder. Several studies have suggested that age at onset (AAO) can distinguish sub-types of depression with specific heritable components. This paper investigates the role of AAO in the genetic susceptibility for depression using genome-wide association data on 2,746 cases and 1,594 screened controls from the RADIANT studies, with replication performed in 1,471 cases and 1,403 controls from two Munich studies. Three methods were used to analyze AAO: First a time-to-event analysis with controls censored, secondly comparing controls to case-subsets defined using AAO cut-offs, and lastly analyzing AAO as a quantitative trait. In the time-to-event analysis three SNPs reached suggestive significance (P < 5E-06), overlapping with the original case-control analysis of this study. In a case-control analysis using AAO thresholds, SNPs in 10 genomic regions showed suggestive association though again none reached genome-wide significance. Lastly, case-only analysis of AAO as a quantitative trait resulted in 5 SNPs reaching suggestive significance. Sex specific analysis was performed as a secondary analysis, yielding one SNP reaching genome-wide significance in early-onset males. No SNPs achieved significance in the replication study after correction for multiple testing. Analysis of AAO as a quantitative trait did suggest that, across all SNPs, common genetic variants explained a large proportion of the variance (51%, P = 0.04). This study provides the first focussed analysis of the genetic contribution to AAO in depression, and establishes a statistical framework that can be applied to a quantitative trait underlying any disorder.

Changes in body weight during pharmacological treatment of depression.

The risk of weight gain is an important determinant of the acceptability and tolerability of antidepressant medication. To compare changes in body weight during treatment with different antidepressants, body weight and height were measured at baseline and after 6, 8, 12 and 26 wk treatment with escitalopram or nortriptyline in 630 adults with moderate-to-severe unipolar depression participating in GENDEP, a part-randomized open-label study. Weight increased significantly more during treatment with nortriptyline compared to escitalopram. The weight gain commenced during the first 6 wk of nortriptyline treatment, reached on average 1.2 kg at 12 wk (0.44-point BMI increase), and continued throughout the 6-month follow-up period. Participants who were underweight at baseline gained most weight. Participants who were obese at baseline did not gain more weight during treatment. Weight gain occurred irrespective of whether weight loss was a symptom of current depressive episode and was identified as an undesired effect of the antidepressant by most participants who gained weight. There was little weight change during treatment with escitalopram, with an average increase of 0.14 kg (0.05-point BMI increase) over 12 wk of treatment. In conclusion, treatment with the tricyclic antidepressant nortriptyline was associated with moderate weight gain, which cannot be explained as a reversal of symptomatic weight loss and is usually perceived as an undesired adverse effect. While treatment with nortriptyline may be recommended in underweight subjects with typical neurovegetative symptoms, escitalopram is a suitable alternative for subjects at risk of weight gain.

Reduced peripheral brain-derived neurotrophic factor mRNA levels are normalized by antidepressant treatment.

Consistent data coming from biochemical studies have evidenced a brain-derived neurotrophic factor (BDNF) serum reduction in depressed patients compared to controls and a restoration following antidepressant treatment. However, to date, no study has evaluated whether BDNF synthesis in leukocytes could contribute to such modulation. Therefore, in this study, we analysed BDNF mRNA levels in leukocytes from 21 depressed patients prior to and during escitalopram treatment and from 23 control subjects showing that BDNF mRNA levels were decreased in drug-free depressed patients and that 12 wk escitalopram treatment was able to reverse this deficit. Interestingly, changes in BDNF mRNA levels paralleled BDNF serum increase during antidepressant treatment, and were correlated with symptoms improvement. Our results indicate that BDNF serum modulation observed in depressed patients is associated with BDNF synthesis alteration in leukocytes and suggest that these peripheral cells might play an active role in the mechanisms of action of antidepressants.

Suicidal ideation during treatment of depression with escitalopram and nortriptyline in genome-based therapeutic drugs for depression (GENDEP): a clinical trial.

