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1.  A Turn-Key Approach for Large-Scale Identification of Complex Posttranslational Modifications 
Journal of Proteome Research  2014;13(3):1190-1199.
The conjugation of complex post-translational modifications (PTMs) such as glycosylation and Small Ubiquitin-like Modification (SUMOylation) to a substrate protein can substantially change the resulting peptide fragmentation pattern compared to its unmodified counterpart, making current database search methods inappropriate for the identification of tandem mass (MS/MS) spectra from such modified peptides. Traditionally it has been difficult to develop new algorithms to identify these atypical peptides because of the lack of a large set of annotated spectra from which to learn the altered fragmentation pattern. Using SUMOylation as an example, we propose a novel approach to generate large MS/MS training data from modified peptides and derive an algorithm that learns properties of PTM-specific fragmentation from such training data. Benchmark tests on data sets of varying complexity show that our method is 80–300% more sensitive than current state-of-the-art approaches. The core concepts of our method are readily applicable to developing algorithms for the identifications of peptides with other complex PTMs.
doi:10.1021/pr400368u
PMCID: PMC3993922  PMID: 24437954
small ubiquitin-like modification (SUMOylation); posttranslational modification (PTM); combinatorial peptide library; peptide fragmentation patterns; algorithms; database search method; linked peptides
2.  Writing and Publishing Your Research Findings 
Writing clearly is critical to the success of your scientific career. Unfortunately, this skill is not taught in medical school or postgraduate training. This article summarizes our approach to the writing and publication of your research. Here we focus on empirical or experimental reports of translational and clinically oriented research. We review the process of choosing what to write, how to write it clearly, and how to navigate the process of submission and publication.
doi:10.231/JIM.0b013e3181aa089f
PMCID: PMC4260692  PMID: 19491626
medical writing; career development
3.  Retention and Attrition Among African Americans in the STAR*D Study: What Causes Research Volunteers to Stay or Stray? 
Depression and anxiety  2013;30(11):10.1002/da.22134.
Background
High attrition rates among African-Americans (AA) volunteers are a persistent problem that makes clinical trials less representative and complicates estimation of treatment outcomes. Many studies contrast AA with other ethnic/racial groups, but few compare the AA volunteers who remain in treatment with those who leave. Here, in addition to comparing patterns of attrition between African Americans and whites, we identify predictors of overall and early attrition among African Americans.
Method
Sample comprised non-Hispanic African-American (n=673) and white (n=2,549) participants in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. Chi-square tests were used to examine racial group differences in reasons for exit. Multivariate logistic regression was used to examine predictors of overall attrition, early attrition (by Level 2) and top reasons cited for attrition among African Americans.
Results
For both African-American and white dropouts, non-compliance reasons for attrition were most commonly cited during the earlier phases of the study while reasons related to efficacy and medication side effects were cited later in the study. Satisfaction with treatment strongly predicted overall attrition among African Americans independent of socioeconomic, clinical, medical or psychosocial factors. Early attrition among African American dropouts was associated with less psychiatric comorbidity, and higher perceived physical functioning but greater severity of clinician-rated depression.
Conclusions
The decision to drop out is a dynamic process that changes over the course of a clinical trial. Strategies aimed at retaining African Americans in such trials should emphasize engagement with treatment and patient satisfaction immediately following enrollment and after treatment initiation.
doi:10.1002/da.22134
PMCID: PMC3818393  PMID: 23723044
Research Volunteers; Ethnic Groups; Blacks; Depression; Disparities; Treatment
4.  Relationship Between Obesity and Depression: Characteristics and Treatment Outcomes with Antidepressant Medication 
Psychosomatic medicine  2013;75(9):863-872.
Objective
Obesity and Major Depressive Disorder (MDD) often co-occur. However, differences between obese and normal-weight depressed patients and the moderating effect of obesity on antidepressant treatment outcome have not been well studied.
Methods
662 subjects in the COmbining Medications to Enhance Depression Outcomes (COMED) were randomized to treatment with escitalopram plus placebo, bupropion plus escitalopram, or venlafaxine plus mirtazapine for a 12 week primary treatment phase and 16 week follow-up. Body Mass Index (BMI) was calculated at baseline. Subjects were divided into BMI classes according to World Health Organization criteria: 1) normal (and low) weight (NW), 2) overweight (OW), 3) obese I (OB1) and 4) obese II+ (OB2). Clinical characteristics were compared using Chi-squared or Kruskall-Wallis testing. Outcomes were assessed using a repeated effects model, unadjusted and adjusted for baseline variables differing across BMI classes.
