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1.  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.
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.
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.
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).
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.
PMCID: PMC3860362  PMID: 22147631
anxiety; change; depression; SSRI; outcome
2.  The Resources for Enhancing Alzheimer’s Caregiver Health (REACH): Project Design and Baseline Characteristics 
Psychology and aging  2003;18(3):375-384.
The Resources for Enhancing Alzheimer’s Cargiver Health (REACH) project was designed to test promising interventions for enhancing family caregiving for persons with dementia. The purpose of this article is to describe the research design, interventions, and outcome measures used in REACH and to characterize the sample recruited for the study. Nine interventions and 2 control conditions were implemented at 6 sites; 1,222 dyads were randomly assigned to an intervention or a control condition. The caregiver sample was 18.6% male with an average age of 62.3 years (56% Caucasian, 24% Black, and 19% Hispanic). Caregivers reported high levels of depressive symptoms and moderate burden. Care recipients were older, with a mean age of 79, and were moderately to severely impaired with mean Mini-Mental State Exam scores of 13/30.
PMCID: PMC2577188  PMID: 14518801
3.  Prospective Evaluation of Hot Flashes during Pregnancy and Postpartum 
Fertility and sterility  2013;100(6):1667-1672.
To determine the prevalence, course, and risk factors for hot flashes during pregnancy and postpartum.
Study Design
Women (N=429) were assessed prospectively during pregnancy (weeks 20, 30, 36) and up to a year after delivery (weeks 2, 12, 26, 52). A clinical interview, physical measurements, and questionnaires were administered at each visit.
Thirty-five percent of women reported hot flashes during pregnancy and 29% reported hot flashes after delivery. In multivariable binomial mixed effects models, women who were younger (per year: OR(95%CI): 0.94(0.88–0.99)), had a higher pre-pregnancy body mass index (BMI; per unit increase: OR(95%CI): 1.05(1.01–1.10)), and had less than a college education (OR(95%CI): 2.58(1.19–5.60); vs. college) were more likely to report hot flashes during pregnancy. Higher depressive symptoms were associated with hot flashes during pregnancy (per unit increase: OR(95%CI): 1.08(1.04–1.13)) and after birth (OR(95%CI): 1.19(1.14–1.25), multivariable models).
Hot flashes, typically considered a menopausal symptom, were reported by over a third of women during pregnancy and/or postpartum. Predictors of hot flashes during this reproductive transition, including depressive symptoms, low education, and higher BMI are similar to those experienced during menopause. Future work should investigate the role of hormonal and affective factors in hot flashes during pregnancy and postpartum.
PMCID: PMC4167790  PMID: 24035604
Hot flashes; pregnancy; postpartum; night sweats; vasomotor symptoms
4.  Relationship Between Obesity and Depression: Characteristics and Treatment Outcomes with Antidepressant Medication 
Psychosomatic medicine  2013;75(9):863-872.
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.
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.
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.
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 Identifier: NCT 00270647
PMCID: PMC3905462  PMID: 24163386
Depression; Obesity; Treatment Resistance
5.  Disturbed Sleep and Inflammatory Cytokines in Depressed and Nondepressed Pregnant Women: An Exploratory Analysis of Pregnancy Outcomes 
Psychosomatic medicine  2013;75(7):670-681.
Disturbed sleep and depression are potential risk factors for pregnancy complications. Both conditions are noted to dysregulate biological pathways responsible for maintaining homeostatic balance and pregnancy health. Depression during pregnancy is associated with poor sleep. Thus, we explored whether disturbed sleep was associated with inflammatory cytokines and risk for adverse pregnancy outcomes, as well as whether depression augmented the sleep-cytokine relationship thereby additively contributing to risk for adverse outcomes.
Interview-assessed sleep and plasma cytokine concentrations were evaluated in a cohort of depressed and non-depressed pregnant women (N= 168) at 20 and 30 weeks gestation. Outcomes evaluated included preterm birth, birth weight, and peripartum events.
Among depressed women, short sleep duration (< 7 hours) was associated with higher IL-8 across time (β=.506, p = .001), poor sleep efficiency (< 85%) was associated with higher IL-6 (β=.205, p = .006), and daytime naps were associated with higher TNF-α (β=.105, p =.024). Aspects of poor sleep were associated with having a lower weight baby (ps < 053). Among depressed women, IFN-γ increased risk for preterm birth (OR = 1.175, p = .032). Trends for IL-6 and higher birth weight (β = 105.2, p = .085); IFN-γ and lower birth weight (β = −19.92, p < .069); and increased IL-8 and babies weighing < 4000g, (OR =.72, p < .083) were observed.
Although speculative, disturbed sleep may disrupt normal immune processes and contribute to adverse pregnancy outcomes. Exploratory analyses indicate depression modifies these relationships.
PMCID: PMC3926698  PMID: 23864582
Sleep; depression; pregnancy; cytokine; outcomes; sleep quality
6.  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.