BACKGROUND: Suicidal thoughts and behaviours during antidepressant treatment, especially during the first weeks of treatment, have prompted warnings by regulatory bodies. The aim of the present study is to investigate the course and predictors of emergence and worsening of suicidal ideation during tricyclic antidepressant and serotonin reuptake inhibitor treatment. METHODS: In a multicentre part-randomised open-label study, 811 adult patients with moderate to severe unipolar depression were allocated to flexible dosage of escitalopram or nortriptyline for 12 weeks. The suicidality items of three standard measures were integrated in a suicidal ideation score. Increases in this score were classified as treatment emergent suicidal ideation (TESI) or treatment worsening suicidal ideation (TWOSI) according to the absence or presence of suicidal ideation at baseline. RESULTS: Suicidal ideation decreased during antidepressant treatment. Rates of TESI and TWOSI peaked in the fifth week. Severity of depression predicted TESI and TWOSI. In men, nortriptyline was associated with a 9.8-fold and 2.4-fold increase in TESI and TWOSI compared to escitalopram, respectively. Retirement and history of suicide attempts predicted TWOSI. CONCLUSION: Increases in suicidal ideation were associated with depression severity and decreased during antidepressant treatment. In men, treatment with escitalopram is associated with lower risk of suicidal ideation compared to nortriptyline. Clinicians should remain alert to suicidal ideation beyond the initial weeks of antidepressant treatment. TRIAL REGISTRATION: EudraCT (No.2004-001723-38) and ISRCTN (No. 03693000).

Genetic predictors of response to antidepressants in the GENDEP project.

The objective of the Genome-based Therapeutic Drugs for Depression study is to investigate the function of variations in genes encoding key proteins in serotonin, norepinephrine, neurotrophic and glucocorticoid signaling in determining the response to serotonin-reuptake-inhibiting and norepinephrine-reuptake-inhibiting antidepressants. A total of 116 single nucleotide polymorphisms in 10 candidate genes were genotyped in 760 adult patients with moderate-to-severe depression, treated with escitalopram (a serotonin reuptake inhibitor) or nortriptyline (a norepinephrine reuptake inhibitor) for 12 weeks in an open-label part-randomized multicenter study. The effect of genetic variants on change in depressive symptoms was evaluated using mixed linear models. Several variants in a serotonin receptor gene (HTR2A) predicted response to escitalopram with one marker (rs9316233) explaining 1.1% of variance (P=0.0016). Variants in the norepinephrine transporter gene (SLC6A2) predicted response to nortriptyline, and variants in the glucocorticoid receptor gene (NR3C1) predicted response to both antidepressants. Two HTR2A markers remained significant after hypothesis-wide correction for multiple testing. A false discovery rate of 0.106 for the three strongest associations indicated that the multiple findings are unlikely to be false positives. The pattern of associations indicated a degree of specificity with variants in genes encoding proteins in serotonin signaling influencing response to the serotonin-reuptake-inhibiting escitalopram, genes encoding proteins in norepinephrine signaling influencing response to the norepinephrine-reuptake-inhibiting nortriptyline and a common pathway gene influencing response to both antidepressants. The single marker associations explained only a small proportion of variance in response to antidepressants, indicating a need for a multivariate approach to prediction.

Differential efficacy of escitalopram and nortriptyline on dimensional measures of depression.

BACKGROUND: Tricyclic antidepressants and serotonin reuptake inhibitors are considered to be equally effective, but differences may have been obscured by internally inconsistent measurement scales and inefficient statistical analyses. AIMS: To test the hypothesis that escitalopram and nortriptyline differ in their effects on observed mood, cognitive and neurovegetative symptoms of depression. METHOD: In a multicentre part-randomised open-label design (the Genome Based Therapeutic Drugs for Depression (GENDEP) study) 811 adults with moderate to severe unipolar depression were allocated to flexible dosage escitalopram or nortriptyline for 12 weeks. The weekly Montgomery-Asberg Depression Rating Scale, Hamilton Rating Scale for Depression, and Beck Depression Inventory were scored both conventionally and in a more novel way according to dimensions of observed mood, cognitive symptoms and neurovegetative symptoms. RESULTS: Mixed-effect linear regression showed no difference between escitalopram and nortriptyline on the three original scales, but symptom dimensions revealed drug-specific advantages. Observed mood and cognitive symptoms improved more with escitalopram than with nortriptyline. Neurovegetative symptoms improved more with nortriptyline than with escitalopram. CONCLUSIONS: The three symptom dimensions provided sensitive descriptors of differential antidepressant response and enabled identification of drug-specific effects.