Results
31.4% of the subjects were normal weight; 46.2% were obese. Higher BMI was associated with greater medical illness (p<0.001), social phobia (p=0.003) and bulimia (p=0.026). Lower BMI was associated with higher rates of Post Traumatic Stress Disorder (p=0.002) and drug abuse. Treatment outcomes, including remission, did not differ across classes. However, lower BMI was associated with more frequent (p=0.024, unadjusted, 0.053 adjusted) and more severe (p=0.008 unadjusted, 0.053 adjusted) side effects.
Conclusions
We found a high rate of obesity compared to the general population and significant differences in presentation and comorbidity, but not medication use and antidepressant outcomes, in subjects across BMI classes. Lower BMI classes had higher rates of comorbidities associated with poor outcome, which may have obscured outcome differences.
Trial Registration
clinicaltrials.gov Identifier: NCT 00270647
doi:10.1097/PSY.0000000000000000
PMCID: PMC3905462  PMID: 24163386
Depression; Obesity; Treatment Resistance
5.  RSK phosphorylates SOS1 creating 14-3-3 docking sites and negatively regulating MAPK activation 
The Biochemical journal  2012;447(1):159-166.
doi:10.1042/BJ20120938
PMCID: PMC4198020  PMID: 22827337
RSK; SOS; 14-3-3; negative feedback; Phosphorylation; Signal Transduction
6.  Fyn Promotes Phosphorylation of Collapsin Response Mediator Protein 1 at Tyrosine 504, a Novel, Isoform-Specific Regulatory Site 
Journal of cellular biochemistry  2010;111(1):20-28.
In vertebrates the Collapsin Response Mediator Proteins (CRMPs) are encoded by five highly-related genes. CRMPs are cytosolic phosphoproteins abundantly expressed in developing and mature mammalian brains. CRMPs are best understood as effectors of Semaphorin 3A signaling regulating growth cone collapse in migratory neurons. Phosphorylation in the carboxyl-terminal regulatory domain of CRMPs by several serine/threonine kinases has been described. These phoshorylation events appear to function, at least in part, to disrupt the interaction of CRMPs with tubulin heterodimers. In a large-scale phosphoproteomic analysis of murine brain, we recently identified a number of in vivo tyrosine phosphorylation sites on CRMP isoforms. Using biochemical approaches and quantitative mass spectrometry we demonstrate that one of these sites, CRMP1 tyrosine 504 (Y504), is a primary target of the Src family of tyrosine kinases (SFKs), specifically Fyn. Y504 is adjacent to CDK5 and GSK-3β sites that regulate the interaction of CRMPs with tubulin. Although Y504 is highly conserved among vertebrate CRMP1 orthologs, a residue corresponding to Y504 is absent in CRMP isoforms 2-5. This suggests an isoform-specific regulatory role for CRMP1 Y504 phosphorylation and may help explain the observation that CRMP1-deficient mice exhibit neuronal migration defects not compensated for by CRMPs 2-5.
doi:10.1002/jcb.22659
PMCID: PMC4198339  PMID: 20506281
Collapsin Response Mediator Protein, CRMP; Fyn; Phosphorylation; Tyrosine Kinase; Quantitative mass spectrometry, quantitative proteomics; Neuronal positioning; Growth Cone; Absolute Quantification, AQUA; Stable Isotope Labeling with Amino Acids in Cell Culture, SILAC
7.  The genetic interacting landscape of 63 candidate genes in Major Depressive Disorder: an explorative study 
BioData Mining  2014;7:19.
Background
Genetic contributions to major depressive disorder (MDD) are thought to result from multiple genes interacting with each other. Different procedures have been proposed to detect such interactions. Which approach is best for explaining the risk of developing disease is unclear.
This study sought to elucidate the genetic interaction landscape in candidate genes for MDD by conducting a SNP-SNP interaction analysis using an exhaustive search through 3,704 SNP-markers in 1,732 cases and 1,783 controls provided from the GAIN MDD study. We used three different methods to detect interactions, two logistic regressions models (multiplicative and additive) and one data mining and machine learning (MDR) approach.
Results
Although none of the interaction survived correction for multiple comparisons, the results provide important information for future genetic interaction studies in complex disorders. Among the 0.5% most significant observations, none had been reported previously for risk to MDD. Within this group of interactions, less than 0.03% would have been detectable based on main effect approach or an a priori algorithm. We evaluated correlations among the three different models and conclude that all three algorithms detected the same interactions to a low degree. Although the top interactions had a surprisingly large effect size for MDD (e.g. additive dominant model Puncorrected = 9.10E-9 with attributable proportion (AP) value = 0.58 and multiplicative recessive model with Puncorrected = 6.95E-5 with odds ratio (OR estimated from β3) value = 4.99) the area under the curve (AUC) estimates were low (< 0.54). Moreover, the population attributable fraction (PAF) estimates were also low (< 0.15).
