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Chronic inflammation has been implicated in the pathophysiology of major depressive disorder (MDD). Activating the resolution of inflammation through ω-3 fatty acid supplementation may prove to be a successful therapeutic strategy for the treatment of MDD. Patients with MDD, body mass index >25 kg/m2, and plasma high-sensitivity C-reactive protein ≥3 μg/mL (n = 61) were enrolled in a 12-week randomized trial consisting of 4 parallel arms: EPA 1, 2, and 4 g/d, and placebo. The supplement contained EPA and DHA in a 3.9:1 ratio. Depression symptoms were assessed using the IDS-C30 scale. Plasma fatty acids and pro-resolving lipid mediators (SPMs) were measured in 42 study completers at baseline and at the end of treatment by liquid chromatography/mass spectrometry. The response rate (≥50% reduction in IDS-30 score) was higher in the 4 g/d EPA arm than placebo (Cohen d = 0.53). In the 4 g/d EPA arm, responders had significantly greater increases in 18-hydroxyeicosapentaenoic acid (18-HEPE) and 13-hydroxydocosahexaenoic acid (13-HDHA) than non-responders (p p p

Individuals experiencing socioeconomic deprivation consistently demonstrate poorer physical and mental health. Income alone is inadequate as a measure of socioeconomic status (SES); a better measure for assessing the deprivation status of individuals is needed.The New Zealand Index of Socioeconomic Deprivation for Individuals, a validated, eight-item measure of deprivation, was modified to create the United States Index of Socioeconomic Deprivation for Individuals (USiDep). The questionnaire was administered to patients with major depressive disorder participating in two clinical trials. Spearman's correlation coefficients evaluated associations between USiDep scores with income and other measures associated with deprivation.The USiDep was completed by 118 participants, demonstrating adequate internal consistency (Crohnbach's alpha = 0.766) and strong item-total correlations. USiDep scores were moderately correlated with past-year personal income (Spearman's rho = -0.362, p.001) and several other measures related to deprivation, including body mass index, level of education, quality of life, severity of childhood traumatic events, self-reported physical health, and negative life events. Patients scoring 5 on the USiDep (the highest possible score, indicating greater deprivation) had significantly lower rates of remission after 12 weeks of treatment than those scoring ≤ 4 (1/12, 8.3% vs 40/98, 40.8%, respectively, p = .03), whereas the lowest income group showed no significant associations with outcomes.The USiDep is a valid, brief questionnaire for assessing SES that has utility for clinical research and may serve as a predictor of treatment outcomes in clinical trials. Validation of the USiDep in healthy controls and other medically and psychiatrically ill populations is warranted.

Introduction: Activation of the locus coeruleus-noradrenergic (LC-NA) system during awakening is associated with an increase in plasma corticosterone and cardiovascular tone. These studies evaluate the role of the LC in this corticosterone and cardiovascular response. Methods: Male rats, on day 0, were treated intraperitoneally with either DSP4 (50 mg/kg body weight) (DSP), an LC-NA specific neurotoxin, or normal saline (SAL). On day 10, animals were surgically prepared with jugular vein (hypothalamic-pituitary-adrenal [HPA] axis) or carotid artery (hemodynamics) catheters and experiments performed on day 14. HPA axis activity, diurnally (circadian) and after stress (transient hemorrhage [14 mL/kg body weight] or air puff-startle), and basal and post-hemorrhage hemodynamics were evaluated. On day 16, brain regions from a subset of rats were dissected for norepinephrine and corticotropin-releasing factor (CRF) assay. Results: In DSP rats compared to SAL rats, (1) regional brain norepinephrine was decreased, but there was no change in median eminence or olfactory bulb CRF content; (2) during HPA axis acrophase, the plasma corticosterone response was blunted; (3) after hemorrhage and air puff-startle, the plasma adrenocorticotropic hormone response was attenuated, whereas the corticosterone response was dependent on stressor category; (4) under basal conditions, hemodynamic measures exhibited altered blood flow dynamics and systemic vasodilation; and (5) after hemorrhage, hemodynamics exhibited asynchronous responses. Conclusion: LC-NA modulation of diurnal and stress-induced HPA axis reactivity occurs via distinct neurocircuits. The integrity of the LC-NA system is important to maintain blood flow dynamics. The importance of increases in plasma corticosterone at acrophase to maintain short- and long-term cardiovascular homeostasis is discussed.

Schizophrenia is a common, chronic and debilitating neuropsychiatric syndrome affecting tens of millions of individuals worldwide. While rare genetic variants play a role in the etiology of schizophrenia, most of the currently explained liability is within common variation, suggesting that variation predating the human diaspora out of Africa harbors a large fraction of the common variant attributable heritability. However, common variant association studies in schizophrenia have concentrated mainly on cohorts of European descent. We describe genome-wide association studies of 6152 cases and 3918 controls of admixed African ancestry, and of 1234 cases and 3090 controls of Latino ancestry, representing the largest such study in these populations to date. Combining results from the samples with African ancestry with summary statistics from the Psychiatric Genomics Consortium (PGC) study of schizophrenia yielded seven newly genome-wide significant loci, and we identified an additional eight loci by incorporating the results from samples with Latino ancestry. Leveraging population differences in patterns of linkage disequilibrium, we achieve improved fine-mapping resolution at 22 previously reported and 4 newly significant loci. Polygenic risk score profiling revealed improved prediction based on trans-ancestry meta-analysis results for admixed African (Nagelkerke’s R2 = 0.032; liability R2 = 0.017; P −52), Latino (Nagelkerke’s R2 = 0.089; liability R2 = 0.021; P −58), and European individuals (Nagelkerke’s R2 = 0.089; liability R2 = 0.037; P −113), further highlighting the advantages of incorporating data from diverse human populations.

Lasting effects of adversity, such as exposure to childhood adversity (CA) on disease risk, may be embedded via epigenetic mechanisms but findings from human studies investigating the main effects of such exposure on epigenetic measures, including DNA methylation (DNAm), are inconsistent. Studies in perinatal tissues indicate that variability of DNAm at birth is best explained by the joint effects of genotype and prenatal environment. Here, we extend these analyses to postnatal stressors. We investigated the contribution of CA, cis genotype (G), and their additive (G + CA) and interactive (G × CA) effects to DNAm variability in blood or saliva from five independent cohorts with a total sample size of 1074 ranging in age from childhood to late adulthood. Of these, 541 were exposed to CA, which was assessed retrospectively using self-reports or verified through social services and registries. For the majority of sites (over 50%) in the adult cohorts, variability in DNAm was best explained by G + CA or G × CA but almost never by CA alone. Across ages and tissues, 1672 DNAm sites showed consistency of the best model in all five cohorts, with G × CA interactions explaining most variance. The consistent G × CA sites mapped to genes enriched in brain-specific transcripts and Gene Ontology terms related to development and synaptic function. Interaction of CA with genotypes showed the strongest contribution to DNAm variability, with stable effects across cohorts in functionally relevant genes. This underscores the importance of including genotype in studies investigating the impact of environmental factors on epigenetic marks.