Moderation of antidepressant response by the serotonin transporter gene.

BACKGROUND: There have been conflicting reports on whether the length polymorphism in the promoter of the serotonin transporter gene (5-HTTLPR) moderates the antidepressant effects of selective serotonin reuptake inhibitors (SSRIs). We hypothesised that the pharmacogenetic effect of 5-HTTLPR is modulated by gender, age and other variants in the serotonin transporter gene. AIMS: To test the hypothesis that the 5-HTTLPR differently influences response to escitalopram (an SSRI) compared with nortriptyline (a noradrenaline reuptake inhibitor). METHOD: The 5-HTTLPR and 13 additional markers across the serotonin transporter gene were genotyped in 795 adults with moderate-to-severe depression treated with escitalopram or nortriptyline in the Genome Based Therapeutic Drugs for Depression (GENDEP) project. RESULTS: The 5-HTTLPR moderated the response to escitalopram, with long-allele carriers improving more than short-allele homozygotes. A significant three-way interaction between 5-HTTLPR, drug and gender indicated that the effect was concentrated in males treated with escitalopram. The single-nucleotide polymorphism rs2020933 also influenced outcome. CONCLUSIONS: The effect of 5-HTTLPR on antidepressant response is SSRI specific conditional on gender and modulated by another polymorphism at the 5' end of the serotonin transporter gene.

Adverse reactions to antidepressants.

BACKGROUND: Adverse drug reactions are important determinants of non-adherence to antidepressant treatment, but their assessment is complicated by overlap with depressive symptoms and lack of reliable self-report measures. AIMS: To evaluate a simple self-report measure and describe adverse reactions to antidepressants in a large sample. METHOD: The newly developed self-report Antidepressant Side-Effect Checklist and the psychiatrist-rated UKU Side Effect Rating Scale were repeatedly administered to 811 adult participants with depression in a part-randomised multicentre open-label study comparing escitalopram and nortriptyline. RESULTS: There was good agreement between self-report and psychiatrists' ratings. Most complaints listed as adverse reactions in people with depression were more common when they were medication-free rather than during their treatment with antidepressants. Dry mouth (74%), constipation (33%) and weight gain (15%) were associated with nortriptyline treatment. Diarrhoea (9%), insomnia (36%) and yawning (16%) were more common during treatment with escitalopram. Problems with urination and drowsiness predicted discontinuation of nortriptyline. Diarrhoea and decreased appetite predicted discontinuation of escitalopram. CONCLUSIONS: Adverse reactions to antidepressants can be reliably assessed by self-report. Attention to specific adverse reactions may improve adherence to antidepressant treatment.

Functional atlas of emotional faces processing: a voxel-based meta-analysis of 105 functional magnetic resonance imaging studies.