Conclusions
We conclude that the top interactions on their own did not explain much of the genetic variance of MDD. The different statistical interaction methods we used in the present study did not identify the same pairs of interacting markers. Genetic interaction studies may uncover previously unsuspected effects that could provide novel insights into MDD risk, but much larger sample sizes are needed before this strategy can be powerfully applied.
doi:10.1186/1756-0381-7-19
PMCID: PMC4181757  PMID: 25279001
Additive interaction; Multiplicative interaction; Logistic regression; Data mining and machine learning; Major depressive disorder
8.  Fluoxetine Increases Suicide Ideation Less than Placebo During Treatment of Adults with Minor Depressive Disorder 
Journal of psychiatric research  2013;47(9):1199-1203.
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 4 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 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.
doi:10.1016/j.jpsychires.2013.05.025
PMCID: PMC3729337  PMID: 23786912
Minor Depressive Disorder; fluoxetine; antidepressant; treatment emergent suicide ideation
9.  Course and Severity of Maternal Depression: Associations with Family Functioning and Child Adjustment 
Journal of youth and adolescence  2008;37(8):906-916.
Number of lifetime episodes, duration of current episode, and severity of maternal depression were investigated in relation to family functioning and child adjustment. Participants were the 151 mother–child pairs in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) child multi-site study. Mothers were diagnosed with Major Depressive Disorder; children (80 males and 71 females) ranged in age from 7 to 17 years. Measures of child adjustment included psychiatric diagnoses, internalizing and externalizing symptoms, and functional impairment. Measures of family functioning included family cohesion, expressiveness, conflict, organization, and household control; parenting measures assessed maternal acceptance and psychological control. Children of mothers with longer current depressive episodes were more likely to have internalizing and externalizing symptoms, with this association being moderated by child gender. Mothers with more lifetime depressive episodes were less likely to use appropriate control in their homes.
doi:10.1007/s10964-007-9216-0
PMCID: PMC4086840  PMID: 25013241
Maternal depression; Family functioning; Child adjustment; Gender
10.  Global analysis of phosphorylation and ubiquitylation crosstalk in protein degradation 
Nature methods  2013;10(7):10.1038/nmeth.2519.
Crosstalk between different types of post-translational modifications (PTMs) on the same protein molecule adds specificity and combinatorial logic to signal processing, but has not been characterized on a large-scale basis. Here, we developed two methods to identify protein isoforms that are both phosphorylated and ubiquitylated in the yeast Saccharomyces cerevisiae, identifying 466 proteins with 2,100 phosphorylation sites co-occurring with 2,189 ubiquitylation sites. We applied these methods quantitatively to identify phosphorylation sites that regulate protein degradation via the ubiquitin-proteasome system. Our results demonstrate that distinct phosphorylation sites are often used in conjunction with ubiquitylation, and these sites are more highly conserved than the entire set of phosphorylation sites. Finally, we investigated how the phosphorylation machinery can be regulated by ubiquitylation. We found evidence for novel regulatory mechanisms of kinases and 14-3-3 scaffold proteins via proteasome-independent ubiquitylation.
doi:10.1038/nmeth.2519
PMCID: PMC3868471  PMID: 23749301
11.  The Clinical Relevance of Self-Reported Premenstrual Worsening of Depressive Symptoms in the Management of Depressed Outpatients: A STAR*D Report 
Journal of Women's Health  2013;22(3):219-229.
Abstract
Objective
To determine the incidence, clinical and demographic correlates, and relationship to treatment outcome of self-reported premenstrual exacerbation of depressive symptoms in premenopausal women with major depressive disorder who are receiving antidepressant medication.
Method
This post-hoc analysis used clinical trial data from treatment-seeking, premenopausal, adult female outpatients with major depression who were not using hormonal contraceptives. For this report, citalopram was used as the first treatment step. We also used data from the second step in which one of three new medications were used (bupropion-SR [sustained release], venlafaxine-XR [extended release], or sertraline). Treatment-blinded assessors obtained baseline treatment outcomes data. We hypothesized that those with reported premenstrual depressive symptom exacerbation would have more general medical conditions, longer index depressive episodes, lower response or remission rates, and shorter times-to-relapse with citalopram, and that they would have a better outcome with sertraline than with bupropion-SR.
Results
At baseline, 66% (n=545/821) of women reported premenstrual exacerbation. They had more general medical conditions, more anxious features, longer index episodes, and shorter times-to-relapse (41.3 to 47.1 weeks, respectively). Response and remission rates to citalopram, however, were unrelated to reported premenstrual exacerbation. Reported premenstrual exacerbation was also unrelated to differential benefit with sertraline and bupropion-SR.