OBJECTIVES: The immunomodulatory effects of eicosapentaenoic acid (EPA) support it as an effective treatment for major depressive disorder (MDD) associated with chronic inflammation. Increased production of specialized pro-resolving mediators (SPM) during EPA supplementation may help reduce inflammation. We compared the effects of different EPA doses on plasma fatty acids and SPM in MDD patients. METHODS: MDD patients with baseline inflammation (N = 61, IDS-C score >25; BMI > 25 kg/m2; serum CRP > 3 mg/L) were enrolled in a 2-site, 12-wk randomized trial comparing EPA 1, 2 and 4 g/d to placebo (soybean oil). Plasma fatty acids (mol%) and SPM (pg/mL) were measured at baseline and 12 wks (n = 8 [10], 12 [11], 11 and 10 in the placebo, EPA 1, 2 and 4 g/d arms, respectively). Dose effects were tested using the Kruskal-Wallis followed by pairwise Wilcoxon rank-sum tests with Benjamini-Hochberg correction. RESULTS: In the placebo arm, plasma EPA and EPA derivatives did not change at 12 wks, relative to baseline. EPA supplementation significantly increased plasma EPA dose-dependently (3-, 3- and 9-fold in the 1, 2 and 4 g/d arms). Similar significant dose-dependent increases in EPA derivatives were observed in the EPA arms, including 18-hydroxy-EPA (18-HEPE, 8-, 7- and 14-fold) and 15-HEPE (4-, 6- and 10-fold). The increase in 18-HEPE, a precursor of EPA-series resolvins (RvE), by 4 g/d EPA was significantly greater than with lower doses. While RvE1 remained undetected in all treatment arms, RvE2 was detected in some subjects at baseline and 12 wks with a dose-dependent median increase (+3, +6 and +8 pg/mL). RvE3, undetectable at baseline, became detectable in more subjects dose-dependently (n = 1, 2, 3 and 6). The reduction in plasma arachidonic acid (AA) by EPA supplementation significantly differed from placebo only at 2 and 4 g/d but not between the two doses. AA derivatives were not affected, except for the pro-resolving lipoxin B4, which was rarely detected at baseline, but became detectable in most subjects after EPA supplementation (median: 46, 59 and 94 pg/mL). CONCLUSIONS: Our results show a robust dose-effect of EPA in increasing plasma EPA and EPA-derived 18-HEPE, which may result in improved conversion to RvE2 and RvE3. Its associations with reduced inflammation and improved IDS-C scores will be further analyzed. FUNDING SOURCES: NCCIH.

This article reviews the current state of knowledge of the role of massage therapy in the treatment of common psychiatric disorders and symptoms. It briefly discusses the prevalence of psychiatric disorders and the popularity of complementary and integrative treatments in the general population. The authors touch on the growing literature describing the biology and neurobiology of massage therapy. The impact of massage as both a therapy for major psychiatric disorders and a treatment for psychiatric symptoms is reviewed, and how massage therapists conceptualize and treat their patients with psychiatric complaints is discussed. If psychiatrists are going to partner with massage therapists, they need to understand how massage therapists' perspectives differ from those of traditional practitioners of allopathic medicine. A model of how psychiatrists and other mental health professionals can work with massage therapists to care for patients is proposed, followed by a summary of the article's key points.

BACKGROUND Cancer-related fatigue (CRF) is a prevalent and debilitating symptom experienced by cancer survivors, yet treatment options for CRF are limited. In this study, we evaluated the efficacy of weekly Swedish massage therapy (SMT) versus an active control condition (light touch [LT]) and waitlist control (WLC) on persistent CRF in breast cancer survivors. METHODS This early phase, randomized, single-masked, 6-week investigation of SMT, LT, and WLC enrolled 66 female stage 0-III breast cancer survivors (age range, 32-72 years) who had received surgery plus radiation and/or chemotherapy/chemoprevention with CRF (Brief Fatigue Inventory > 25). The primary outcome was the Multidimensional Fatigue Inventory (MFI), with the National Institutes of Health PROMIS Fatigue scale secondary. RESULTS Mean baseline MFI scores for 57 evaluable subjects were 62.95 for SMT, 55.00 for LT, and 60.41 for WLC. SMT resulted in a mean (standard deviation) 6-week reduction in MFI total scores of −16.50 (6.37) (n = 20) versus −8.06 (6.50) for LT (n = 20) and an increase of 5.88 (6.48) points for WLC (n = 17) (treatment-by-time P

The Predictors of Remission in Depression to Individual and Combined Treatments [PReDICT] study aimed to identify clinical and biological factors predictive of treatment outcomes in major depressive disorder among treatment-naive adults. The authors evaluated the efficacy of cognitive-behavioral therapy (CBT) and two antidepressant medications (escitalopram and duloxetine) in patients with major depression and examined the moderating effect of patients' treatment preferences on outcomes.Adults aged 18-65 with treatment-naive major depression were randomly assigned with equal likelihood to 12 weeks of treatment with escitalopram (10-20 mg/day), duloxetine (30-60 mg/day), or CBT (16 50-minute sessions). Prior to randomization, patients indicated whether they preferred medication or CBT or had no preference. The primary outcome was change in the 17-item Hamilton Depression Rating Scale (HAM-D), administered by raters blinded to treatment.A total of 344 patients were randomly assigned, with a mean baseline HAM-D score of 19.8 (SD=3.8). The mean estimated overall decreases in HAM-D score did not significantly differ between treatments (CBT: 10.2, escitalopram: 11.1, duloxetine: 11.2). Last observation carried forward remission rates did not significantly differ between treatments (CBT: 41.9%, escitalopram: 46.7%, duloxetine: 54.7%). Patients matched to their preferred treatment were more likely to complete the trial but not more likely to achieve remission.Treatment guidelines that recommend either an evidence-based psychotherapy or antidepressant medication for nonpsychotic major depression can be extended to treatment-naive patients. Treatment preferences among patients without prior treatment exposure do not significantly moderate symptomatic outcomes.

