Genetic associations of prolactin increase in olanzapine/fluoxetine combination-treated patients.

In patients from two clinical trials, we investigated the associations of single nucleotide polymorphisms (SNPs) in candidate genes with prolactin level changes during treatment with olanzapine/fluoxetine combination. In both cohorts, three dopamine receptor D2 (DRD2) SNPs were associated with prolactin changes. DRD2 may influence susceptibility to hyperprolactinemia associated with antipsychotic treatment.

Predictors and correlates for weight changes in patients co-treated with olanzapine and weight mitigating agents; a post-hoc analysis.

BACKGROUND: This study focuses on exploring the relationship between changes in appetite or eating behaviors and subsequent weight change for adult patients with schizophrenia or bipolar disorder treated with olanzapine and adjunctive potential weight mitigating pharmacotherapy. The aim is not to compare different weight mitigating agents, but to evaluate patients' characteristics and changes in their eating behaviors during treatment. Identification of patient subgroups with different degrees of susceptibility to the effect of weight mitigating agents during olanzapine treatment may aid clinicians in treatment decisions. METHODS: Data were obtained from 3 randomized, double-blind, placebo-controlled, 16-week clinical trials. Included were 158 patients with schizophrenia or bipolar disorder and a body mass index (BMI) > or = 25 kg/m2 who had received olanzapine treatment in combination with nizatidine (n = 68), sibutramine (n = 42), or amantadine (n = 48). Individual patients were analyzed for categorical weight loss > or= 2 kg and weight gain > or = 1 kg. Variables that were evaluated as potential predictors of weight outcomes included baseline patient characteristics, factors of the Eating Inventory, individual items of the Eating Behavior Assessment, and the Visual Analog Scale. RESULTS: Predictors/correlates of weight loss > or = 2 kg included: high baseline BMI, low baseline interest in food, and a decrease from baseline to endpoint in appetite, hunger, or cravings for carbohydrates. Reduced cognitive restraint, increase in hunger, and increased overeating were associated with a higher probability of weight gain > or = 1 kg. CONCLUSION: The association between weight gain and lack of cognitive restraint in the presence of increased appetite suggests potential benefit of psychoeducational counseling in conjunction with adjunctive pharmacotherapeutic agents in limiting weight gain during antipsychotic drug therapy. TRIAL REGISTRATION: This analysis was not a clinical trial and did not involve any medical intervention.

Gene set enrichment analysis for non-monotone association and multiple experimental categories.

BACKGROUND: Recently, microarray data analyses using functional pathway information, e.g., gene set enrichment analysis (GSEA) and significance analysis of function and expression (SAFE), have gained recognition as a way to identify biological pathways/processes associated with a phenotypic endpoint. In these analyses, a local statistic is used to assess the association between the expression level of a gene and the value of a phenotypic endpoint. Then these gene-specific local statistics are combined to evaluate association for pre-selected sets of genes. Commonly used local statistics include t-statistics for binary phenotypes and correlation coefficients that assume a linear or monotone relationship between a continuous phenotype and gene expression level. Methods applicable to continuous non-monotone relationships are needed. Furthermore, for multiple experimental categories, methods that combine multiple GSEA/SAFE analyses are needed. RESULTS: For continuous or ordinal phenotypic outcome, we propose to use as the local statistic the coefficient of multiple determination (i.e., the square of multiple correlation coefficient) R2 from fitting natural cubic spline models to the phenotype-expression relationship. Next, we incorporate this association measure into the GSEA/SAFE framework to identify significant gene sets. Unsigned local statistics, signed global statistics and one-sided p-values are used to reflect our inferential interest. Furthermore, we describe a procedure for inference across multiple GSEA/SAFE analyses. We illustrate our approach using gene expression and liver injury data from liver and blood samples from rats treated with eight hepatotoxicants under multiple time and dose combinations. We set out to identify biological pathways/processes associated with liver injury as manifested by increased blood levels of alanine transaminase in common for most of the eight compounds. Potential statistical dependency resulting from the experimental design is addressed in permutation based hypothesis testing. CONCLUSION: The proposed framework captures both linear and non-linear association between gene expression level and a phenotypic endpoint and thus can be viewed as extending the current GSEA/SAFE methodology. The framework for combining results from multiple GSEA/SAFE analyses is flexible to address practical inference interests. Our methods can be applied to microarray data with continuous phenotypes with multi-level design or the meta-analysis of multiple microarray data sets.