Conclusions
Self-reported premenstrual exacerbation has moderate clinical utility in the management of depressed patients, although it is not predictive of overall treatment response. Factors that contribute to a more chronic or relapsing course may also play a role in premenstrual worsening of major depressive disorder (MDD).
doi:10.1089/jwh.2011.3186
PMCID: PMC3634137  PMID: 23480315
12.  Do Menopausal Status and Use of Hormone Therapy Affect Antidepressant Treatment Response? Findings from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) Study 
Journal of Women's Health  2013;22(2):121-131.
Abstract
Background
Menopausal status and use of hormonal contraception or menopausal hormone therapy (HT) may affect treatment response to selective serotonin reuptake inhibitors (SSRIs). This report evaluates whether menopausal status and use of hormonal contraceptives or menopausal HT affect outcome in women treated with citalopram.
Methods
In the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, 896 premenopausal and 544 postmenopausal women were treated with citalopram for 12–14 weeks. Baseline demographic and clinical characteristics were used in adjusted analysis of the effect of menopausal status and use of hormonal contraceptives or menopausal HT on outcomes. Remission was defined as final Hamilton Rating Scale for Depression-17 (HRSD17) ≤7 or Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR16) score ≤5 and response as ≥50% decrease from the baseline QIDS-SR16 score.
Results
Premenopausal and postmenopausal women differed in multiple clinical and demographic baseline variables but did not differ in response or remission rates. Premenopausal women taking hormonal contraceptives had significantly greater unadjusted remission rates on the HRSD17 and the QIDS-SR16 than women not taking contraception. Response and remission rates were not different between postmenopausal women taking vs. not taking HT. Adjusted results showed no significant difference in any outcome measure across menopause status in women who were not taking contraception/HT. There were no significant differences in adjusted results across HT status in premenopausal or postmenopausal women.
Conclusions
In this study, citalopram treatment outcome was not affected by menopausal status. Hormonal contraceptives and HT also did not affect probability of good outcome.
doi:10.1089/jwh.2012.3479
PMCID: PMC3613168  PMID: 23398127
13.  Cross-Disorder Genomewide Analysis of Schizophrenia, Bipolar Disorder, and Depression 
The American journal of psychiatry  2010;167(10):10.1176/appi.ajp.2010.09091335.
Background
Family and twin studies indicate substantial overlap of genetic influences on psychotic and mood disorders. Linkage and candidate gene studies have also suggested overlap across schizophrenia (SCZ), bipolar disorder (BPD), and major depressive disorder (MDD). The objective of this study was to apply genomewide association study (GWAS) analysis to address the specificity of genetic effects on these disorders.
Method
We combined GWAS data from three large effectiveness studies of SCZ (CATIE, genotyped n = 741), BPD (STEP-BD, n = 1575) and MDD (STAR*D, n= 1938) and psychiatrically-screened controls (NIMH-GI controls, n = 1204). We applied a two-stage analytic procedure involving an omnibus test of allele frequency differences among case and control groups followed by a model selection step to identify the best-fitting model of allelic effects across disorders.
Results
The strongest result was seen for a single nucleotide polymorphism near the adrenomedullin (ADM) gene (rs6484218, p = 3.93 × 10−8), with the best-fitting model indicating that the effect is specific to bipolar II disorder. We also observed evidence suggesting that several genes may have effects that transcend clinical diagnostic boundaries including variants in NPAS3 that showed pleiotropic effects across SCZ, BPD, and MDD.
Conclusions
This study provides the first genomewide significant evidence implicating variants near the ADM gene on chromosome 11p15 in psychopathology, with effects that appear to be specific to bipolar II disorder. Although we do not detect genomewide significant evidence of cross-disorder effects, our study provides evidence that there are both pleiotropic and disorder-specific effects on major mental illness and illustrates an approach to dissecting the genetic basis of mood and psychotic disorders that can inform future large-scale cross-disorder GWAS analyses.
doi:10.1176/appi.ajp.2010.09091335
PMCID: PMC3880556  PMID: 20713499
14.  Rationale and Design of the Chronic Kidney Disease Antidepressant Sertraline Trial (CAST) 
Contemporary clinical trials  2012;34(1):136-144.