BACKGROUND: Most of our social interactions involve perception of emotional information from the faces of other people. Furthermore, such emotional processes are thought to be aberrant in a range of clinical disorders, including psychosis and depression. However, the exact neurofunctional maps underlying emotional facial processing are not well defined. METHODS: Two independent researchers conducted separate comprehensive PubMed (1990 to May 2008) searches to find all functional magnetic resonance imaging (fMRI) studies using a variant of the emotional faces paradigm in healthy participants. The search terms were: "fMRI AND happy faces," "fMRI AND sad faces," "fMRI AND fearful faces," "fMRI AND angry faces," "fMRI AND disgusted faces" and "fMRI AND neutral faces." We extracted spatial coordinates and inserted them in an electronic database. We performed activation likelihood estimation analysis for voxel-based meta-analyses. RESULTS: Of the originally identified studies, 105 met our inclusion criteria. The overall database consisted of 1785 brain coordinates that yielded an overall sample of 1600 healthy participants. Quantitative voxel-based meta-analysis of brain activation provided neurofunctional maps for 1) main effect of human faces; 2) main effect of emotional valence; and 3) modulatory effect of age, sex, explicit versus implicit processing and magnetic field strength. Processing of emotional faces was associated with increased activation in a number of visual, limbic, temporoparietal and prefrontal areas; the putamen; and the cerebellum. Happy, fearful and sad faces specifically activated the amygdala, whereas angry or disgusted faces had no effect on this brain region. Furthermore, amygdala sensitivity was greater for fearful than for happy or sad faces. Insular activation was selectively reported during processing of disgusted and angry faces. However, insular sensitivity was greater for disgusted than for angry faces. Conversely, neural response in the visual cortex and cerebellum was observable across all emotional conditions. LIMITATIONS: Although the activation likelihood estimation approach is currently one of the most powerful and reliable meta-analytical methods in neuroimaging research, it is insensitive to effect sizes. CONCLUSION: Our study has detailed neurofunctional maps to use as normative references in future fMRI studies of emotional facial processing in psychiatric populations. We found selective differences between neural networks underlying the basic emotions in limbic and insular brain regions.

VEGF serum levels in depressed patients during SSRI antidepressant treatment.

Recent evidence indicates that the vascular endothelial growth factor (VEGF) may be involved in the neuronal mechanisms underlying both the depression aetiology and the response to pharmacological and non pharmacological antidepressant treatments. To investigate whether VEGF peripheral levels are altered in depression and are modulated by antidepressant therapies, we analyzed the serum VEGF concentrations in 25 subjects affected by major depression (MD) before (T0) and after 8 (T8) and 12 (T12) weeks of escitalopram treatment. No significant alterations in VEGF serum levels were found at T0, even considering possible effects of confounders such as gender and smoking habit (r2=0.227 p=0.74). No changes appeared during the treatment (F(1.83, 43.86)=0.962; p=0.383) and there was no correlation between percentage VEGF variations at T12 and symptoms improvements (p=0.823). The present work represents the first report on the evaluation of serum VEGF levels in MD patients. However, before discarding serum VEGF as a biochemical marker in the diagnosis and treatment of depression, our negative results need to be confirmed in larger patient samples stratified for clinical characteristics, co-morbidities, cardiovascular diseases and confounding factors.

Clinical characteristics in long-term care psychiatric patients: a descriptive study.

OBJECTIVE: The purpose of this study was to describe the clinical characteristics and related comorbid conditions of psychiatric patients admitted to residential facilities (RFs) and their impact on the levels of functioning of such patients. METHODS: We assessed 426 patients admitted to residential facilities, by using SCID-I, SCID-II, BPRS, GAF and DAS. RESULTS: The most common diagnostic category was schizophrenia/psychotic disorders (41.8%), followed by affective disorders (35.4%), personality disorders (14.1%), and other disorders (8.7%). In addition 33.3% had a psychiatric comorbidity, and 62.6% had a medical comorbidity. Low levels of functioning were significantly correlated with both medical and psychiatric comorbid conditions. CONCLUSIONS: Comorbidity is common in patients requiring long-term residential care. Thus improved detection and treatment of these conditions in people with severe mental illnesses will have significant benefits for their psychosocial functioning and overall quality of life.

Effect of cytochrome CYP2C19 metabolizing activity on antidepressant response and side effects: Meta-analysis of data from genome-wide association studies.