PMCID: PMC4086840  PMID: 25013241
Maternal depression; Family functioning; Child adjustment; Gender
7.  Retrospective age-at-onset of bipolar disorder and outcome during two-year follow-up: results from the STEP-BD study 
Bipolar disorders  2009;11(4):391-400.
Symptoms of bipolar disorder are increasingly recognized among children and adolescents, but little is known about the course of bipolar disorder among adults who experience childhood onset of symptoms.
We examined prospective outcomes during up to two years of naturalistic treatment among 3,658 adult bipolar I and II outpatients participating in a multicenter clinical effectiveness study, the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). Age at illness onset was identified retrospectively by clinician assessment at study entry.
Compared to patients with onset of mood symptoms after age 18 years (n = 1,187), those with onset before age 13 years (n = 1,068) experienced earlier recurrence of mood episodes after initial remission, fewer days of euthymia, and greater impairment in functioning and quality of life over the two-year follow-up. Outcomes for those with onset between age 13 and 18 years (n = 1,403) were generally intermediate between these two groups.
Consistent with previous reports in smaller cohorts, adults with retrospectively obtained early-onset bipolar disorder appear to be at greater risk for recurrence, chronicity of mood symptoms, and functional impairment during prospective observation.
PMCID: PMC3992980  PMID: 19500092
age of onset; bipolar disorder; chronicity; depression; maintenance; mania; recurrence
8.  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.
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.
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.
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.
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).
PMCID: PMC3634137  PMID: 23480315
9.  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.
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.
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.
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.
In this study, citalopram treatment outcome was not affected by menopausal status. Hormonal contraceptives and HT also did not affect probability of good outcome.
PMCID: PMC3613168  PMID: 23398127
10.  MRI assessment of cerebral blood flow after experimental traumatic brain injury combined with hemorrhagic shock in mice 
Secondary insults such as hypotension or hemorrhagic shock (HS) can greatly worsen outcome after traumatic brain injury (TBI). We recently developed a mouse combined injury model of TBI and HS using a controlled cortical impact (CCI) model and showed that 90 minutes of HS can exacerbate neuronal death in hippocampus beneath the contusion. This combined injury model has three clinically relevant phases, a shock, pre hospital, and definitive care phases. Mice were randomly assigned to four groups, shams as well as a CCI only, an HS only, and a CCI+HS groups. The CCI and HS reduced cerebral blood flow (CBF) in multiple regions of interest (ROIs) in the hemisphere ipsilateral and contralateral to injury. Hemorrhagic shock to a level of ∼30 mm Hg exacerbated the CCI-induced CBF reductions in multiple ROIs ipsilateral to injury (hemisphere and thalamus) and in the hemisphere contralateral to injury (hemisphere, thalamus, hippocampus, and cortex, all P<0.05 versus CCI only, HS only or both). An important effect of HS duration was also seen after CCI with maximal CBF reduction seen at 90 minutes (P<0.0001 group-time effect in ipsilateral hippocampus). Given that neuronal death in hippocampus is exacerbated by 90 minutes of HS in this model, our data suggest an important role for exacerbation of posttraumatic ischemia in mediating the secondary injury in CCI plus HS. In conclusion, the serial, non invasive assessment of CBF using ASL-MRI (magnetic resonance imaging with arterial spin labeling) is feasible in mice even in the complex setting of combined CCI+HS. The impact of resuscitation therapies and various mutant mouse strains on CBF and other outcomes merits investigation in this model.
PMCID: PMC3597358  PMID: 23072750
ASL-MRI; hemorrhagic shock; traumatic brain injury
11.  Cognitive Therapy Alone and in Combination with Antidepressants for Anxious Depression: A STAR*D Report 
Journal of affective disorders  2012;142(1-3):213-218.
Anxious depression, defined as MDD with high levels of anxiety, has been associated with lower rates of antidepressant response and remission as well as greater chronicity, suicidality and antidepressant side-effect burden. The primary aim of this study was to assess the effectiveness of cognitive therapy (CT) alone or in combination with medications for anxious versus non-anxious depression.
We assessed the STAR*D study participants who were partial or non-responders to citalopram. Subjects were then either switched (n = 696) to a new antidepressant or to CT alone, or they were kept on citalopram and augmented (n = 577) with another antidepressant or CT. We compared response and remission rates of those who met criteria for anxious depression to those who did not across treatment conditions.
Those with anxious depression had significantly lower remission rates based on the QIDS, whether assigned to switch or augmentation, compared to those with non-anxious depression. Those with anxious depression, compared to those without, had significantly lower response rates based on the QIDS only in the switch group. There was no significant interaction between anxious depression and treatment assignment.
Limitations include the use of citalopram as the only Level 1 pharmacotherapy and medication augmentation option, depression-focused CT rather than anxiety-focused CT, and focus on acute treatment outcomes.
Individuals with anxious depression appear to experience higher risk of poorer outcome following pharmacotherapy and/or CT after an initial course of SSRI, and continued efforts to target this challenging form of depression are needed.