Major depressive disorder (MDD) affects one in five patients with Chronic Kidney Disease (CKD) and is an independent risk factor for hospitalization and death before and after dialysis initiation. However, it remains an under-recognized and under-treated problem, in part due to the lack of well-controlled studies that support or refute the efficacy and safety of antidepressant medications in CKD patients. Major trials of antidepressant treatment excluded patients with stages 3–5 CKD, precisely those at higher risk for both depression and increased mortality. The Chronic Kidney Disease Antidepressant Sertraline Trial (CAST) is a randomized, double-blinded, placebo-controlled trial of sertraline, a selective serotonin reuptake inhibitor (SSRI). It will enroll 200 adults with stages 3–5 CKD and MDD excluding kidney transplant and chronic dialysis patients. Sertraline will be administered at an initial dose of 50 mg once daily or matching placebo followed by a dose escalation strategy consisting of 50 mg increments at 2 weeks intervals (as tolerated) to a maximum dose of 200 mg. The primary outcome is improvement in depression symptom severity measured by the Quick Inventory of Depressive Symptomatology scale. Secondary outcomes include safety endpoints and improvement in quality of life. Changes in cognitive function, adherence to medications, nutritional status, inflammation, and platelet function will be explored as potential mechanisms by which depression may mediate poor outcomes. We discuss the rationale and design of the CAST study, the largest placebo-controlled trial aimed to establish safety and efficacy of a SSRI in the acute phase treatment of CKD patients with MDD.
doi:10.1016/j.cct.2012.10.004
PMCID: PMC3525806  PMID: 23085503
depression; chronic kidney disease; sertraline; randomized trial; treatment
15.  What Are the Clinical Implications of New Onset or Worsening Anxiety During the First Two Weeks of SSRI Treatment for Depression? 
Depression and anxiety  2011;29(2):10.1002/da.20917.
Objective
To evaluate the prevalence of new onset or worsening of anxiety symptoms, as well as their clinical implications, during the first two weeks of Selective Serotonin Reuptake Inhibitor (SSRI) pharmacotherapy for depression.
Method
Adult outpatients with non-psychotic major depressive disorder were enrolled in an 8-week acute phase SSRI treatment trial at 15 clinical sites across the US. Worsening anxiety was defined as a greater than 2 point increase on the Beck Anxiety Inventory (BAI) between baseline and Week 2. New onset of anxiety symptoms was ascribed when the BAI baseline rating was 0 and the Week 2 value was greater or equal to 2 points on the BAI.
Results
Overall, after two weeks of treatment, 48.8% (98 of 201 participants) reported improvement in anxiety symptoms, 36.3% (73 of 201) reported minimal symptom change, and 14.9% (30 of 201) reported worsening of anxiety symptoms. No association was found between change in anxiety symptoms within the first two weeks and change in depressive symptoms or remission at the end of 8 weeks of treatment. For participants with clinically meaningful anxiety symptoms at baseline, however, worsening of anxiety during the first two weeks of treatment was associated with worsening depressive symptoms by 8 weeks (p = .054).
Conclusions
The trajectory of anxiety symptom change early in SSRI treatment is an important indicator of eventual outcome for outpatients with major depression and baseline anxiety symptoms.
doi:10.1002/da.20917
PMCID: PMC3860362  PMID: 22147631
anxiety; change; depression; SSRI; outcome
16.  Comparative Phosphoproteomic Analysis of Neonatal and Adult Murine Brain 
Proteomics  2012;12(13):10.1002/pmic.201200003.
Developmental processes are governed by diverse regulatory mechanisms including a suite of signaling pathways employing reversible phosphorylation. With the advent of large-scale phosphoproteomics it is now possible to identify thousands of phosphorylation sites from tissues at distinct developmental stages. We describe here the identification of over 6,000 non-redundant phosphorylation sites from neonatal murine brain. When compared to nearly three times the number of phosphorylation sites identified from three-week-old murine brain, remarkably one-third of the neonatal sites were unique. This fraction only dropped to one-quarter when allowing the site to stray plus or minus 15 residues. This provides evidence for considerable change in the profiles of developmentally-regulated phosphoproteomes. Using quantitative mass spectrometry we characterized a novel phosphorylation site (Ser265) identified uniquely in the neonatal brain on Doublecortin (Dcx), a protein essential for proper mammalian brain development. While the relative levels of Dcx and phospho-Ser265 Dcx between embryonic and neonatal brain were similar, their levels fell precipitously by postnatal day 21, as did phospho-Ser297, a site required for proper neuronal migration. Both sites lie near the microtubule-binding domain and may provide functionally similar regulation via different kinases.
doi:10.1002/pmic.201200003
PMCID: PMC3816108  PMID: 22807455
Phosphoproteomics; Brain Development; Quantitative Mass Spectrometry; Doublecortin (Dcx); phosphorylation
17.  Genome-Wide Association Study of Suicide Attempts in Mood Disorder Patients 
The American journal of psychiatry  2010;167(12):1499-1507.