The purpose of this article was to inform the first-line treatment choice between cognitive-behavioral therapy (CBT) or an antidepressant medication for treatment-naive adults with major depressive disorder by defining a neuroimaging biomarker that differentially identifies the outcomes of remission and treatment failure to these interventions.Functional MRI resting-state functional connectivity analyses using a bilateral subcallosal cingulate cortex (SCC) seed was applied to 122 patients from the Prediction of Remission to Individual and Combined Treatments (PReDICT) study who completed 12 weeks of randomized treatment with CBT or antidepressant medication. Of the 122 participants, 58 achieved remission (Hamilton Depression Rating Scale [HAM-D] score ≤7 at weeks 10 and 12), and 24 had treatment failure (30% decrease from baseline in HAM-D score). A 2×2 analysis of variance using voxel-wise subsampling permutation tests compared the interaction of treatment and outcome. Receiver operating characteristic curves constructed using brain connectivity measures were used to determine possible classification rates for differential treatment outcomes.The resting-state functional connectivity of the following three regions with the SCC was differentially associated with outcomes of remission and treatment failure to CBT and antidepressant medication and survived application of the subsample permutation tests: the left anterior ventrolateral prefrontal cortex/insula, the dorsal midbrain, and the left ventromedial prefrontal cortex. Using the summed SCC functional connectivity scores for these three regions, overall classification rates of 72%-78% for remission and 75%-89% for treatment failure was demonstrated. Positive summed functional connectivity was associated with remission with CBT and treatment failure with medication, whereas negative summed functional connectivity scores were associated with remission to medication and treatment failure with CBT.Imaging-based depression subtypes defined using resting-state functional connectivity differentially identified an individual's probability of remission or treatment failure with first-line treatment options for major depression. This biomarker should be explored in future research through prospective testing and as a component of multivariate treatment prediction models.

In 2008, the NIH launched an undiagnosed diseases program to investigate difficult to diagnose, and typically, multi-system diseases. The objective of this study was to evaluate the presence of psychiatric symptoms or psychiatric diagnoses in a cohort of patients seeking care at the Emory Special Diagnostic Service clinic. We hypothesized that psychiatric symptoms would be prevalent and associated with trauma exposure, and a decreased quality of life and functioning. This is a cross-sectional, retrospective analysis of 247 patients seen between February 7, 2014 and May 31, 2017. The sources for data included the Emory Health History Questionnaire (HHQ) that had the work and social adjustment and quality of life enjoyment and satisfaction questionnaire–short form (QLSQ) embedded in it; medical records, and the comprehensive standardized special diagnostic clinic forms. Primary outcomes were presence of any psychiatric symptom, based on report of the symptom on the HHQ or medical record, or presence of a confirmed preexisting psychiatric disorder. Seventy-two percent of patients had at least one psychiatric symptom while 24.3% of patients had a pre-existing psychiatric diagnosis. Patients with any psychiatric symptom had significantly diminished Q-LES-Q scores (45.27 ± 18.63) versus patients with no psychiatric symptoms (62.01 ± 21.57, t = 5.60, df = 225, p

Acute treatment of Generalized Anxiety Disorder often requires 3 months or more of care in order to optimize response. As part of an exploratory grant we have previously demonstrated that six weeks of twice-weekly Swedish Massage Therapy (SMT) was more effective than an active control in decreasing Hamilton Anxiety Rating Scale Scores (HAM-A). An additional goal of this project was to determine if an additional six weeks of twice-weekly SMT led to greater clinical and statistical benefit. We found that HAM-A scores did continue to decrease with an additional six weeks of therapy but that the greatest benefit occurred during the first versus the second 12 sessions (-9.91 vs.-3.09, t = 2.21; df = 10; p = 0.052). These preliminary findings suggest that the majority of benefit in symptom reduction occurs in the first six weeks and that six weeks of twice-weekly SMT may be sufficient for the majority of patients.

Background Eicosapentaenoic acid (EPA) supplementation is an effective treatment option in major depressive disorder (MDD) associated with chronic low-grade inflammation. EPA is the precursor of specialized pro-resolving lipid mediators (SPMs) termed resolvins (Rv), that serve important roles in the resolution of inflammation. The objective of this study was to assess the effects of different doses of EPA on plasma concentrations of EPA metabolites and SPMs in MDD patients. Methods In a 2-site study, 61 MDD patients with body mass index >25 kg/m2 and serum high-sensitivity C-reactive protein ≥3 μg/mL were enrolled in a 12-week randomized trial comparing EPA 1, 2, and 4 g/d to placebo. Plasma EPA (mol%) and SPMs (pg/mL) were measured in 42 study completers at baseline and at the end of treatment by liquid chromatography/mass spectrometry. Results Plasma EPA and SPM concentrations did not change in the placebo group during 12 weeks of treatment. Plasma EPA and EPA-derived metabolites increased significantly and dose-dependently in all EPA supplementation arms. The increase in 18-hydroxyeicosapentaenoic acid (18-HEPE), the precursor of RvE1–3, was significantly greater with the 4 g/d EPA dose than the other doses from week 4 to 12. RvE1 was undetected in all treatment groups, while RvE2 was detected in half of the subjects both at baseline and after treatment, with dose-dependent increases. RvE3 was detected only after supplementation, dose-dependently. A significant reduction in plasma arachidonic acid (AA), relative to baseline, was observed in all EPA arms. This was in contrast with an increase in AA-derived SPM lipoxin B4 (LXB4) in the 4 g/d arm. Conclusions Our results show a robust effect of EPA 4 g/d supplementation in increasing plasma EPA and 18-HEPE levels, associated with improved conversion to RvE2–3, and LXB4 levels.

OBJECTIVE Generalized anxiety disorder (GAD) is a prevalent and costly disorder for which many patients may prefer nontraditional treatment. A proof-of-concept study of was conducted to evaluate the acute effects of Swedish massage therapy (SMT) as a monotherapy for the treatment of subjects with GAD. METHODS A randomized, single-masked, clinical trial was conducted between March 2012 and May 2013 at the Mood and Anxiety Disorders Program of Emory University. Forty-seven currently untreated subjects with a DSM-IV diagnosis of GAD were randomly assigned to twice-weekly SMT versus a light touch control condition for 6 weeks. The primary outcome measure was reduction in Hamilton Anxiety Rating Scale (HARS) scores after 6 weeks of treatment for SMT versus light touch, as determined by mixed model repeated-measures analysis of 40 evaluable subjects. RESULTS Mean HARS baseline scores were 20.05 (SD = 3.34) for SMT and 19.58 (SD = 4.90) for light touch. At week 6, the difference in mean (standard error of the mean [SEM]) HARS score reduction was 3.26 points (SMT: -11.67 [1.09]; light touch: -8.41 [1.01]; t₁₀₆ = -2.19; P = .030; effect size = -0.69). Treatment group differences were significant (P < .05) starting at the end of week 3. CONCLUSION This first monotherapy trial suggests that a complementary and alternative manual therapy, SMT, is an effective acute treatment for GAD. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT01337713.