Genes related to apoptosis predict necrosis of the liver as a phenotype observed in rats exposed to a compendium of hepatotoxicants.

BACKGROUND: Some of the biochemical events that lead to necrosis of the liver are well-known. However, the pathogenesis of necrosis of the liver from exposure to hepatotoxicants is a complex biological response to the injury. We hypothesize that gene expression profiles can serve as a signature to predict the level of necrosis elicited by acute exposure of rats to a variety of hepatotoxicants and postulate that the expression profiles of the predictor genes in the signature can provide insight to some of the biological processes and molecular pathways that may be involved in the manifestation of necrosis of the rat liver. RESULTS: Rats were treated individually with one of seven known hepatotoxicants and were analyzed for gene expression by microarray. Liver samples were grouped by the level of necrosis exhibited in the tissue. Analysis of significantly differentially expressed genes between adjacent necrosis levels revealed that inflammation follows programmed cell death in response to the agents. Using a Random Forest classifier with feature selection, 21 informative genes were identified which achieved 90%, 80% and 60% prediction accuracies of necrosis against independent test data derived from the livers of rats exposed to acetaminophen, carbon tetrachloride, and allyl alcohol, respectively. Pathway and gene network analyses of the genes in the signature revealed several gene interactions suggestive of apoptosis as a process possibly involved in the manifestation of necrosis of the liver from exposure to the hepatotoxicants. Cytotoxic effects of TNF-alpha, as well as transcriptional regulation by JUN and TP53, and apoptosis-related genes possibly lead to necrosis. CONCLUSION: The data analysis, gene selection and prediction approaches permitted grouping of the classes of rat liver samples exhibiting necrosis to improve the accuracy of predicting the level of necrosis as a phenotypic end-point observed from the exposure. The strategy, along with pathway analysis and gene network reconstruction, led to the identification of 1) expression profiles of genes as a signature of necrosis and 2) perturbed regulatory processes that exhibited biological relevance to the manifestation of necrosis from exposure of rat livers to the compendium of hepatotoxicants.

ATM requirement in gene expression responses to ionizing radiation in human lymphoblasts and fibroblasts.

The heritable disorder ataxia telangiectasia (AT) is caused by mutations in the AT-mutated (ATM) gene with manifestations that include predisposition to lymphoproliferative cancers and hypersensitivity to ionizing radiation (IR). We investigated gene expression changes in response to IR in human lymphoblasts and fibroblasts from seven normal and seven AT-affected individuals. Both cell types displayed ATM-dependent gene expression changes after IR, with some responses shared and some responses varying with cell type and dose. Interestingly, after 5 Gy IR, lymphoblasts displayed ATM-independent responses not seen in the fibroblasts at this dose, which likely reflect signaling through ATM-related kinases, e.g., ATR, in the absence of ATM function.

Folate deficiency in normal human fibroblasts leads to altered expression of genes primarily linked to cell signaling, the cytoskeleton and extracellular matrix.

The molecular basis linking folate deficiency to certain health conditions and developmental defects is not fully understood. We examined the consequences of folate deficiency on global gene expression by microarray and compared transcript levels in normal human fibroblast cells (GM03349) grown in folate-deficient and -sufficient medium. The largest represented groups from the selected genes functioned in cell signaling, the cytoskeleton and the extracellular matrix and included the Wnt pathway genes DKK1, WISP1 and WNT5A. Twelve selected genes were further validated by qRT-PCR. Analysis of six genes at 4, 7, 10 and 14 days indicated that the relative differences in transcript levels between folate-sufficient and -deficient cells increases with time. Transcripts for 7 of the 12 selected genes were detected in the human lymphoblast cell line GM02257, and of these, changes in 4 genes corresponded to the results with fibroblast cells. Fibroblast cells were treated with the compounds homocysteine, methotrexate and the MEK1/2 inhibitor U0126, and relative transcript levels of six genes were determined. U0126 caused changes that more closely mimicked those detected in folate-deficient cells. The response of the DKK1 and TAGLN gene promoters to folate deficiency and compounds was examined in NIH3T3 cells using luciferase reporter plasmids. Promoter activity for both genes was decreased by folate deficiency and methotrexate and unaffected by homocysteine. U0126 caused a decrease in DKK1 promoter activity at 50 microM and had no effect on TAGLN promoter activity. These findings suggest an alternative mechanism for how folate deficiency leads to changes in gene expression and altered cell function.