Objective
Family and twin studies suggest that liability for suicide attempts is heritable and distinct from mood disorder susceptibility. The authors therefore examined the association between common genomewide variation and lifetime suicide attempts.
Method
The authors analyzed data on lifetime suicide attempts from genomewide association studies of bipolar I and II disorder as well as major depressive disorder. Bipolar disorder subjects were drawn from the Systematic Treatment Enhancement Program for Bipolar Disorder cohort, the Wellcome Trust Case Control Consortium bipolar cohort, and the University College London cohort. Replication was pursued in the NIMH Genetic Association Information Network bipolar disorder project and a German clinical cohort. Depression subjects were drawn from the Sequential Treatment Alternatives to Relieve Depression cohort, with replication in the Netherlands Study of Depression and Anxiety/Netherlands Twin Register depression cohort.
Results
Strongest evidence of association for suicide attempt in bipolar disorder was observed in a region without identified genes (rs1466846); five loci also showed suggestive evidence of association. In major depression, strongest evidence of association was observed for a single nucleotide polymorphism in ABI3BP, with six loci also showing suggestive association. Replication cohorts did not provide further support for these loci. However, meta-analysis incorporating approximately 8,700 mood disorder subjects identified four additional regions that met the threshold for suggestive association, including the locus containing the gene coding for protein kinase C-epsilon, previously implicated in models of mood and anxiety.
Conclusions
The results suggest that inherited risk for suicide among mood disorder patients is unlikely to be the result of individual common variants of large effect. They nonetheless provide suggestive evidence for multiple loci, which merit further investigation.
doi:10.1176/appi.ajp.2010.10040541
PMCID: PMC3795390  PMID: 21041247
18.  Association Between Bipolar Spectrum Features and Treatment Outcomes in Outpatients With Major Depressive Disorder 
Archives of general psychiatry  2010;68(4):351-360.
Context
It has been suggested that patients with major depressive disorder (MDD) who display pretreatment features suggestive of bipolar disorder or bipolar spectrum features might have poorer treatment outcomes.
Objective
To assess the association between bipolar spectrum features and antidepressant treatment outcome in MDD.
Design
Open treatment followed by sequential randomized controlled trials.
Setting
Primary and specialty psychiatric outpatient centers in the United States.
Participants
Male and female outpatients aged 18 to 75 years with a DSM-IV diagnosis of nonpsychotic MDD who participated in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study.
Interventions
Open treatment with citalopram followed by up to 3 sequential next-step treatments.
Main Outcome Measures
Number of treatment levels required to reach protocol-defined remission, as well as failure to return for the postbaseline visit, loss to follow-up, and psychiatric adverse events. For this secondary analysis, putative bipolar spectrum features, including items on the mania and psychosis subscales of the Psychiatric Diagnosis Screening Questionnaire, were examined for association with treatment outcomes.
Results
Of the 4041 subjects who entered the study, 1198 (30.0%) endorsed at least 1 item on the psychosis scale and 1524 (38.1%) described at least 1 recent manic-like/hypomaniclike symptom. Irritability and psychotic-like symptoms at entry were significantly associated with poorer outcomes across up to 4 treatment levels, as were shorter episodes and some neurovegetative symptoms of depression. However, other indicators of bipolar diathesis including recent maniclike symptoms and family history of bipolar disorder as well as summary measures of bipolar spectrum features were not associated with treatment resistance.
Conclusion
Self-reported psychoticlike symptoms were common in a community sample of outpatients with MDD and strongly associated with poorer outcomes. Overall, the data do not support the hypothesis that unrecognized bipolar spectrum illness contributes substantially to antidepressant treatment resistance.
doi:10.1001/archgenpsychiatry.2010.179
PMCID: PMC3794668  PMID: 21135313
19.  Pharmacogenetics Studies in STAR*D: Strengths, Limitations, and Results 
Several lines of evidence support an important genetic contribution to the wide individual variation in therapeutic response to antidepressant medications. The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study provided the largest cohort assembled to date of DNA from patients with nonpsychotic major depressive disorder, uniformly treated with citalopram and followed prospectively for up to 12 weeks. This pivotal study changed the face of pharmacogenetics research by increasing the sample size by an order of magnitude as well as by providing detailed prospective information about antidepressant response and tolerability. Several groups have identified markers in genes and tested the replication of previous findings of genes associated with outcome and side effects of antidepressant treatment. Variants in HTR2A, GRIK4, and KCNK2 were associated with citalopram treatment outcome. Replication was achieved in markers in the FKBP5 gene. Other findings in PDE11A and BDNF were not successfully replicated, and reports of potential confounders in previous associations with serotonin transporter variation (SLC6A4) were identified. Polymorphisms in pharmacokinetic genes involved in metabolism and transmembrane transport were also not associated with antidepressant response. Adverse events were also tested. Treatment-emergent suicidal ideation was associated with GRIK2, GRIA3, PAPLN, IL28RA, and CREB1. Sexual dysfunction was linked with variation in GRIN3A, GRIA1 GRIA3, and GRIK2. Reported and future findings of pharmacogenetics studies in STAR*D could help elucidate pathways involved in major depression and those pertinent to antidepressant outcome and side effects. Replication of these findings in independent samples could lead to the development of new treatments and to optimization of available treatments.