Background Irritability is a adverse effect of many antiseizure medications (ASMs), but there are no validated measures currently available to characterize this behavioral risk. We examined both child and parent/guardian versions of the Affective Reactivity Index (ARI), a validated measure developed for application in adolescent psychiatry, to determine its sensitivity to ASM-related irritability. We hypothesized irritability increases associated with levetiracetam (LEV) but not lamotrigine (LTG) or oxcarbazepine (OXC). Method The ARI was administered to 71 child and parent/guardian pairs randomized to one of three common ASMs (LEV, LTG, OXC) used to treat new-onset focal (localization-related) epilepsy. Subjects were recruited as part of a prospective multicenter, randomized, open-label, parallel group design. The ARI was administered at baseline prior to treatment initiation and again at 3 months after ASM initiation. Results There was a significant increase in ARI ratings for both child and parent/guardian ratings for LEV but not LTG or OXC when assessed 3 months after treatment initiation. When examined on the individual subject level using a criterion of at least a 3-point ARI increase, there was an increase associated with LEV for child ratings but not parent/guardian scores. Conclusion Both child and parent/guardian versions of the ARI appear sensitive to medication-induced irritability associated with LEV on both the group and individual levels. The findings extend the applicability of ARI from characterizing the presence of clinical irritability as a psychiatric diagnostic feature to a more modifiable aspect of behavior change related to medication management and support its use in clinical trial applications.

This study explores whether inflammatory biomarkers act as moderators of clinical response to omega-3 (n-3) fatty acids in subjects with major depressive disorder (MDD). One hundred fifty-five subjects with Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) MDD, a baseline 17-item Hamilton Depression Rating Scale (HAM-D-17) score ⩾ 15 and baseline biomarker data (interleukin (IL)-1ra, IL-6, high-sensitivity C-reactive protein (hs-CRP), leptin and adiponectin) were randomized between 18 May 2006 and 30 June 2011 to 8 weeks of double-blind treatment with eicosapentaenoic acid (EPA)-enriched n-3 1060 mg day(-1), docosahexaenoic acid (DHA)-enriched n-3 900 mg day(-1) or placebo. Outcomes were determined using mixed model repeated measures analysis for 'high' and 'low' inflammation groups based on individual and combined biomarkers. Results are presented in terms of standardized treatment effect size (ES) for change in HAM-D-17 from baseline to treatment week 8. Although overall treatment group differences were negligible (ES=-0.13 to +0.04), subjects with any 'high' inflammation improved more on EPA than placebo (ES=-0.39) or DHA (ES=-0.60) and less on DHA than placebo (ES=+0.21); furthermore, EPA-placebo separation increased with increasing numbers of markers of high inflammation. Subjects randomized to EPA with 'high' IL-1ra or hs-CRP or low adiponectin ('high' inflammation) had medium ES decreases in HAM-D-17 scores vs subjects 'low' on these biomarkers. Subjects with 'high' hs-CRP, IL-6 or leptin were less placebo-responsive than subjects with low levels of these biomarkers (medium to large ES differences). Employing multiple markers of inflammation facilitated identification of a more homogeneous cohort of subjects with MDD responding to EPA vs placebo in our cohort. Studies are needed to replicate and extend this proof-of-concept work.

Background Medication and psychotherapy treatments for posttraumatic stress disorder (PTSD) provide insufficient benefit for many patients. Substantial preclinical and clinical data indicate abnormalities in the hypothalamic-pituitary-adrenal axis, including signaling by corticotropin-releasing factor, in the pathophysiology of PTSD. Methods We conducted a double-blind, placebo-controlled, randomized, fixed-dose clinical trial evaluating the efficacy of GSK561679, a corticotropin-releasing factor receptor 1 (CRF 1 receptor) antagonist in adult women with PTSD. The trial randomized 128 participants, of whom 96 completed the 6-week treatment period. Results In both the intent-to-treat and completer samples, GSK561679 failed to show superiority over placebo on the primary outcome of change in Clinician-Administered PTSD Scale total score. Adverse event frequencies did not significantly differ between GSK561679- and placebo-treated subjects. Exploration of the CRF 1 receptor single nucleotide polymorphism rs110402 found that response to GSK561679 and placebo did not significantly differ by genotype alone. However, subjects who had experienced a moderate or severe history of childhood abuse and who were also GG homozygotes for rs110402 showed significant improvement after treatment with GSK561679 ( n = 6) but not with placebo ( n = 7) on the PTSD Symptom Scale–Self-Report. Conclusions The results of this trial, the first evaluating a CRF 1 receptor antagonist for the treatment of PTSD, combined with other negative trials of CRF 1 receptor antagonists for major depressive disorder, generalized anxiety disorder, and social anxiety disorder, suggest that CRF 1 receptor antagonists lack efficacy as monotherapy agents for these conditions.

Cancer-related fatigue (CRF) is a prevalent and debilitating symptom experienced by cancer survivors, yet treatment options for CRF are limited. In this study, we evaluated the efficacy of weekly Swedish massage therapy (SMT) versus an active control condition (light touch [LT]) and waitlist control (WLC) on persistent CRF in breast cancer survivors.This early phase, randomized, single-masked, 6-week investigation of SMT, LT, and WLC enrolled 66 female stage 0-III breast cancer survivors (age range, 32-72 years) who had received surgery plus radiation and/or chemotherapy/chemoprevention with CRF (Brief Fatigue Inventory 25). The primary outcome was the Multidimensional Fatigue Inventory (MFI), with the National Institutes of Health PROMIS Fatigue scale secondary.Mean baseline MFI scores for 57 evaluable subjects were 62.95 for SMT, 55.00 for LT, and 60.41 for WLC. SMT resulted in a mean (standard deviation) 6-week reduction in MFI total scores of -16.50 (6.37) (n = 20) versus -8.06 (6.50) for LT (n = 20) and an increase of 5.88 (6.48) points for WLC (n = 17) (treatment-by-time P .0001). The mean baseline PROMIS Fatigue scores were SMT, 22.25; LT, 22.05; and WLC, 23.24. The mean (standard deviation) reduction in PROMIS Fatigue scores was -5.49 (2.53) points for SMT versus -3.24 (2.57) points for LT and -0.06 (1.88) points for WLC (treatment-by-time P = .0008). Higher credibility, expectancy, and preference for SMT than for LT did not account for these results.SMT produced clinically significant relief of CRF. This finding suggests that 6 weeks of a safe, widely accepted manual intervention causes a significant reduction in fatigue, a debilitating sequela for cancer survivors. Cancer 2018;124:546-54. © 2017 American Cancer Society.