An ATR- and Chk1-dependent S checkpoint inhibits replicon initiation following UVC-induced DNA damage.

Inhibition of replicon initiation is a stereotypic DNA damage response mediated through S checkpoint mechanisms not yet fully understood. Studies were undertaken to elucidate the function of checkpoint proteins in the inhibition of replicon initiation following irradiation with 254 nm UV light (UVC) of diploid human fibroblasts immortalized by the ectopic expression of telomerase. Velocity sedimentation analysis of nascent DNA molecules revealed a 50% inhibition of replicon initiation when normal human fibroblasts were treated with a low dose of UVC (1 J/m(2)). Ataxia telangiectasia (AT), Nijmegen breakage syndrome (NBS), and AT-like disorder fibroblasts, which lack an S checkpoint response when exposed to ionizing radiation, responded normally when exposed to UVC and inhibited replicon initiation. Pretreatment of normal and AT fibroblasts with caffeine or UCN-01, inhibitors of ATR (AT mutated and Rad3 related) and Chk1, respectively, abolished the S checkpoint response to UVC. Moreover, overexpression of kinase-inactive ATR in U2OS cells severely attenuated UVC-induced Chk1 phosphorylation and reversed the UVC-induced inhibition of replicon initiation, as did overexpression of kinase-inactive Chk1. Taken together, these data suggest that the UVC-induced S checkpoint response of inhibition of replicon initiation is mediated by ATR signaling through Chk-1 and is independent of ATM, Nbs1, and Mre11.

Predictors of relapse or maintenance of response in pediatric and adult patients with attention-deficit/hyperactivity disorder following discontinuation of long-term treatment with atomoxetine.

We identified relapse/maintenance-of-response (MOR) predictors following discontinuation of long-term atomoxetine treatment in pediatric and adult patients with attention-deficit/hyperactivity disorder (ADHD) and assessed correlations between ADHD symptoms and quality of life (QoL). Post hoc analyses of data from two randomized, double-blind, placebo-controlled, phase 3 withdrawal studies in patients with ADHD meeting predefined response criteria before randomization. Study 1: patients (N = 163; 6-15 years) received atomoxetine (1.2-1.8 mg/kg/day) for 1 year, followed by randomization to atomoxetine (n = 81) or placebo (n = 82) for 6 months. Study 2: patients (N = 524; 18-50 years) received atomoxetine (80-100 mg/day) for ~6 months, followed by randomization to atomoxetine (n = 266) or placebo (n = 258) for ~6 months. Placebo patients were used for the analyses. Relapse: ≥50% worsening of prerandomization improvement in ADHD symptoms and ≥2 level severity increase on the Clinical Global Impression-Severity (CGI-S) scale at 2 consecutive visits; MOR: retaining ≥75% of prerandomization symptom improvement and CGI-S ≤ 2 at all visits (study 1); retaining ≥70% of prerandomization symptom improvement and CGI-S ≤ 3 at all visits (study 2). In adults, statistically significantly (P ≤ .05) increased likelihood of relapse was associated with prerandomization presence of Conners' Adult Attention-Deficit/Hyperactivity Disorder Rating Scale-Investigator-Rated:Screening Version (CAARS-Inv:SV) items "difficulty awaiting turn" and "careless mistakes." In pediatric patients, less MOR was associated with prerandomization presence of ADHD Rating Scale-IV-Parent Version Investigator-Rated item "does not listen"; in adults, less MOR was associated with prerandomization presence of CAARS-Inv:SV items "loses things" and "difficulty awaiting turn." Changes in patients' QoL after withdrawal from atomoxetine moderately correlated with changes in ADHD symptoms in pediatric patients and mildly in adults.

Phenotypic anchoring of acetaminophen-induced oxidative stress with gene expression profiles in rat liver.