Cytochrome (CYP) P450 enzymes have a primary role in antidepressant metabolism and variants in these polymorphic genes are targets for pharmacogenetic investigation. This is the first meta-analysis to investigate how CYP2C19 polymorphisms predict citalopram/escitalopram efficacy and side effects. CYP2C19 metabolic phenotypes comprise poor metabolizers (PM), intermediate and intermediate+ metabolizers (IM; IM+), extensive and extensive+ metabolizers (EM [wild type]; EM+) and ultra-rapid metabolizers (UM) defined by the two most common CYP2C19 functional polymorphisms (rs4244285 and rs12248560) in Caucasians. These polymorphisms were genotyped or imputed from genome-wide data in four samples treated with citalopram or escitalopram (GENDEP, STAR*D, GenPod, PGRN-AMPS). Treatment efficacy was assessed by standardized percentage symptom improvement and by remission. Side effect data were available at weeks 2-4, 6 and 9 in three samples. A fixed-effects meta-analysis was performed using EM as the reference group. Analysis of 2558 patients for efficacy and 2037 patients for side effects showed that PMs had higher symptom improvement (SMD = 0.43, CI = 0.19-0.66) and higher remission rates (OR = 1.55, CI = 1.23-1.96) compared to EMs. At weeks 2-4, PMs showed higher risk of gastro-intestinal (OR = 1.26, CI = 1.08-1.47), neurological (OR = 1.28, CI = 1.07-1.53) and sexual side effects (OR = 1.52, CI = 1.23-1.87; week 6 values were similar). No difference was seen at week 9 or in total side effect burden. PMs did not have higher risk of dropout at week 4 compared to EMs. Antidepressant dose was not different among CYP2C19 groups. CYP2C19 polymorphisms may provide helpful information for guiding citalopram/escitalopram treatment, despite PMs being relatively rare among Caucasians (∼2%).

Neurofunctional correlates of vulnerability to psychosis: a systematic review and meta-analysis.

An understanding of the neurobiological correlates of vulnerability to psychosis is fundamental to research on schizophrenia. We systematically reviewed data from studies published from 1992 to 2006 on the neurocognitive correlates (as measured by fMRI) of increased vulnerability to psychosis. We also conducted a meta-analysis of abnormalities of activation in the prefrontal cortex (PFC) in high-risk and first episode subjects, and reviewed neuroimaging studies of high-risk subjects that used PET, SPECT and MRS. Twenty-four original fMRI papers were identified, most of which involved tasks that engaged the PFC. In fMRI studies, vulnerability to psychosis was associated with medium to large effect sizes when prefrontal activation was contrasted with that in controls. Relatives of patients affected with psychosis, the co-twins of patients and subjects with an At Risk Mental State (ARMS) appear to share similar neurocognitive abnormalities. Furthermore, these are qualitatively similar but less severe than those observed in the first episode of illness. These abnormalities have mainly been described in the prefrontal and anterior cingulated cortex, the basal ganglia, hippocampus and cerebellum.

[Mental Health Recovery Star: features and validation study of the Italian version]. / La Mental Health Recovery Star: caratteristiche e studio di validazione della versione italiana.

AIM: Mental Health Recovery Star (MHRS) is an instrument that helps to assess recovery processes of mental health patients through a collaborative approach. The aim of the study is to describe the features of the instrument and to report the results of the Italian validation study. METHODS: The study involved 117 users which were evaluated in two phases. Besides MRHS, HoNOS, WHOQoL-brief, GAF were used. Acceptability for users and key-workers of the instruments and its main psychometric properties, as test-retes (ICC) and concurrent validity (Pearson's correlation coefficient), were evaluated. RESULTS: MHRS showed to have temporal stability in all its areas. Significant correlations were found between the MHRS and the most closely related areas of the scales used. Inter-rater reliability were studied in an unsatisfactory way. MHRS was appreciated and easy to use. Collaborative evaluations were completed mostly in less than 45 minutes. CONCLUSIONS: MHRS is an acceptable tool for users and staff-members, distinguishing itself from the use of useful visual aids; helps to identify the patient's recovery path and supports a collaborative approach between user and operator. The results of the psychometric properties of the instrument appeared promising but not exhaustive. Although further efforts should be addressed to the implementation of such aspects of the instrument and reflections should be raised with respect to the traditional methods to detect the complex meaning of recovery (subjective-objective aspects), the valuable collaborative contribution of MHRS can not be denied in favoring the user's responsibility and supporting the professional worker in his role of case manager.