Objective To compare 2 omega-3 (n-3) preparations enriched with eicosapentaenoic acid (EPA) versus docosahexaenoic acid (DHA) as monotherapy for major depressive disorder (MDD) in a 2-site, placebo-controlled, randomized, double-blind clinical trial. Method 196 adults (53% female; mean [SD] age = 44.7 [13.4] years) with DSM-IV MDD and a baseline 17-item Hamilton Depression Rating Scale (HDRS-17) score ≥ 15 were randomized equally from May 18, 2006, to June 30, 2011, to 8 weeks of double-blind treatment with oral EPA-enriched n-3 1000 mg/d, DHA-enriched n-3 1,000 mg/d, or placebo. Results 154 subjects completed the study. Modified intent-to-treat (mITT) analysis (n = 177 subjects with ≥ 1 postbaseline visit; 59.3% female, mean [SD] age 45.8 [12.5] years) employed mixed-model repeated measures (MMRM). All 3 groups demonstrated statistically significant improvement in the HDRS-17 (primary outcome measure), 16-item Quick Inventory of Depressive Symptomatology-Self Report (QIDS-SR-16), and Clinical Global Improvement-Severity Scale (CGI-S) (P .05). Response and remission rates were in the range of 40%-50% and 30%, respectively, for all treatments, with no significant differences between groups. One subject receiving EPA-enriched n-3 discontinued due to worsening depression, and 1 subject receiving placebo discontinued due to an unspecified "negative reaction" to pills. Conclusions Neither EPA-enriched nor DHA-enriched n-3 was superior to placebo for the treatment of MDD. Trial registration ClinicalTrials.gov identifier: NCT00517036.

Objective Some reports suggest an increase in suicide ideations and behaviors in patients treated with antidepressants. This is an analysis of the impact of fluoxetine on suicide ideations in outpatients with minor depressive disorder. Methods Research subjects were adult outpatients with minor depressive disorder ( N = 162), who received fluoxetine or placebo in a prospective, 12-week, double-blind randomized trial. The research participants were evaluated weekly with standard rating scales that included four suicide-related items: item 3 of the Hamilton Rating Scale for Depression (HRSD), item 18 of Inventory of Depressive Symptomatology (IDS-C), and items 15 and 59 of the Hopkins Symptom Checklist (SCL-90). Clinically significant intensification of suicide ideation was defined as an increase of ≥2 points on any of these items. Results Overall 60/162 subjects (37%) had an increase of ≥1 point during treatment and 17/162 (10.5%) of ≥2 points on at least one suicide item, with 12/81 (14.8%) placebo and 5/81 (6.2%) fluoxetine-treated subjects having a ≥2 point gain. Of the study participants with baseline suicide ideation, 9/22 (40.9%) placebo and 3/24 (12.5%) fluoxetine treated had ≥2 point increase ( p = 0.04). Survival analysis revealed that subjects on placebo were significantly more likely ( p = 0.050) to experience a ≥2 point increase on one or more item, a difference that emerged early and continued throughout the 12-week trial. Conclusions Compared to placebo, fluoxetine was not associated with a clinically significant increase in suicide ideation among adults with minor depressive disorder during 12 weeks of treatment.

Background The Protocol Training and Assessment Model (Model) was developed through collaboration between Emory University School of Medicine and Atlanta School of Massage to minimize intra- and inter-therapist variability for two research massage therapist (rMT) applied intervention arms in the Massage for Cancer-Related Fatigue (MCRF) early-phase study. The Model was followed to maintain and assess protocol integrity for the study’s manualized Swedish massage therapy (SMT) and light touch (LT) interventions. Methods The Model includes initial rMT training, quarterly retraining sessions, accessible resources (scripts, treatment guides, weekly research personnel meetings), and ongoing monitoring. Model efficacy was assessed by monitoring data collected at retraining sessions, through audio recording review, and through subject and rMT reporting. Results Model application resulted in a high level of intervention consistency throughout the study. Protocol-related session comment rate by subjects was 2.7%. Few study participants reported intra-rMT or inter-rMT treatment delivery differences. Observation during retraining sessions indicated massage therapists continued to adhere to protocols. Importantly rMTs increased their participation beyond core duties, suggesting additional ways to standardize subject treatment experience. Conclusions Through systematic application of the Protocol Training and Assessment Model, continuous and collaborative quality improvement discussions between scientists and research massage therapists resulted in reliable, standardized SMT and LT interventions for the MCRF early-phase study. Future research can apply the Model to support and assess consistent rMT-delivered intervention applications.

Background Neurochemical studies have pointed to a modulatory role in human aggression for a variety of central neurotransmitters; some seem to play an inhibitory role, whereas others seem to play a facilitory role in the modulation of aggression. Laboratory animal studies of substance P suggest a facilitory role for this undecapeptide in the modulation of aggression, but no studies of substance P have yet been reported with regard to human aggression. Methods Basal lumbar cerebrospinal fluid samples were obtained from 38 physically healthy subjects with personality disorder (PD) and substance P-like immunoreactivity was measured and correlated with measures of aggression and impulsivity. Results The cerebrospinal fluid substance P-like immunoreactivity levels were directly correlated with a composite measure of aggression and, more specifically, with Buss-Durkee Aggression. No correlation was seen with any measure of impulsivity or of general dimensions of personality. Conclusions These data suggest a direct relationship between central nervous system substance P containing neural circuits and aggression in human subjects. This finding adds to the complex picture of the central neuromodulatory role of impulsive aggression in human subjects.

The factors that influence the timing of puberty and the onset of adult fertility are poorly understood. While focus on the juvenile period has provided insights into how growth-related cues affect pubertal timing, growth velocity during infancy that is sustained into the juvenile period may be important. On the other hand, social factors, specifically exposure to psychosocial stressors, can delay sexual maturation, possibly by altering growth velocities during development. Using female rhesus monkeys, the present study used a prospective analysis to determine how neonatal growth hormone (GH) inhibition with a sandostatin analog or suppression of the pituitary-gonadal axis with a GnRH analog affected growth and sexual maturation. A separate retrospective analysis was done assessing the effects of social dominance status during development on pubertal timing. Because a specific polymorphism in the gene encoding the serotonin (5HT) reuptake transporter increases vulnerability to psychosocial stressors, females were also genotyped and were then classified as socially dominant, having both alleles for the long promoter variant or having at least one allele for the short promoter variant, or as socially subordinate, having the long variant or having the short variant. Neonatal treatments were not balanced for social status or genotype, so analyses were performed separately. Although the neonatal treatments reduced GH secretion postnatally and through the juvenile period, neither growth nor sexual maturation was affected. In contrast, the retrospective analysis showed sexual maturation was delayed significantly in subordinate females carrying at least one allele of the short promoter variant in the gene encoding the 5HT reuptake transporter, and this delay was associated with reduced GH and leptin secretion during the juvenile phase but not with differences in growth velocities from birth. These data suggest that decreased neonatal GH secretion does not adversely affect sexual maturation, but that polymorphisms in the gene encoding the 5HT transporter modulate the adverse consequences of social subordination on the timing of puberty in female rhesus monkeys.