Toxicogenomics provides the ability to examine in greater detail the underlying molecular events that precede and accompany toxicity, thus allowing prediction of adverse events at much earlier times compared to classical toxicological end points. Acetaminophen (APAP) is a pharmaceutical that has similar metabolic and toxic responses in rodents and humans. Recent gene expression profiling studies with APAP found an oxidative stress signature at a subtoxic dose that we hypothesized can be phenotypically anchored to conventional biomarkers of oxidative stress. Liver tissue was obtained from experimental animals used to generate microarray data, where male rats were given APAP at subtoxic (150 mg/kg) or overtly toxic (1500 and 2000 mg/kg) doses and sacrificed at 6, 24, or 48 h. Oxidative stress in liver was evaluated by a diverse panel of markers that included assessing expression of base excision repair (BER) genes, quantifying oxidative lesions in genomic DNA, and evaluating protein and lipid oxidation. A subtoxic dose of APAP produced significant accumulation of nitrotyrosine protein adducts. Both subtoxic and toxic doses caused a significant increase in 8-hydroxy-deoxyguanosine (8-OH-dG) as well as a significant decrease in glutathione (GSH) content. Only toxic doses of APAP significantly induced expression levels of BER genes. None of the doses examined resulted in a significant increase in the number of abasic sites or in the amount of lipid peroxidation. The accumulation of nitrotyrosine and 8-OH-dG adducts along with reduced GSH content in the liver phenotypically anchors the oxidative stress gene expression signature observed with a subtoxic dose of APAP, lending support to the validity of gene expression studies as a sensitive and biologically meaningful end point in toxicology.

Cellular and molecular targets of protein S-glutathiolation.

Oxidative stress and reactive oxygen species play a major role in both normal and pathophysiologic cellular processes. Although many cellular constituents can be damaged by oxidant exposure, cysteine thiol groups are among the most readily oxidized moieties found within cells. To avoid potentially irreversible cysteine thiol oxidation, cells have developed multiple antioxidant defenses to preserve these moieties. Among these defenses, protein S-glutathiolation has emerged as an important mechanism, both in the maintenance of thiol stability during oxidant exposure and as a rapid and efficient mechanism regulating protein activity and cellular metabolic pathways. Here we review the known molecular targets of S-glutathiolation, with emphasis on the varying molecular effects of S-glutathiolation on different proteins.

Validation of the adult attention-deficit/hyperactivity disorder quality-of-life scale in European patients: comparison with patients from the USA.

The adult attention-deficit/hyperactivity disorder (ADHD) quality-of-life (AAQoL) scale was previously validated in adult patients in the USA; here, the AAQoL is validated in adult European patients. Data from a 12-week open-label acute treatment period with atomoxetine (80-100 mg/day) in adults with ADHD were used. Patients (≥ 18 to ≤ 50 years old) had a score ≥ 2 on ≥ 6 items on the inattentive or hyperactive core subscales of Conners' Adult ADHD Rating Scale-Investigator Rated: Screening Version (CAARS-Inv:SV); a CAARS-Inv:SV 18-item total ADHD symptom score ≥ 20; and Conners' Adult ADHD Rating Scale-Observer: Screening Version 6-item inattentive or hyperactive core subscale scores ≥ 2. Data were stratified based on patients' geographic region (Europe vs USA). Scale validation psychometric properties results were very similar between European (n = 1,217; 57.7 % male; mean age 33.0 years) and US (n = 602; 62.1 % male; mean age 33.5 years) patients, including factor loading, internal consistency, convergent and discriminant validity, and responsiveness. Exploratory factor analysis confirmed four AAQoL subscales. Internal consistency was acceptable (Cronbach's alpha > 0.70 for all subscales). The AAQoL total score showed moderate convergent validity with CAARS-Inv:SV 18-item total ADHD symptom and clinical global impression-ADHD-severity (CGI-ADHD-S) scores; and strong convergent validity with Behavior Rating Inventory of Executive Function-Adult Version: Self-Report Global-Executive-Composite Index scores. Mean AAQoL total scores were significantly different among patients grouped by CGI-ADHD-S scores, suggesting good discriminant validity. The AAQoL total and subscale scores presented good responsiveness from baseline to 12 weeks. The AAQoL scale shows comparable validity in European and US adults with ADHD.

ATM-dependent and -independent gene expression changes in response to oxidative stress, gamma irradiation, and UV irradiation.