PMCID: PMC3483355  PMID: 22877961
anxious depression; MDD; CT; psychosocial interventions; STAR*D
12.  Risk Factors for Mortality in Children with Abusive Head Trauma 
The Journal of pediatrics  2012;161(4):716-722.e1.
We sought to identify risk factors for mortality in a large clinical cohort of children with abusive head trauma.
Study design
Bivariate analysis and multivariable logistic regression models identified demographic, physical examination and radiologic findings associated with in-hospital mortality of children with abusive head trauma at four pediatric centers. An initial Glasgow Coma Scale (GCS) ≤ 8 defined severe abusive head trauma. Data are shown as OR (95% CI).
Analysis included 386 children with abusive head trauma. Multivariable analysis showed children with initial GCS either 3 or 4 – 5 had increased mortality versus children with GCS 12 – 15 (OR 57.8 [12.1 – 277.6] and 15.6 [2.6 – 95.1], respectively, p < 0.001). Additionally, retinal hemorrhage (RH), intraparenchymal hemorrhage and cerebral edema were independently associated with mortality. In the subgroup with severe abusive head trauma and RH (n = 117), cerebral edema and initial GCS of 3 or 4 – 5 were independently associated with mortality. Chronic subdural hematoma was independently associated with survival.
Low initial GCS score, RH, intraparenchymal hemorrhage and cerebral edema are independently associated with mortality in abusive head trauma. Knowledge of these risk factors may enable researchers and clinicians to improve the care of these vulnerable children.
PMCID: PMC3437227  PMID: 22578583
child physical abuse; Glasgow Coma Scale; retinal hemorrhage; subdural hematoma; pediatric; traumatic brain injury
13.  The impact of local anesthetic distribution on block onset in Ultrasound-guided interscalene block 
Acta anaesthesiologica Scandinavica  2012;56(9):1146-1151.
Recent investigations of local anesthetic distribution in the lower extremity have revealed that completely surrounding the sciatic nerve with local anesthetic provides the advantage of more rapid and complete anesthesia in the territory served by the nerve. We hypothesized that a pattern of distribution which entirely envelops the targeted nerve roots during interscalene block would provide similar benefits of more rapid anesthesia onset.
During interscalene block guided by ultrasound with nerve-stimulator confirmation, the pattern of local anesthetic distribution was recorded and later classified as complete or incomplete envelopment of the visible nerve elements in 50 patients undergoing ambulatory shoulder arthroscopic surgery. The pattern was then compared to the extent of block set-up at predetermined intervals, as well as to postoperative pain levels and block duration.
22 patients (44%) had complete envelopment of the nerves in the plane of injection during ultrasound imaging of the interscalene block. There was no difference in the fraction of blocks that were fully set-up at 10 minutes with regards to complete or incomplete envelopment of the nerves by local anesthetic. All of the patients had complete set-up of the block by 20 minutes. In addition, the postoperative pain levels and duration of block did not vary among the two groups with complete versus incomplete local anesthetic distribution around the nerves.
The presence or absence of complete envelopment of the nerve elements in the interscalene groove by local anesthetic did not determine the likelihood of complete block effect at predetermined time intervals after the procedure.
PMCID: PMC3653130  PMID: 22845687
14.  Severe Brief Pressure-Controlled Hemorrhagic Shock after Traumatic Brain Injury Exacerbates Functional Deficits and Long-Term Neuropathological Damage in Mice 
Journal of Neurotrauma  2012;29(12):2192-2208.
Hypotension after traumatic brain injury (TBI) worsens outcome. We published the first report of TBI plus hemorrhagic shock (HS) in mice using a volume-controlled approach and noted increased neuronal death. To rigorously control blood pressure during HS, a pressure-controlled HS model is required. Our hypothesis was that a brief, severe period of pressure-controlled HS after TBI in mice will exacerbate functional deficits and neuropathology versus TBI or HS alone. C57BL6 male mice were randomized into four groups (n=10/group): sham, HS, controlled cortical impact (CCI), and CCI+HS. We used a pressure-controlled shock phase (mean arterial pressure [MAP]=25–27 mm Hg for 35 min) and its treatment after mild to moderate CCI including, a 90 min pre-hospital phase, during which lactated Ringer's solution was given to maintain MAP >70 mm Hg, and a hospital phase, when the shed blood was re-infused. On days 14–20, the mice were evaluated in the Morris water maze (MWM, hidden platform paradigm). On day 21, the lesion and hemispheric volumes were quantified. Neuropathology and hippocampal neuron counts (hematoxylin and eosin [H&E], Fluoro-Jade B, and NeuN) were evaluated in the mice (n=60) at 24 h, 7 days, or 21 days (n=5/group/time point). HS reduced MAP during the shock phase in the HS and CCI+HS groups (p<0.05). Fluid requirements during the pre-hospital phase were greatest in the CCI+HS group (p<0.05), and were increased in HS versus sham and CCI animals (p<0.05). MWM latency was increased on days 14 and 15 after CCI+HS (p<0.05). Swim speed and visible platform latency were impaired in the CCI+HS group (p<0.05). CCI+HS animals had increased contusion volume versus the CCI group (p<0.05). Hemispheric volume loss was increased 33.3% in the CCI+HS versus CCI group (p<0.05). CA1 cell loss was seen in CCI+HS and CCI animals at 24 h and 7 days (p<0.05). CA3 cell loss was seen after CCI+HS (p<0.05 at 24 h and 7 days). CA1 cell loss at 21 days was seen only in CCI+HS animals (p<0.05). Brief, severe, pressure-controlled HS after CCI produces robust functional deficits and exacerbates neuropathology versus CCI or HS alone.