Recent preclinical and clinical research has demonstrated that the neuropeptide substance P (SP) plays a role in the central nervous system (CNS) response to stress, and perhaps in the etiology of major depression and/or anxiety disorders. The nature of this role, however, is poorly understood. A limited body of evidence suggests that in medication-free depressed patients, cerebrospinal fluid (CSF) concentrations of SP may be elevated relative to healthy controls. Two studies have shown that antidepressant treatment does not significantly change CSF concentrations of SP. Using standard lumbar puncture techniques, baseline CSF samples were obtained from 19 medication-free healthy controls and 19 medicated patients with treatment-resistant depression (TRD). Mean CSF SP concentration was significantly lower in TRD patients on psychotropic medications than in the group of healthy subjects. After 10-12 weeks of treatment with adjunct vagus nerve stimulation (VNS), CSF SP concentrations were not significantly changed. Low CSF SP may reflect a biological marker of the subtype of severe and chronic depression that is resistant to standard therapies.

Background Brattleboro rats (BRATs) have natural deficits in prepulse inhibition (PPI) of the startle response similar to those exhibited by schizophrenia patients, which are reversed by antipsychotics. We sought to determine whether they also have increases in striatal dopamine-2 (D2) receptors found in some studies examining the brains of schizophrenia patients. Methods Several days after startle testing, the brains of BRAT and Long Evans (LE) rats were removed, and D1 and D2 receptor levels were measured by autoradiography. Results PPI was lower in BRATs consistent with previous reports. D2, but not D1, receptor binding was significantly higher in the nucleus accumbens shell and the dorsomedial caudate of BRAT compared with LE rats, consistent with some findings in schizophrenia patients. Furthermore, individual rat PPI was inversely correlated with D2 binding density. Conclusions These findings suggest that the dopamine system in BRATs is dysregulated and these abnormalities may contribute to the PPI deficits observed in these rats.

Neurotensin (NT), an endogenous brain-gut peptide, has a close anatomical and functional relationship with the mesocorticolimbic and neostriatal dopamine system. Dysregulation of NT neurotransmission in this system has been hypothesized to be involved in the pathogenesis of schizophrenia. Additionally, NT containing circuits have been demonstrated to mediate some of the mechanisms of action of antipsychotic drugs, as well as the rewarding and/or sensitizing properties of drugs of abuse. NT receptors have been suggested to be novel targets for the treatment of psychoses or drug addiction.

Objective: The authors tested the hypothesis that concentrations of the paintransmitting neuropeptide substance P are elevated in the CSF of patients with major depression or posttraumatic stress disorder (PTSD), which have overlapping symptoms. The authors also sought to determine if CNS substance P concentrations change on provocation of symptoms in PTSD patients. Method: The authors measured CSF substance P concentrations in medicationfree patients with either major depression or PTSD and in healthy comparison subjects. Next, using a within-subject, crossover design, the authors sampled CSF for 6 hours through an indwelling subarachnoid catheter in PTSD patients before, during, and after exposure to a 60-minute traumatic or neutral videotape stimulus. Results: Both depressed and PTSD patients had significantly elevated basal CSF substance P concentrations. In the challenge study, marked increases in CSF substance P concentrations were found only after precipitation of PTSD symptoms. CSF substance P concentrations increased by 169% and 90.6% of baseline levels at 10 and 70 minutes, respectively, after the start of the traumatic videotape but changed by only 1.1% and –8.1% of baseline levels 10 and 70 minutes after the start of the neutral videotape. Conclusions: These results suggest that elevated CNS substance P concentrations are involved in both major depression and PTSD. The marked increase in CSF substance P concentrations during and after the symptom-provoking stimulus, but not after the neutral stimulus, implicates CNS release of substance P in the mechanism of acute PTSD symptoms. These data also reveal that CNS substance P responds acutely to psychological stress

Antipsychotic drugs (APDs) have previously been shown to alter Fos expression in a regionally specific manner. Increases in Fos expression in the nucleus accumbens (NAcc) are common to all clinically effective APDs. In contrast, APD-induced Fos expression increases in the caudate-putamen (CPu) and prefrontal cortex (PFC) are associated with the extrapyramidal side effect liability of typical APDs or the effectiveness against negative symptoms of atypical APDs, respectively. Considerable evidence suggests that the neuropeptide neurotensin (NT) mediates some of the effects of APDs. To determine whether NT neurotransmission is also involved in APD-induced Fos expression in brain regions relevant for therapeutic efficacy, the NT receptor antagonist SR 142948A (10 or 100 microg/kg i.p.) was coadministered with APDs (haloperidol (2.0 mg/kg s.c.), olanzapine (5 mg/kg i.p.), or clozapine (20 mg/kg s.c.)). Fos expression was evaluated in the PFC, NAcc shell, dorsomedial, and dorsolateral CPu and the lateral septum. SR 142948A attenuated haloperidol-induced Fos expression in the CPu but, in contrast, increased olanzapine-induced Fos expression in this brain region. The effects of the NT receptor antagonist were paralleled by its effects on catalepsy in olanzapine--but not haloperidol--treated animals.

Patterns in G-protein-coupled receptors' hydrophobically transformed amino-acid sequences can be computationally characterized as hierarchies of autocorrelation waves, "hydrophobic eigenmodes", using autocovariance matrix decomposition and all poles power spectral and wavelet transformations. L- or D-amino acid (retro-inverso) 12-18 residue peptides targeting these modes can be designed using eigenvector templates derived from these computations. In all, 12 human long-form D(2) dopamine receptor eigenmode-targeted 15 mer peptides were designed, synthesized, and shown to modulate and/or indirectly activate the extracellular acidification response, EAR, in stably receptor-transfected CHO and LtK cells, with an 83% hit rate. Representative L- and D-amino-acid retro-inverso peptides injected bilaterally in the nucleus accumbens demonstrated changes in rat exploratory behavior and prepulse inhibition similar to those observed following parenteral amphetamine. In contrast with geometric models used for ligand design, such as pharmacophores, the hydrophobic eigenmode approach to lead modulatory peptide design targets hydrophobic eigenmode-bearing subsequences, including those not visible from X-ray and NMR studies such as extracellular segments and loops.

Despite evidence from a variety of experimental approaches implicating the neuropeptide neurotensin in both the mechanism of action of antipsychotic drugs and the pathophysiology of schizophrenia, there has been some debate as to whether a peripherally administered neurotensin receptor agonist represents a sound strategy for the development of a novel class of antipsychotic drugs.