Ataxia telangiectasia (AT) is an autosomal recessive disorder characterized by progressive cerebellar degeneration, immunodeficiencies, telangiectasias, sensitivity to ionizing radiation, and high predisposition for malignancies. The ataxia telangiectasia mutated (ATM) gene encodes a protein (ATM) with serine/threonine kinase activity. DNA-double strand breaks are known to increase its kinase activity. While cells from individuals with AT are attenuated in their G(1)-, S- and G(2)-phase cell cycle checkpoint functions in response to gamma irradiation and oxidative stress, their response to UV irradiation appears to be equivalent to that of wild-type cells. In this study, we investigated changes in gene expression in response to gamma irradiation, oxidative stress, and UV irradiation, focusing on the dependence on ATM. Doses for all three treatments were selected that resulted in roughly an equivalent induction of a G(1) checkpoint response and inhibition of progression through S phase. To investigate gene expression changes, logarithmically growing wild-type and AT dermal diploid fibroblasts were exposed to either gamma radiation (5 Gy), oxidative stress (75 micro M t-butyl-hydroperoxide), or UV radiation (7.5 J/m(2)), and RNA was harvested 6 h after treatment. Gene expression analysis was performed using the NIEHS Human ToxChip 2.0 with approximately 1900 cDNA clones representing known genes and ESTs. All three treatments resulted in distinct patterns of gene expression changes, as shown previously. ATM-dependent and ATM-independent components were detected within these patterns, as were novel indications of involvement of ATM in regulation of transcription factors such as SP1, AP1 and MTF1.

Gene expression profiling of rat livers reveals indicators of potential adverse effects.

This study tested the hypothesis that gene expression profiling can reveal indicators of subtle injury to the liver induced by a low dose of a substance that does not cause overt toxicity as defined by conventional criteria of toxicology (e.g., abnormal clinical chemistry and histopathology). For the purpose of this study we defined this low dose as subtoxic, i.e., a dose that elicits effects which are below the detection of conventional toxicological parameters. Acetaminophen (APAP) was selected as a model hepatotoxicant because (1) considerable information exists concerning the mechanism of APAP hepatotoxicity that can occur following high doses, (2) intoxication with APAP is the leading cause of emergency room visits involving acute liver failure within the United States, and (3) conventional clinical markers have poor predictive value. Rats treated with a single dose of 0, 50, 150, or 1500 mg/kg APAP were examined at 6, 24, or 48 h after exposure for conventional toxicological parameters and for gene expression alterations. Patterns of gene expression were found which indicated cellular energy loss as a consequence of APAP toxicity. Elements of these patterns were apparent even after exposure to subtoxic doses. With increasing dose, the magnitude of changes increased and additional members of the same biological pathways were differentially expressed. The energy loss suggested by gene expression changes was confirmed at the 1500 mg/kg dose exposure by measuring ATP levels. Only by ultrastructural examination could any indication of toxicity be identified after exposure to a subtoxic dose of APAP and that was occasional mitochondrial damage. In conclusion, this study provides evidence that supports the hypothesis that gene expression profiling may be a sensitive means of identifying indicators of potential adverse effects in the absence of the occurrence of overt toxicity.

Validity of conners' adult attention-deficit/hyperactivity disorder rating Scale-investigator rated: screening version in patients from within and outside of Europe.

In adult patients with attention-deficit/hyperactivity disorder from within and outside of Europe, Conners' Adult Attention-Deficit/Hyperactivity Disorder (ADHD) Rating Scale-Investigator Rated: Screening Version showed good internal consistency (Cronbach's α=0.930 and 0.938, respectively) and convergent validity with the Clinical (Pearson's correlation coefficients: 0.65-0.82, P<0.001) Global Impression-ADHD-Severity scale over 12 weeks of pharmacological treatment.

Association of common variations in the norepinephrine transporter gene with response to olanzapine-fluoxetine combination versus continued-fluoxetine treatment in patients with treatment-resistant depression: a candidate gene analysis.