PMCID: PMC3472682  PMID: 22738159
blast injury; controlled cortical impact; head injury; head trauma; Morris water maze; polytrauma; secondary insult
15.  Running in Place: Implications of HIV Incidence Estimates among Urban Men Who Have Sex with Men in the United States and Other Industrialized Countries 
AIDS and behavior  2009;13(4):615-629.
Attempts to document changing HIV incidence rates among MSM are compromised by issues of generalizability and statistical power. To address these issues, this paper reports annualized mean HIV incidence rates from the entire published incidence literature on MSM from Europe, North America and Australia for the period 1995–2005. Publications that met the entry criteria were coded for region of the world, sampling method and year of study. From these reports, we calculated a mean incidence rate with confidence intervals for these variables. Although no differences in mean incidence rates were found for MSM from 1995 to 2005, HIV incidence rates are lower in Australia than either North America or Europe. We calculated a mean incidence rate of 2.39% for MSM in the United States, which if sustained within a cohort of MSM, would yield HIV prevalence rate of approximately 40% at age 40. These extrapolations overlap published HIV prevalence rates for MSM younger than age 40 in the United States. HIV incidence rates in the 2–3% range will adversely affect the health of gay male communities for decades to come. This analysis suggests that greater attention should be devoted to the question of how best to design prevention interventions that will lower HIV incidence rates among gay men.
PMCID: PMC3738434  PMID: 19205867
Men who have sex with men; HIV/AIDS; Epidemiology; Prevention
16.  Increases in cerebrospinal fluid caffeine concentration are associated with favorable outcome after severe traumatic brain injury in humans 
Caffeine, the most widely consumed psychoactive drug and a weak adenosine receptor antagonist, can be neuroprotective or neurotoxic depending on the experimental model or neurologic disorder. However, its contribution to pathophysiology and outcome in traumatic brain injury (TBI) in humans is undefined. We assessed serial cerebrospinal fluid (CSF) concentrations of caffeine and its metabolites (theobromine, paraxanthine, and theophylline) by high-pressure liquid chromatography/ultraviolet in 97 ventricular CSF samples from an established bank, from 30 adults with severe TBI. We prospectively selected a threshold caffeine level of ≥1 μmol/L (194 ng/mL) as clinically significant. Demographics, Glasgow Coma Scale (GCS) score, admission blood alcohol level, and 6-month dichotomized Glasgow Outcome Scale (GOS) score were assessed. Mean time from injury to initial CSF sampling was 10.77±3.13 h. On initial sampling, caffeine was detected in 24 of 30 patients, and the threshold was achieved in 9 patients. Favorable GOS was seen more often in patients with CSF caffeine concentration ≥ versus < the threshold (55.6 versus 11.8%, P = 0.028). Gender, age, admission CGS score, admission blood alcohol level, and admission systolic arterial blood pressure did not differ between patients with CSF caffeine concentration ≥ versus < the threshold. Increases in CSF concentrations of the caffeine metabolites theobromine and paraxanthine were also associated with favorable outcome (P = 0.018 and 0.056, respectively). Caffeine and its metabolites are commonly detected in CSF in patients with severe TBI and in an exploratory assessment are associated with favorable outcome. We speculate that caffeine may be neuroprotective by long-term upregulation of adenosine A1 receptors or acute inhibition of A2a receptors.
PMCID: PMC3714395  PMID: 17684518
adenosine; alcohol; coffee; head injury; head trauma; theobromine
17.  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.
PMCID: PMC3708141  PMID: 22057975
depression; anxiety; rating scales; STAR*D; measurement-based care
18.  How Influenza Vaccination Policy May affect Vaccine Logistics 
Vaccine  2012;30(30):4517-4523.
When policymakers make decision about the target populations and timing of influenza vaccination, they may not consider the impact on the vaccine supply chains, which may in turn affect vaccine availability.
Our goal is to explore the effects on the Thailand vaccine supply chain of introducing influenza vaccines and varying the target populations and immunization time-frames.
Utilized our custom-designed software HERMES (Highly Extensible Resource for Modeling Supply Chains), we developed a detailed, computational discrete-event simulation model of the Thailand's National Immunization Program (NIP) supply chain in Trang Province, Thailand., A suite of experiments simulated introducing influenza vaccines for different target populations and over different time-frames prior to and during the annual influenza season.