Pharmacogenetics of antidepressant response: A polygenic approach.

BACKGROUND: Major depressive disorder (MDD) has a high personal and socio-economic burden and >60% of patients fail to achieve remission with the first antidepressant. The biological mechanisms behind antidepressant response are only partially known but genetic factors play a relevant role. A combined predictor across genetic variants may be useful to investigate this complex trait. METHODS: Polygenic risk scores (PRS) were used to estimate multi-allelic contribution to: 1) antidepressant efficacy; 2) its overlap with MDD and schizophrenia. We constructed PRS and tested whether these predicted symptom improvement or remission from the GENDEP study (n=736) to the STAR*D study (n=1409) and vice-versa, including the whole sample or only patients treated with escitalopram or citalopram. Using summary statistics from Psychiatric Genomics Consortium for MDD and schizophrenia, we tested whether PRS from these disorders predicted symptom improvement in GENDEP, STAR*D, and five further studies (n=3756). RESULTS: No significant prediction of antidepressant efficacy was obtained from PRS in GENDEP/STAR*D but this analysis might have been underpowered. There was no evidence of overlap in the genetics of antidepressant response with either MDD or schizophrenia, either in individual studies or a meta-analysis. Stratifying by antidepressant did not alter the results. DISCUSSION: We identified no significant predictive effect using PRS between pharmacogenetic studies. The genetic liability to MDD or schizophrenia did not predict response to antidepressants, suggesting differences between the genetic component of depression and treatment response. Larger or more homogeneous studies will be necessary to obtain a polygenic predictor of antidepressant response.

Neuroimaging and electrophysiological studies of the effects of acute tryptophan depletion: a systematic review of the literature.

RATIONALE: There is a growing psychopharmacological literature on the use of Acute Tryptophan Depletion (ATD) for experimental modulation of the serotonergic system. To date, no systematic review has been undertaken assessing the neurophysiological effects following this acute central 5-HT manipulation. MATERIALS AND METHODS: A comprehensive MEDLINE, EMBASE, PsycINFO search was performed for reports on neural substrates of Acute Tryptophan Depletion in healthy individuals and in clinical population. RESULTS: Twenty-eight placebo-controlled studies were included in the review. Although tryptophan depletion reduced plasma serotonin levels in all studies, significant effects on mood were only observed in studies with recovered depressed patients. In functional neuroimaging studies ATD was consistently found to modulate cortical activity in prefrontal areas implicated in mnemonic and executive functions and in orbitofrontal, cingulate, and subcortical regions associated with emotional processing. Electrophysiological studies indicated that ATD has a significant effect on both "selective" and "involuntary" attention. CONCLUSIONS: The combination of ATD with modern brain imaging techniques allows the investigation of the neurophysiological effects of reduced 5-HT synthesis on global brain activity, executive functions, memory, attention, and affect.

Transcriptomics and the mechanisms of antidepressant efficacy.

The mechanisms by which antidepressants have their effects are not clear and the reasons for variability in treatment outcomes are also unknown. However, there is evidence from candidate gene research that indicates gene expression changes may be involved in antidepressant action. In this study, we examined antidepressant-induced alterations in gene expression on a transcriptome-wide scale, exploring associations with treatment response. Blood samples were taken from a subset of depressed patients from the GENDEP study (n=136) before and after eight weeks of treatment with either escitalopram or nortriptyline. Transcriptomic data were obtained from these samples using Illumina HumanHT-12 v4 Expression BeadChip microarrays. When analysing individual genes, we observed that changes in the expression of two genes (MMP28 and KXD1) were associated with better response to nortriptyline. Considering connectivity between genes, we identified modules of genes that were highly coexpressed. In the whole sample, changes in one of the ten identified coexpression modules showed significant correlation with treatment response (cor=0.27, p=0.0029). Using transcriptomic approaches, we have identified gene expression correlates of the therapeutic effects of antidepressants, highlighting possible molecular pathways involved in efficacious antidepressant treatment.