OBJECTIVE: To determine whether single-nucleotide polymorphisms (SNPs) in candidate genes are associated with response to olanzapine-fluoxetine combination. METHOD: A post hoc analysis of a priori-selected SNPs used data from a clinical trial (dates: April 2002-July 2005) of olanzapine-fluoxetine combination, fluoxetine, and olanzapine in patients with major depressive disorder (DSM-IV criteria) and with nonresponse to prestudy antidepressant treatment and nonresponse to fluoxetine treatment during the study. Patients received open-label treatment with fluoxetine for 8 weeks (2 weeks, 25 mg/d; then 6 weeks, 50 mg/d), at the end of which nonresponders (< 25% decline in the 17-item Hamilton Depression Rating Scale score) were randomized to receive double-blind, monotherapy treatment with olanzapine-fluoxetine combination (6/50-18/50 mg/d, n = 71), fluoxetine (50 mg/d, n = 78), or olanzapine (6-18 mg/d, n = 56) for 8 weeks. Statistical significance was assessed at P < .05. The primary efficacy measure for within-study treatment was improvement on the Montgomery-Asberg Depression Rating Scale (MADRS). RESULTS: Rs36024, an intronic SNP in the norepinephrine transporter (SLC6A2), as well as 3 SNPs in melanocortin 3 receptor (MC3R) and 2 SNPs in tryptophan hydroxylase 2 (TPH2), were associated with MADRS-defined response to treatment with olanzapine-fluoxetine combination (adjusted Li-Nyholt P < .05). Except for 1 SNP in TPH2, identified SNPs were not significantly associated with response to continued-fluoxetine or olanzapine treatments. CONCLUSIONS: Our findings further support the hypothesis that the synergistic effect of olanzapine and fluoxetine on prefrontal cortical levels of norepinephrine and dopamine might be an underlying mechanism for the efficacy of olanzapine-fluoxetine combination in the treatment of treatment-resistant depression and, if replicated, may form a basis on which response to olanzapine-fluoxetine combination versus continued fluoxetine can be predicted based on variants in SLC6A2. TRIAL REGISTRATION: Parent study registered at ClinicalTrials.gov identifier: NCT00035321.

Review of Efficacy and Safety of Duloxetine 40 to 60 mg Once Daily in Patients with Diabetic Peripheral Neuropathic Pain.

We summarize efficacy and safety findings from 4 double-blind, placebo-controlled, 12-week studies and 1 open-label, uncontrolled, 34-week maintenance-of-effect (MOE) study that examine duloxetine 40 and 60 mg once daily (QD) in patients with diabetic peripheral neuropathic pain (DPNP). In all placebo-controlled studies, duloxetine showed significantly (P ≤ .01) greater reduction in pain severity (weekly mean of 24-hour average pain severity ratings, primary outcome measure) compared with placebo. In all placebo-controlled studies, duloxetine showed significantly (P ≤ .05) greater improvement on brief pain inventory-Interference ratings. Patient global impression of improvement ratings were superior to placebo (P ≤ .01) for duloxetine patients in all placebo-controlled studies. Response rates (based on 30% pain reduction) ranged from 57% to 68% for duloxetine and from 35% to 47% for placebo and were statistically significantly different (P ≤ .01) between treatment groups in 3 out of 4 studies. The open-label study showed maintenance of analgesic effect of duloxetine in DPNP. In the duloxetine groups, 4.3% to 14.9% of patients discontinued because of adverse events (placebo groups: 2.6% to 7.4%). Most commonly reported treatment-emergent adverse events were nausea, somnolence, and headache. Duloxetine 40 and 60 mg QD was efficacious and well tolerated in the management of DPNP.

Evaluation of genetic models for response in a randomized clinical trial of duloxetine in major depressive disorder.

In self-identified white patients with major depressive disorder (N=126) treated with open-label duloxetine (60-120 mg/d), a significant association of (P=0.020) of a composite risk score (based on SLC6A2 rs5569 [G1287A] AA, HTR1A rs6295 [C(-1019)G] GG, and COMT rs174697 AA/AG) with 17-item Hamilton Depression Rating Scale total score change from baseline to 12 weeks was observed.

Early improvement in pain predicts pain response at endpoint in patients with fibromyalgia.

UNLABELLED: An unanswered, but clinically important question is whether there are early indicators that a patient might respond to duloxetine treatment for fibromyalgia pain. To address this question, pooled data from 4 double-blind, placebo-controlled trials in duloxetine-treated patients (N = 797) with primary fibromyalgia as defined by the American College for Rheumatology were analyzed. Classification and Regression Tree (CART) analysis was used to determine what level of early pain improvement as measured by the 24-hour average pain severity question on the Brief Pain Inventory (BPI) best predicted later response. The predictor variables tested were 10, 15, 20, 25, and 30% decrease in BPI 24-hour average pain from baseline to Week 1 and Week 2. The results of the CART analysis showed that for patients with ≥15% improvement in pain at Week 1 and ≥30% improvement at Week 2, the probability of response at 3 months was 75%. For patients with <15% improvement at both Week 1 and Week 2, the probability of not responding at 3 months was 86%. Quantifiable early improvement in pain during the first 2 weeks of treatment with duloxetine was highly predictive of response or nonresponse after 3 months of treatment. PERSPECTIVE: This article presents early indicators that can highly predict later pain response or nonresponse in fibromyalgia patients treated with duloxetine. The results may aid clinicians to predict the likelihood of response at 3 months within the first 2 weeks of treatment.