Introducing influenza vaccines creates bottlenecks that reduce the availability of both influenza vaccines as well as the other NIP vaccines, with provincial to district transport capacity being the primary constraint. Even covering only 25% of the Advisory Committee on Immunization Practice-recommended population while administering the vaccine over six months hinders overall vaccine availability so that only 62% of arriving patients can receive vaccines. Increasing the target population from 25% to 100% progressively worsens these bottlenecks, while increasing influenza vaccination time - frame from 1 to 6 months decreases these bottlenecks.
Since the choice of target populations for influenza vaccination and the time-frame to deliver this vaccine can substantially affect the flow of all vaccines, policy-makers may want to consider supply chain effects when choosing target populations for a vaccine.
PMCID: PMC3592980  PMID: 22537993
Influenza vaccine; supply chain; immunization policy
19.  Residual Symptoms in Depressed Outpatients Who Respond by 50% But Do Not Remit to Antidepressant Medication 
Little is known about the quantity or quality of residual depressive symptoms in patients with major depressive disorder (MDD) who have responded but not remitted with antidepressant treatment. This report describes the residual symptom domains and individual depressive symptoms in a large representative sample of outpatients with nonpsychotic MDD who responded without remitting after up to 12 weeks of citalopram treatment in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. Response was defined as 50% or greater reduction in baseline 16-item Quick Inventory of Depressive Symptomatology—Self-Report (QIDS-SR16) by treatment exit, and remission as a final QIDS-SR16 of less than 6. Residual symptom domains and individual symptoms were based on the QIDS-SR16 and classified as either persisting from baseline or emerging during treatment. Most responders who did not remit endorsed approximately 5 residual symptom domains and 6 to 7 residual depressive symptoms. The most common domains were insomnia (94.6%), sad mood (70.8%), and decreased concentration (69.6%). The most common individual symptoms were midnocturnal insomnia (79.0%), sad mood (70.8%), and decreased concentration/decision making (69.6%). The most common treatment-emergent symptoms were midnocturnal insomnia (51.4%) and decreased general interest (40.0%). The most common persistent symptoms were midnocturnal insomnia (81.6%), sad mood (70.8%), and decreased concentration/decision making (70.6%). Suicidal ideation was the least common treatment-emergent symptom (0.7%) and the least common persistent residual symptom (17.1%). These findings suggest that depressed outpatients who respond by 50% without remitting to citalopram treatment have a broad range of residual symptoms. Individualized treatments are warranted to specifically address each patient's residual depressive symptoms.
PMCID: PMC3677201  PMID: 21346613
depression; STAR*D; residual; symptoms; treatment response
To compare the correlation of intracranial pressure (ICP) measurement and time to detection of ICP crises (defined as ICP ≥ 20 mm Hg for ≥ 5 min) between an intraparenchymal (IP) monitor and external ventricular drain (EVD) in children where continuous cerebrospinal fluid (CSF) diversion was used as a therapy for severe traumatic brain injury (TBI).
Academic, pediatric intensive care unit.
Retrospective review of a prospectively-collected Pediatric Neurotrauma database.
Children with severe TBI (GCS ≤ 8) who underwent ICP monitoring with both IP and EVD techniques were studied. In Cohort 1 (n = 58), hourly ICP measurements were extracted from the medical record. In Cohort 2 (n = 4), ICP measurements were collected every minute by an automated data collection system.
Measurements and Main Results
The mean absolute difference in ICP (|ICP|) and intraclass correlation coefficients (ICC) were calculated. Timing to detection of ICP crises was analyzed. Data expressed as mean ± SEM. In cohort 1, 7,387 hours of data were analyzed and 399 hours (23,940 min) were analyzed in Cohort 2. In Cohort 1, |ICP| = 3.10 ± 0.04 mm Hg (ICC = 0.98, p < 0.001). |ICP| in Cohort 2 was 3.30 ± 0.05 mm Hg (ICC = 0.98, p < 0.001). In Cohort 2, a total of 75 ICP crises were observed. Fifty-five (73%) were detected first by the IP monitor, of which 35 were not identified by the EVD monitor. Time between IP and EVD detection of a crisis was 12.60 ± 2.34 min.
EVD and IP measurements of ICP were highly correlated, although intermittent EVD ICP measurements may fail to identify ICP events when continuously draining CSF. In institutions using continuous CSF diversion as a therapy, a two-monitor system may be valuable for accomplishing monitoring and therapeutic goals.