Francisco Aboitiz*, F. Xavier Castellanos and Ximena Carrasco Departamento de Psiquiatria, Facultad de Medicina, and Centro Interdisciplinario de Neurociencia, Pontificia Universidad Catolica de Chile, Santiago, Chile New York University Child Study Center, Nathan Kline Institute for Psychiatric Research, New York, NY, USA Servicio de Neurologia y Psiquiatria infantil, Hospital Luis Calvo Mackenna Facultad de Medicina, Universidad de Chile, Santiago, Chile

The effects of antipsychotic drugs on the neurotensin (NT) system have been well characterized in adult male animals. There is considerable evidence that the NT system undergoes distinct age-related changes during development of the rat brain. This observation in conjunction with antipsychotic pharmacotherapy in children and breast feeding women led us to characterize the effects of antipsychotic drug administration in neonatal rats. The effects of a single subcutaneous injection of haloperidol (2.0 mg/kg) on the developing NT system were determined between postnatal days 10 and 21. Haloperidol significantly increased NT/neuromedin N (NT/NN) mRNA expression and NT concentrations in the caudate/putamen as early as postnatal day 10. Haloperidol did not increase NT/NN mRNA expression in the nucleus accumbens until postnatal day 15 and did not increase NT concentrations in this brain region until postnatal day 21. These results demonstrate that there is a critical time point in development before which the NT system does not respond to antipsychotic drug administration in the same manner as the mature rat.

The possibility that the neuropeptide neurotensin (NT) may function as an endogenous antipsychotic compound was first hypothesized almost two decades ago. Since that time, considerable effort has been directed towards determining whether NT neurons mediate the effects of antipsychotic drugs (APDs). The anatomic, biochemical, behavioral, and clinical relevance of this hypothesis is reviewed. Although the majority of the available evidence is indirect, the availability of several NT receptor (NTR) antagonists have now made possible the direct examination of the involvement of the NT system in the mechanism of action of APDs. Preliminary studies in our laboratory demonstrate the ability of a selective NTR antagonist to block the effects of APDs in two models of sensory motor gating deficits characteristic of schizophrenia. These data, taken together with a compelling series of studies demonstrating that increases of NT/neuromedin N mRNA expression and NT content in the nucleus accumbens and striatum after chronic administration of APDs are predictive of clinical efficacy and extrapyramidal side effects, respectively, provide direct preclinical evidence for a role of the NT system in the clinical efficacy of APDs. Although effects of selective NTR antagonists in normal volunteers or schizophrenic patients have not been studied, and nonpeptidergic NTR agonists have not yet been identified, these cumulative results provide the groundwork for the use of NT-ergic compounds in the treatment of schizophrenia.

Introduction Retrodialysis, as used in neuropharmacological research, is a technique for in vivo delivery of neuroactive agents with concurrent monitoring of their effects on cellular activity with a separation between certain degree of spatial and temporal resolution. Typically, this is accomplished either by the use of a liquid-switch requiring multiple pumps, or by exchange of flow tubing requiring stopping and restarting dialysis. In the present study, we describe the use of a medium pressure injection valve for retrodialysis that overcomes these problems. Methods The valve was configured with a loop to deliver 20 μL of solution, and artificial CSF flow from the pump to the probe was established via this device. The application of this setup was evaluated in urethane anesthetized adult male C57BL/6J mice prepared with a CMA 11 probe implanted in the ventral hippocampus. By switching between the load and inject positions, the loop was filled with escitalopram solution (0.3 μM) and delivered at a rate of 1 μL/min at the probe for retrodialysis. Escitalopram (2 mg/kg BW) was administered subcutaneously for microdialysis studies. During these treatments, dialysate fractions were collected for the determination of serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA). Results Irrespective of route of escitalopram administration, the pattern of dialysate 5-HT, and 5-HIAA response was comparable to that reported by other investigators. Accordingly, the in-line valve assembly did not compromise retrodialysis or microdialysis sampling. The manipulations to carry out retrodialysis using the valve setup are easy and simple. Discussion An in-line injection valve is a promising adaptation for retrodialysis studies and can be incorporated as a standard part of in vivo dialysis instrumentation.

The Alzheimer's disease (AD) epidemic is a looming crisis, with an urgent need for new therapies to delay or prevent symptom onset and progression. There is growing awareness that clinical trials must target stage-appropriate pathophysiological mechanisms to effectively develop disease-modifying treatments. Advances in AD biomarker research have demonstrated changes in amyloid-beta (Aβ), brain metabolism and other pathophysiologies prior to the onset of memory loss, with some markers possibly changing one or two decades earlier. These findings suggest that amyloid-based therapies would optimally be targeted at the earliest clinically detectable stage (such as mild cognitive impairment (MCI)) or before. Postmortem data indicate that tau lesions in the locus coeruleus (LC), the primary source of subcortical norepinephrine (NE), may be the first identifiable pathology of AD, and recent data from basic research in animal models of AD indicate that loss of NE incites a neurotoxic proinflammatory condition, reduces Aβ clearance and negatively impacts cognition - recapitulating key aspects of AD. In addition, evidence linking NE deficiency to neuroinflammation in AD also exists. By promoting proinflammatory responses, suppressing anti-inflammatory responses and impairing Aβ degradation and clearance, LC degeneration and NE loss can be considered a triple threat to AD pathogenesis. Remarkably, restoration of NE reverses these effects and slows neurodegeneration in animal models, raising the possibility that treatments which increase NE transmission may have the potential to delay or reverse AD-related pathology. This review describes the evidence supporting a key role for noradrenergic-based therapies to slow or prevent progressive neurodegeneration in AD. Specifically, since MCI coincides with the onset of clinical symptoms and brain atrophy, and LC pathology is already present at this early stage of AD pathogenesis, MCI may offer a critical window of time to initiate novel noradrenergic-based therapies aimed at the secondary wave of events that lead to progressive neurodegeneration. Because of the widespread clinical use of drugs with a NE-based mechanism of action, there are immediate opportunities to repurpose existing medications. For example, NE transport inhibitors and NE-precursor therapies that are used for treatment of neurologic and psychiatric disorders have shown promise in animal models of AD, and are now prime candidates for early-phase clinical trials in humans.