The association of single nucleotide polymorphisms in the catechol-O-methyltransferase gene and pain scores in female patients with major depressive disorder.

UNLABELLED: We tested the hypothesis that single nucleotide polymorphisms (SNPs) in the catechol-O-methyltransferase (COMT) gene are associated with baseline pain levels in patients with major depressive disorder (MDD). Pain levels were quantified using a visual analog scale (VAS) for pain. Data from 159 female and 93 male self-reported white patients with MDD were analyzed. The associations between a haplotype previously associated with pain sensitivity created using COMT SNPs rs6269, rs4633, rs4818, and rs4680, and the proportion of female patients with "Pain While Awake" and "Overall Pain" at baseline were statistically significant (P < .05). In male patients, no statistically significant associations between COMT haplotypes and baseline pain scores were seen. The rs165599 SNP, which has previously been associated with response of depressive symptoms to treatment in patients with MDD, did not impact baseline pain in either gender. In conclusion, baseline pain levels appear to be associated with the COMT pain sensitivity haplotype in female patients with MDD. PERSPECTIVE: This article presents associations of the COMT pain sensitivity haplotype and baseline pain levels in female patients with MDD. This finding could potentially help clinicians who seek to assess how genetic polymorphisms may contribute to a patient's pain experience.

Therapeutic options for treatment-resistant depression.

Treatment-resistant depression (TRD) presents major challenges for both patients and clinicians. There is no universally accepted definition of TRD, but results from the US National Institute of Mental Health's (NIMH) STAR*D (Sequenced Treatment Alternatives to Relieve Depression) programme indicate that after the failure of two treatment trials, the chances of remission decrease significantly. Several pharmacological and nonpharmacological treatments for TRD may be considered when optimized (adequate dose and duration) therapy has not produced a successful outcome and a patient is classified as resistant to treatment. Nonpharmacological strategies include psychotherapy (often in conjunction with pharmacotherapy), electroconvulsive therapy and vagus nerve stimulation. The US FDA recently approved vagus nerve stimulation as adjunctive therapy (after four prior treatment failures); however, its benefits are seen only after prolonged (up to 1 year) use. Other nonpharmacological options, such as repetitive transcranial stimulation, deep brain stimulation or psychosurgery, remain experimental and are not widely available. Pharmacological treatments of TRD can be grouped in two main categories: 'switching' or 'combining'. In the first, treatment is switched within and between classes of compounds. The benefits of switching include avoidance of polypharmacy, a narrower range of treatment-emergent adverse events and lower costs. An inherent disadvantage of any switching strategy is that partial treatment responses resulting from the initial treatment might be lost by its discontinuation in favour of another medication trial. Monotherapy switches have also been shown to have limited effectiveness in achieving remission. The advantage of combination strategies is the potential to build upon achieved improvements; they are generally recommended if partial response was achieved with the current treatment trial. Various non-antidepressant augmenting agents, such as lithium and thyroid hormones, are well studied, although not commonly used. There is also evidence of efficacy and increasing use of atypical antipsychotics in combination with antidepressants, for example, olanzapine in combination with fluoxetine (OFC) or augmentation with aripiprazole. The disadvantages of a combination strategy include multiple medications, a broader range of treatment-emergent adverse events and higher costs. Several experimental pharmaceutical treatment alternatives for TRD are also being explored in combination with antidepressants or as monotherapy. These less studied alternative compounds include pindolol, inositol, CNS stimulants, hormones, herbal supplements, omega-3 fatty acids, S-adenosyl-L-methionine, folic acid, lamotrigine, modafinil, riluzole and topiramate. In summary, despite an increasing variety of choices for the treatment of TRD, this condition remains universally undefined and represents an area of unmet medical need. There are few known approved pharmacological agents for TRD (aripiprazole and OFC) and overall outcomes remain poor. This might be an indication that depression itself is a heterogeneous condition with a great diversity of pathologies, highlighting the need for careful evaluation of individuals with depressive symptoms who are unresponsive to treatment. Clearly, more research is needed to provide clinicians with better guidance in making those treatment decisions--especially in light of accumulating evidence that the longer patients are unsuccessfully treated, the worse their long-term prognosis tends to be.