PMCID: PMC3670608  PMID: 20625341
21.  Common genetic variants in the CLDN2 and PRSS1-PRSS2 loci alter risk for alcohol-related and sporadic pancreatitis 
Whitcomb, David C. | LaRusch, Jessica | Krasinskas, Alyssa M. | Klei, Lambertus | Smith, Jill P. | Brand, Randall E. | Neoptolemos, John P. | Lerch, Markus M. | Tector, Matt | Sandhu, Bimaljit S. | Guda, Nalini M. | Orlichenko, Lidiya | Alkaade, Samer | Amann, Stephen T. | Anderson, Michelle A. | Baillie, John | Banks, Peter A. | Conwell, Darwin | Coté, Gregory A. | Cotton, Peter B. | DiSario, James | Farrer, Lindsay A. | Forsmark, Chris E. | Johnstone, Marianne | Gardner, Timothy B. | Gelrud, Andres | Greenhalf, William | Haines, Jonathan L. | Hartman, Douglas J. | Hawes, Robert A. | Lawrence, Christopher | Lewis, Michele | Mayerle, Julia | Mayeux, Richard | Melhem, Nadine M. | Money, Mary E. | Muniraj, Thiruvengadam | Papachristou, Georgios I. | Pericak-Vance, Margaret A. | Romagnuolo, Joseph | Schellenberg, Gerard D. | Sherman, Stuart | Simon, Peter | Singh, Vijay K. | Slivka, Adam | Stolz, Donna | Sutton, Robert | Weiss, Frank Ulrich | Wilcox, C. Mel | Zarnescu, Narcis Octavian | Wisniewski, Stephen R. | O'Connell, Michael R. | Kienholz, Michelle L. | Roeder, Kathryn | Barmada, M. Michael | Yadav, Dhiraj | Devlin, Bernie | Albert, Marilyn S. | Albin, Roger L. | Apostolova, Liana G. | Arnold, Steven E. | Baldwin, Clinton T. | Barber, Robert | Barnes, Lisa L. | Beach, Thomas G. | Beecham, Gary W. | Beekly, Duane | Bennett, David A. | Bigio, Eileen H. | Bird, Thomas D. | Blacker, Deborah | Boxer, Adam | Burke, James R. | Buxbaum, Joseph D. | Cairns, Nigel J. | Cantwell, Laura B. | Cao, Chuanhai | Carney, Regina M. | Carroll, Steven L. | Chui, Helena C. | Clark, David G. | Cribbs, David H. | Crocco, Elizabeth A. | Cruchaga, Carlos | DeCarli, Charles | Demirci, F. Yesim | Dick, Malcolm | Dickson, Dennis W. | Duara, Ranjan | Ertekin-Taner, Nilufer | Faber, Kelley M. | Fallon, Kenneth B. | Farlow, Martin R. | Ferris, Steven | Foroud, Tatiana M. | Frosch, Matthew P. | Galasko, Douglas R. | Ganguli, Mary | Gearing, Marla | Geschwind, Daniel H. | Ghetti, Bernardino | Gilbert, John R. | Gilman, Sid | Glass, Jonathan D. | Goate, Alison M. | Graff-Radford, Neill R. | Green, Robert C. | Growdon, John H. | Hakonarson, Hakon | Hamilton-Nelson, Kara L. | Hamilton, Ronald L. | Harrell, Lindy E. | Head, Elizabeth | Honig, Lawrence S. | Hulette, Christine M. | Hyman, Bradley T. | Jicha, Gregory A. | Jin, Lee-Way | Jun, Gyungah | Kamboh, M. Ilyas | Karydas, Anna | Kaye, Jeffrey A. | Kim, Ronald | Koo, Edward H. | Kowall, Neil W. | Kramer, Joel H. | Kramer, Patricia | Kukull, Walter A. | LaFerla, Frank M. | Lah, James J. | Leverenz, James B. | Levey, Allan I. | Li, Ge | Lin, Chiao-Feng | Lieberman, Andrew P. | Lopez, Oscar L. | Lunetta, Kathryn L. | Lyketsos, Constantine G. | Mack, Wendy J. | Marson, Daniel C. | Martin, Eden R. | Martiniuk, Frank | Mash, Deborah C. | Masliah, Eliezer | McKee, Ann C. | Mesulam, Marsel | Miller, Bruce L. | Miller, Carol A. | Miller, Joshua W. | Montine, Thomas J. | Morris, John C. | Murrell, Jill R. | Naj, Adam C. | Olichney, John M. | Parisi, Joseph E. | Peskind, Elaine | Petersen, Ronald C. | Pierce, Aimee | Poon, Wayne W. | Potter, Huntington | Quinn, Joseph F. | Raj, Ashok | Raskind, Murray | Reiman, Eric M. | Reisberg, Barry | Reitz, Christiane | Ringman, John M. | Roberson, Erik D. | Rosen, Howard J. | Rosenberg, Roger N. | Sano, Mary | Saykin, Andrew J. | Schneider, Julie A. | Schneider, Lon S. | Seeley, William W. | Smith, Amanda G. | Sonnen, Joshua A. | Spina, Salvatore | Stern, Robert A. | Tanzi, Rudolph E. | Trojanowski, John Q. | Troncoso, Juan C. | Tsuang, Debby W. | Valladares, Otto | Van Deerlin, Vivianna M. | Van Eldik, Linda J. | Vardarajan, Badri N. | Vinters, Harry V. | Vonsattel, Jean Paul | Wang, Li-San | Weintraub, Sandra | Welsh-Bohmer, Kathleen A. | Williamson, Jennifer | Woltjer, Randall L. | Wright, Clinton B. | Younkin, Steven G. | Yu, Chang-En | Yu, Lei
Nature genetics  2012;44(12):1349-1354.