doi:10.1176/appi.ps.60.11.1446
PMCID: PMC3775610  PMID: 19880459
20.  Estimating Individualized Treatment Rules Using Outcome Weighted Learning 
There is increasing interest in discovering individualized treatment rules for patients who have heterogeneous responses to treatment. In particular, one aims to find an optimal individualized treatment rule which is a deterministic function of patient specific characteristics maximizing expected clinical outcome. In this paper, we first show that estimating such an optimal treatment rule is equivalent to a classification problem where each subject is weighted proportional to his or her clinical outcome. We then propose an outcome weighted learning approach based on the support vector machine framework. We show that the resulting estimator of the treatment rule is consistent. We further obtain a finite sample bound for the difference between the expected outcome using the estimated individualized treatment rule and that of the optimal treatment rule. The performance of the proposed approach is demonstrated via simulation studies and an analysis of chronic depression data.
doi:10.1080/01621459.2012.695674
PMCID: PMC3636816  PMID: 23630406
Dynamic Treatment Regime; Individualized Treatment Rule; Weighted Support Vector Machine; RKHS; Risk Bound; Bayes Classifier; Cross Validation
21.  Absolute quantification of protein and post-translational modification abundance with stable isotope–labeled synthetic peptides 
Nature protocols  2011;6(2):175-186.
In the analysis of biological systems, it is of interest to identify the components of the system and to monitor their changes in abundance under different conditions. The AQUA (for ‘absolute quantification’) method allows sensitive and specific targeted quantification of protein and post-translational modifications in complex protein mixtures using stable isotope–labeled peptides as internal standards. Each AQUA experiment is composed of two stages: method development and application to a biological scenario. In the method development stage, peptides from the protein of interest are chosen and then synthesized with stable isotopes such as 13C, 2H or 15N. The abundance of these internal standards and their endogenous counterparts can be measured by mass spectrometry with selected reaction monitoring or selected ion monitoring methods. Once an AQUA method is established, it can be rapidly applied to a wide range of biological samples, from tissue culture cells to human plasma and tissue. After AQUA peptide synthesis, the development, optimization and application of AQUA analyses to a specific biological problem can be achieved in ~1 week. Here we demonstrate the usefulness of this method by monitoring both Polo-like kinase 1 (Plk1) protein abundance in multiple lung cancer cell lines and the extent of Plk1 activation loop phosphorylation (pThr-210) during release from S phase.
doi:10.1038/nprot.2010.196
PMCID: PMC3736726  PMID: 21293459
22.  Pharmacometabolomics of Response to Sertraline and to Placebo in Major Depressive Disorder – Possible Role for Methoxyindole Pathway 
PLoS ONE  2013;8(7):e68283.
Therapeutic response to selective serotonin (5-HT) reuptake inhibitors in Major Depressive Disorder (MDD) varies considerably among patients, and the onset of antidepressant therapeutic action is delayed until after 2 to 4 weeks of treatment. The objective of this study was to analyze changes within methoxyindole and kynurenine (KYN) branches of tryptophan pathway to determine whether differential regulation within these branches may contribute to mechanism of variation in response to treatment. Metabolomics approach was used to characterize early biochemical changes in tryptophan pathway and correlated biochemical changes with treatment outcome. Outpatients with MDD were randomly assigned to sertraline (n = 35) or placebo (n = 40) in a double-blind 4-week trial; response to treatment was measured using the 17-item Hamilton Rating Scale for Depression (HAMD17). Targeted electrochemistry based metabolomic platform (LCECA) was used to profile serum samples from MDD patients. The response rate was slightly higher for sertraline than for placebo (21/35 [60%] vs. 20/40 [50%], respectively, χ2(1)  = 0.75, p = 0.39). Patients showing a good response to sertraline had higher pretreatment levels of 5-methoxytryptamine (5-MTPM), greater reduction in 5-MTPM levels after treatment, an increase in 5-Methoxytryptophol (5-MTPOL) and Melatonin (MEL) levels, and decreases in the (KYN)/MEL and 3-Hydroxykynurenine (3-OHKY)/MEL ratios post-treatment compared to pretreatment. These changes were not seen in the patients showing poor response to sertraline. In the placebo group, more favorable treatment outcome was associated with increases in 5-MTPOL and MEL levels and significant decreases in the KYN/MEL and 3-OHKY/MEL; changes in 5-MTPM levels were not associated with the 4-week response. These results suggest that recovery from a depressed state due to treatment with drug or with placebo could be associated with preferential utilization of serotonin for production of melatonin and 5-MTPOL.