Objective To explore which symptoms are common in patients who experience a range of symptom severity that spans minor depression and major depressive disorder (MDD). Method A post hoc analysis of subjects entering outpatient, pharmacologic treatment studies for minor depression or MDD who provided baseline data on the Inventory for Depressive Symptomatology-Clinician Rated (IDS-C) was performed in November 2000. The minor depression sample included 161 patients diagnosed according to the National Institute of Mental Health Diagnostic Interview Schedule, while the MDD subjects included 969 subjects diagnosed according to the Structured Clinical Interview for DSM-III-R. Descriptive statistics were calculated for the total IDS-C score and for each item-rating score for both groups. The percentages of patients within the low, medium, and high severity groups of minor depression and MDD endorsing each IDS-C item were calculated and used to identify specific patterns of prevalence across the 6 groups: symptoms with high prevalence in all groups (core symptoms), those with increasing prevalence across groups (continuum symptoms), and those that become prominent only at a certain threshold of illness severity. Results The mean (SD) IDS-C score was 21.18 (5.37) for minor depression patients, while it was 37.14 (7.27) for the MDD patients (P = .0001). Ten items pertaining mostly to mood state and cognition were identified as "core" symptoms of depression based on their high prevalence in all groups. Fourteen items consisting mostly of neurovegetative and somatic symptoms were identified as "continuum" symptoms based on their general pattern of increasing prevalence across the 6 severity groups. Four "threshold" symptoms, including suicidal ideation, psychomotor slowing, gastrointestinal symptoms, and panic/phobic symptoms, were prevalent in only the most severely depressed groups. Conclusions The presence of core, continuum, and threshold depressive symptoms indicates central features of both minor depression and MDD as well as symptoms that increase or emerge with depressive illness severity. Some of the core symptoms of minor depression and MDD are not included in DSM depressive criteria or traditional assessment rating scales.

article i nfo Prepulse inhibition Locomotion D-amphetamine Apomorphine Dizocilpine c-fos Neurotensin The neuropeptide neurotensin (NT) is closely associated with dopaminergic and glutamatergic systems in the rat brain. Central injection of NT into the nucleus accumbens (NAcc) or peripheral administration of NT receptor agonists, reduces many of the behavioral effects of psychostimulants. However, the role of endoge- nous NT in the behavioral effects of psychostimulants (e.g. DA agonists and NMDA receptor antagonists) remains unclear. Using a NTR antagonist, SR142948A, the current studies were designed to examine the role of endogenous NT in DA receptor agonist- and NMDA receptor antagonist-induced disruption of prepulse inhibition of the acoustic startle response (PPI), locomotor hyperactivity and brain-region specific c-fos mRNA expression. Adult male rats received a single i.p. injection of SR142948A or vehicle followed by D-amphetamine, apomorphine or dizocilpine challenge. SR142948A had no effect on baseline PPI, but dose-dependently attenuated D-amphetamine- and dizocilpine-induced PPI disruption and enhanced apomorphine-induced PPI disruption. SR142948A did not significantly affect either baseline locomotor activity or stimulant-induced hyperlocomotion. Systemic SR142948A administration prevented c-fos mRNA induction in mesolimbic terminal fields (prefrontal cortex, lateral septum, NAcc, ventral subiculum) induced by all three psychostimulants implicating the VTA as the site for NT modulation of stimulant-induced PPI disruption. Further characterization of the NT system may be valuable to find clinical useful compounds for schizophrenia and drug addiction.

Background Limited controlled data exist to guide treatment choices for clinicians caring for patients with major depressive disorder (MDD). Although many putative predictors of treatment response have been reported, most were identified through retrospective analyses of existing datasets and very few have been replicated in a manner that can impact clinical practice. One major confound in previous studies examining predictors of treatment response is the patient’s treatment history, which may affect both the predictor of interest and treatment outcomes. Moreover, prior treatment history provides an important source of selection bias, thereby limiting generalizability. Consequently, we initiated a randomized clinical trial designed to identify factors that moderate response to three treatments for MDD among patients never treated previously for the condition. Methods/design Treatment-naïve adults aged 18 to 65 years with moderate-to-severe, non-psychotic MDD are randomized equally to one of three 12-week treatment arms: (1) cognitive behavior therapy (CBT, 16 sessions); (2) duloxetine (30–60 mg/d); or (3) escitalopram (10–20 mg/d). Prior to randomization, patients undergo multiple assessments, including resting state functional magnetic resonance imaging (fMRI), immune markers, DNA and gene expression products, and dexamethasone-corticotropin-releasing hormone (Dex/CRH) testing. Prior to or shortly after randomization, patients also complete a comprehensive personality assessment. Repeat assessment of the biological measures (fMRI, immune markers, and gene expression products) occurs at an early time-point in treatment, and upon completion of 12-week treatment, when a second Dex/CRH test is also conducted. Patients remitting by the end of this acute treatment phase are then eligible to enter a 21-month follow-up phase, with quarterly visits to monitor for recurrence. Non-remitters are offered augmentation treatment for a second 12-week course of treatment, during which they receive a combination of CBT and antidepressant medication. Predictors of the primary outcome, remission, will be identified for overall and treatment-specific effects, and a statistical model incorporating multiple predictors will be developed to predict outcomes. Discussion The PReDICT study’s evaluation of biological, psychological, and clinical factors that may differentially impact treatment outcomes represents a sizeable step toward developing personalized treatments for MDD. Identified predictors should help guide the selection of initial treatments, and identify those patients most vulnerable to recurrence, who thus warrant maintenance or combination treatments to achieve and maintain wellness. Trial registration Clinicaltrials.gov Identifier: NCT00360399. Registered 02 AUG 2006. First patient randomized 09 FEB 2007.

The substance P-neurokinin-1 receptor (SP-NK 1 R) system has been extensively studied in experimental models of stress, fear, and reward. Elevated cerebrospinal fluid (CSF) SP levels were reported previously in combat-related PTSD. No medication specifically targeting this system has been tested in PTSD. This proof-of-concept randomized, double-blind, placebo-controlled trial evaluated the selective NK 1 R antagonist GR205171 in predominately civilian PTSD. Following a 2-week placebo lead-in, 39 outpatients with chronic PTSD and a Clinician-Administered PTSD Scale (CAPS) score ≥ 50 were randomized to a fixed dose of GR205171 ( N = 20) or placebo ( N = 19) for 8 weeks. The primary endpoint was mean change from baseline to endpoint in the total CAPS score. Response rate (≥ 50% reduction in baseline CAPS) and safety/tolerability were secondary endpoints. CSF SP concentrations were measured in a subgroup of patients prior to randomization. There was significant improvement in the mean CAPS total score across all patients over time, but no significant difference was found between GR205171 and placebo. Likewise, there was no significant effect of drug on the proportion of responders [40% GR205171 versus 21% placebo ( p = 0.30)]. An exploratory analysis showed that GR205171 treatment was associated with significant improvement compared to placebo on the CAPS hyperarousal symptom cluster. GR205171 was well-tolerated, with no discontinuations due to adverse events. CSF SP concentrations were positively correlated with baseline CAPS severity. The selective NK 1 R antagonist GR205171 had fewer adverse effects but was not significantly superior to placebo in the short-term treatment of chronic PTSD. (ClinicalTrials.gov Identifier: NCT 00211861, NCT 00383786)