Pancreatitis is a complex, progressively destructive inflammatory disorder. Alcohol was long thought to be the primary causative agent, but genetic contributions have been of interest since the discovery that rare PRSS1, CFTR, and SPINK1 variants were associated with pancreatitis risk. We now report two significant genome-wide associations identified and replicated at PRSS1-PRSS2 (1×10-12) and x-linked CLDN2 (p < 1×10-21) through a two-stage genome-wide study (Stage 1, 676 cases and 4507 controls; Stage 2, 910 cases and 4170 controls). The PRSS1 variant affects susceptibility by altering expression of the primary trypsinogen gene. The CLDN2 risk allele is associated with atypical localization of claudin-2 in pancreatic acinar cells. The homozygous (or hemizygous male) CLDN2 genotype confers the greatest risk, and its alleles interact with alcohol consumption to amplify risk. These results could partially explain the high frequency of alcohol-related pancreatitis in men – male hemizygous frequency is 0.26, female homozygote is 0.07.
PMCID: PMC3510344  PMID: 23143602
22.  Postpartum Lipid Levels in Women with Major Depression 
Journal of Women's Health  2012;21(5):534-538.
Maternal plasma lipids, including total cholesterol, low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C), increase during pregnancy, remaining elevated over prepregnancy levels through the immediate postpartum period. Triglycerides decrease rapidly to prepregnancy levels after delivery. Few data on postpartum lipid levels are available, and levels in postpartum women with depression have not been evaluated. We sought to determine the cross-sectional levels of total cholesterol, LDL-C, HDL-C, and triglycerides between 1 and 14 weeks postpartum in postpartum women with DSM-4 diagnoses of major depression and determine if they are similarly elevated to published levels in other postpartum populations.
As part of screening for a randomized controlled trial comparing treatments for postpartum depression (PPD), women (n=120) had postpartum fasting lipid levels determined. Linear regression models were used to assess the association between time postpartum and lipid levels. Analysis of covariance models (ANCOVA) assessed the association of baseline characteristics with lipids.
Total cholesterol levels were >200 mg/dL in 45% of the sample at baseline. Mean baseline total cholesterol was 196±39 mg/dL. There was an inverse linear relationship between postpartum week and total cholesterol, with cholesterol values decreasing an average of 4.5 mg/dL per week. Similarly, LDL-C and HDL-C trended down over time. Triglycerides were stable and within the normal range during the observation period.
Total cholesterol, HDL-C, and LDL-C are significantly elevated in the early postpartum period and do not return to <200 mg/dL until 6 weeks postpartum in women with PPD. The magnitude and duration of elevation are consistent with the sparse published data on nondepressed women.
PMCID: PMC3353826  PMID: 22283499
23.  Validity of a Pediatric Version of the Glasgow Outcome Scale–Extended 
Journal of Neurotrauma  2012;29(6):1126-1139.
The Glasgow Outcome Scale (GOS) and its most recent revision, the GOS–Extended (GOS-E), provide the gold standard for measuring traumatic brain injury (TBI) outcome. The GOS-E exhibits validity when used with adults and some adolescents, but validity with younger children is not established. Because the GOS-E lacks the developmental specificity necessary to evaluate children, toddlers, and infants, we modified the original version to create the GOS-E Pediatric Revision (GOS-E Peds), a developmentally appropriate structured interview, to classify younger patients. The criterion, predictive, and discriminant validity of the GOS-E Peds was measured in 159 subjects following TBI (mild: 36%; moderate: 12%; severe: 50%) at 3 and 6 months after injury. Participants were included from two studies completed at the Pediatric Neurotrauma Center at Children's Hospital of Pittsburgh. We assessed the relationship among GOS-E Peds, the GOS, and the Vineland Adaptive Behavior Scales as well as other standardized measures of functional, behavioral, intellectual, and neuropsychological outcome. Premorbid function was assessed 24–36 h after injury. The GOS-E Peds showed a strong correlation with the GOS at 3 and 6 month time points. Criterion-related validity was also indicated by GOS-E Peds' association with most measures at both time points and at injury severity levels. The 3 month GOS-E Peds was associated with the 6 month GOS-E Peds, everyday function, behavior, and most cognitive abilities. Discriminant validity is suggested by weak correlations between both 3 and 6 month GOS-E Peds and premorbid measures. The GOS-E Peds is sensitive to severity of injury and is associated with changes in TBI sequelae over time. This pediatric revision provides a valid outcome measure in infants, toddlers, children, and adolescents through age 16. Findings support using the GOS-E Peds as the primary outcome variable in pediatric clinical trials.