doi:10.1371/journal.pone.0068283
PMCID: PMC3714282  PMID: 23874572
23.  Assessing anxious features in depressed outpatients 
Both the 17-item Hamilton Rating Scale for Depression (HRSD17) and 30-item Inventory of Depressive Symptomatology – Clinician-rated (IDS-C30) contain a subscale that assesses anxious symptoms. We used classical test theory and item response theory methods to assess and compare the psychometric properties of the two anxiety subscales (HRSDANX and IDS-CANX) in a large sample (N = 3453) of outpatients with non-psychotic major depressive disorder in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. Approximately 48% of evaluable participants had at least one concurrent anxiety disorder by the self-report Psychiatric Diagnostic Screening Questionnaire (PDSQ). The HRSDANX and IDS-CANX were highly correlated (r = 0.75) and both had moderate internal consistency given their limited number of items (HRSDANX Cronbach’s alpha = 0.48; IDS-CANX Cronbach’s alpha = 0.58). The optimal threshold for ascribing the presence/absence of anxious features was found at a total score of eight or nine for the HRSDANX and seven or eight for the IDS-CANX. It would seem beneficial to delete item 17 (loss of insight) from the HRSDANX as it negatively correlated with the scale’s total score. Both the HRSDANX and IDS-CANX subscales have acceptable psychometric properties and can be used to identify anxious features for clinical or research purposes.
doi:10.1002/mpr.353
PMCID: PMC3708141  PMID: 22057975
depression; anxiety; rating scales; STAR*D; measurement-based care
24.  Faster Remission of Chronic Depression With Combined Psychotherapy and Medication Than With Each Therapy Alone 
The main aim of the present novel reanalysis of archival data was to compare the time to remission during 12 weeks of treatment of chronic depression following antidepressant medication (n = 218), psychotherapy (n = 216), and their combination (n = 222). Cox regression survival analyses revealed that the combination of medication and psychotherapy produced full remission from chronic depression more rapidly than either of the single modality treatments, which did not differ from each other. Receiver operating characteristic curve analysis was used to explore predictors (treatment group, demographic, clinical, and psychosocial) of remission. For those receiving the combination treatment, the most likely to succeed were those with low baseline depression (24-item Hamilton Rating Scale for Depression [HRSD; M. Hamilton, 1967] score < 26) and those with high depression scores but low anxiety (HRSD ≥ 26 and Hamilton Anxiety Rating Scale [M. Hamilton, 1959] <14). Both profiles were associated with at least 40% chance of attaining full remission. The model did not identify predictors for those receiving medication or psychotherapy alone, and it did not distinguish between the 2 monotherapies. The authors conclude that combined antidepressant medications and psychotherapy result in faster full remission of chronic forms of major depressive disorder.
doi:10.1037/0022-006X.76.3.459
PMCID: PMC3694578  PMID: 18540739
chronic depression; remission; psychotherapy; antidepressant medications; combined treatments
25.  Relief of Expressed Suicidal Intent by ECT: A Consortium for Research in ECT Study 
The American journal of psychiatry  2005;162(5):977-982.
Objective
This study assessed the incidence, severity, and course of expressed suicidal intent in depressed patients who were treated with ECT. The data are from the first phase of an ongoing, collaborative multicenter study, the overall aim of which was to compare continuation ECT with pharmacotherapy in the prevention of relapse after a successful course of ECT.
Method
Suicidal intent, as expressed by patients during an interview, was scored at baseline and before each ECT session with item 3 on the 24-item Hamilton Depression Rating Scale in 444 patients with unipolar depression.
Results
One hundred thirty-one patients (29.5%) reported suicidal thoughts and acts (score of 3 or 4) at baseline. Scores decreased to 0 after 1 week (three ECT sessions) in 38.2% of the patients, after 2 weeks (six ECT sessions) in 61.1%, and in 80.9% at the end of the course of treatment.
Conclusions
Expressed suicidal intent in depressed patients was rapidly relieved with ECT. Evidence-based treatment algorithms for major depressive mood disorders should include dichotomization according to suicide risk, as assessed by interview. For patients at risk, ECT should be considered earlier than at its conventional “last resort” position.
doi:10.1176/appi.ajp.162.5.977
PMCID: PMC3684568  PMID: 15863801

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