PMCID: PMC3325553  PMID: 22220819
children; GOS-E; infants; pediatrics; TBI; toddlers; Vineland Adaptive Behavior Scales
24.  The Impact of HAART on the Respiratory Complications of HIV Infection: Longitudinal Trends in the MACS and WIHS Cohorts 
PLoS ONE  2013;8(3):e58812.
To review the incidence of respiratory conditions and their effect on mortality in HIV-infected and uninfected individuals prior to and during the era of highly active antiretroviral therapy (HAART).
Two large observational cohorts of HIV-infected and HIV-uninfected men (Multicenter AIDS Cohort Study [MACS]) and women (Women’s Interagency HIV Study [WIHS]), followed since 1984 and 1994, respectively.
Adjusted odds or hazards ratios for incident respiratory infections or non-infectious respiratory diagnoses, respectively, in HIV-infected compared to HIV-uninfected individuals in both the pre-HAART (MACS only) and HAART eras; and adjusted Cox proportional hazard ratios for mortality in HIV-infected persons with lung disease during the HAART era.
Compared to HIV-uninfected participants, HIV-infected individuals had more incident respiratory infections both pre-HAART (MACS, odds ratio [adjusted-OR], 2.4; 95% confidence interval [CI], 2.2–2.7; p<0.001) and after HAART availability (MACS, adjusted-OR, 1.5; 95%CI 1.3–1.7; p<0.001; WIHS adjusted-OR, 2.2; 95%CI 1.8–2.7; p<0.001). Chronic obstructive pulmonary disease was more common in MACS HIV-infected vs. HIV-uninfected participants pre-HAART (hazard ratio [adjusted-HR] 2.9; 95%CI, 1.02–8.4; p = 0.046). After HAART availability, non-infectious lung diseases were not significantly more common in HIV-infected participants in either MACS or WIHS participants. HIV-infected participants in the HAART era with respiratory infections had an increased risk of death compared to those without infections (MACS adjusted-HR, 1.5; 95%CI, 1.3–1.7; p<0.001; WIHS adjusted-HR, 1.9; 95%CI, 1.5–2.4; p<0.001).
HIV infection remained a significant risk for infectious respiratory diseases after the introduction of HAART, and infectious respiratory diseases were associated with an increased risk of mortality.
PMCID: PMC3595204  PMID: 23554932
25.  Baseline depression severity as a predictor of single and combination antidepressant treatment outcome: Results from the CO-MED Trial 
European Neuropsychopharmacology  2011;22(3):183-199.
The objective of this manuscript is to report associations between baseline depressive severity and (1) baseline sociodemographic and clinical characteristics, (2) treatment outcomes, and (3) differential outcomes for three treatment groups. Six hundred and sixty-five outpatients with nonpsychotic, major depressive disorder were prospectively randomized to treatment with either a selective serotonin reuptake inhibitor (SSRI) monotherapy (escitalopram plus placebo) or one of two antidepressant medication combinations (bupropion-sustained release plus escitalopram, or venlafaxine-extended release plus mirtazapine). For purposes of these analyses, participants were divided into four groups based on baseline severity by the 16-item Quick Inventory of Depressive Symptomatology - Self-Report (QIDS-SR16) total score: mild (0–10) [N=81], moderate (11–15) [N=238], severe (16–20) [N=260] and very severe (21–27) [N=67]. Treatment outcomes at 12 and 28 weeks were compared among the four severity groups. A history of childhood neglect and/or abuse was strongly associated with the severity of adult depression (1/2 of participants in the very severy group versus 1/5–1/4 of those in the mild group reported abuse and/or neglect). The degree of suicidality (e.g., 15/.4% of the very severe group ever attempted suicide versus none in the mild group), the number of suicide attempts (e.g., mean of .41 +/− 1.99 suicide attempts in the severe group versus o.o +/−0.0 in the mild group) and severity of suicidality (e.g., 9.2% of participants in very severe group had a plan or made a gesture versus 5.6% in moderate group and none in the mild group) were increased in more severe groups. Participants with a greater baseline depressive severity reported significantly more psychiatric comorbitities (e..g. [at p < 0.05] increased rates of agoraphobia, bulimia, generalized anxiety, hypocondriasis, panic disorder, post-traumatic stress disorder, social phobia and somatoform disorder, with 23.9 % of participants in the very severe group having reported four or more psychiatric disorders versus 1.2% of the mild group). Combination medication treatments were no more effective in treating severe depressions than was SSRI monotherapy. Remission (61.7% of participants in the mild group achieved remission versus 28.4% in the very severe group) is more difficult to achieve in more severe groups than is response (48.8% of participants in the mild group achieved response versus 58.2% in the very severe group) (p < 0.03) . These data may help us to understand the impact of baseline features on antidepressant medication effectiveness and to inform the personalization of depression treatment across the spectrum of depressive severity.
PMCID: PMC3273676  PMID: 21920711
Depression; abuse; suicide; combination treatment severity; response; remission

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