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1.  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
2.  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
3.  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
4.  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
5.  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
6.  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
7.  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
8.  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
9.  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
10.  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
12.  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
13.  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
14.  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
15.  Psychosocial Treatments for Bipolar Depression: A 1-Year Randomized Trial From the Systematic Treatment Enhancement Program 
Archives of general psychiatry  2007;64(4):419-426.
Psychosocial interventions have been shown to enhance pharmacotherapy outcomes in bipolar disorder.
To examine the benefits of 4 disorder-specific psychotherapies in conjunction with pharmacotherapy on time to recovery and the likelihood of remaining well after an episode of bipolar depression.
Randomized controlled trial.
Fifteen clinics affiliated with the Systematic Treatment Enhancement Program for Bipolar Disorder.
A total of 293 referred outpatients with bipolar I or II disorder and depression treated with protocol pharmacotherapy were randomly assigned to intensive psychotherapy (n=163) or collaborative care (n=130), a brief psychoeducational intervention.
Intensive psychotherapy was given weekly and biweekly for up to 30 sessions in 9 months according to protocols for family-focused therapy, interpersonal and social rhythm therapy, and cognitive behavior therapy. Collaborative care consisted of 3 sessions in 6 weeks.
Main Outcome Measures
Outcome assessments were performed by psychiatrists at each pharmacotherapy visit. Primary outcomes included time to recovery and the proportion of patients classified as well during each of 12 study months.
All analyses were by intention to treat. Rates of attrition did not differ across the intensive psychotherapy (35.6%) and collaborative care (30.8%) conditions. Patients receiving intensive psychotherapy had significantly higher year-end recovery rates (64.4% vs 51.5%) and shorter times to recovery than patients in collaborative care (hazard ratio, 1.47; 95% confidence interval, 1.08–2.00; P=.01). Patients in intensive psychotherapy were 1.58 times (95% confidence interval, 1.17–2.13) more likely to be clinically well during any study month than those in collaborative care (P=.003). No statistically significant differences were observed in the outcomes of the 3 intensive psychotherapies.
Intensive psychosocial treatment as an adjunct to pharmacotherapy was more beneficial than brief treatment in enhancing stabilization from bipolar depression. Future studies should compare the cost-effectiveness of models of psychotherapy for bipolar disorder.
Trial Registration Identifier: NCT00012558
PMCID: PMC3579612  PMID: 17404119
16.  The Effect of Concurrent Substance Use Disorder on the Effectiveness of Single and Combination Antidepressant Medications for the Treatment of Major Depression: An Exploratory Analysis of a Single-Blind Randomized Trial 
Depression and Anxiety  2012;29(2):111-122.
The co-occurrence of substance use disorder (SUD) and major depressive disorder (MDD) is common and is often thought to impair response to antidepressant therapy. These patients are often excluded from clinical trials, resulting in a significant knowledge gap regarding optimal pharmacotherapy for the treatment of MDD with concurrent SUD.
In the Combining Medications to Enhance Depression Outcomes study, 665 adult outpatients with chronic and/or recurrent MDD were prospectively treated with either escitalopram monotherapy (escitalopram and placebo) or an antidepressant combination (venalfaxine-XR and mirtazapine or escitalopram and bupropion-SR). Participants with MDD and concurrent SUD (13.1%) were compared to those without SUD (86.9%) on sociodemographic and clinical characteristics at baseline and treatment response at 12-week and 28-week endpoints.
The participants with MDD and SUD were more likely to be male and have current suicidal thoughts/plans, and had a greater lifetime severity and number of suicide attempts, and a higher number of concurrent Axis I disorders, particularly concurrent anxiety disorders. There were no significant differences between the MDD with or without SUD groups in terms of dose, time in treatment, response or remission at week 12 and 28. Furthermore, no significant differences in response or remission rates were noted between groups on the basis of the presence or absence of SUD and treatment assignment.
Although significant baseline sociodemographic and clinical differences exist, patients with MDD and concurrent SUD are as likely to respond and remit to a single or combination antidepressant treatment as those presenting without SUD.
PMCID: PMC3325509  PMID: 22495941
major depressive disorder; substance use disorder; dual diagnosis; combination antidepressants; treatment outcome
17.  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
Depression and anxiety  2009;26(8):701-710.
There is growing evidence suggesting that early adversity may be a marker for a distinct pathway to major depressive disorder (MDD). We examined associations between childhood adversity and a broad variety of clinical characteristics and response to pharmacotherapy in a large sample of patients with chronic forms of MDD.
Subjects included 808 patients with chronic forms of MDD (chronic MDD, double depression, or recurrent MDD with incomplete recovery between episodes and a total continuous duration of >2 years) who were enrolled in a 12-week open-label trial of algorithm-guided pharmacotherapy. Baseline assessments included a semi-structured diagnostic interview, and clinician- and self-rated measures of depressive symptoms, social functioning, depressotypic cognitions, and personality traits, and childhood adversity. Patients were re-evaluated every 2 weeks.
A longer duration of illness; earlier onset; greater number of episodes, symptom severity, self-rated functional impairment, suicidality, and comorbid anxiety disorder; and higher levels of dysfunctional attitudes and self-criticism were each associated with multiple forms of childhood adversity. A history of maternal overcontrol, paternal abuse, paternal indifference, sexual abuse, and an index of clinically significant abuse each predicted a lower probability of remission. Among patients completing the 12-week trial, 32% with a history of clinically significant abuse, compared to 44% without such a history, achieved remission.
These findings indicate that a history of childhood adversity is associated with an especially chronic form of MDD that is less responsive to antidepressant pharmacotherapy.
PMCID: PMC3528400  PMID: 19434623
major depression; mood disorders; childhood maltreatment; clinical features; treatment response
19.  Reduction in the Incidence of Influenza A but Not Influenza B Associated with Use of Hand Sanitizer and Cough Hygiene in Schools: A Randomized Controlled Trial 
Laboratory-based evidence is lacking regarding the efficacy of non-pharmaceutical interventions such as alcohol-based hand sanitizer and respiratory hygiene to reduce the spread of influenza.
The Pittsburgh Influenza Prevention Project was a cluster-randomized trial conducted in ten Pittsburgh, PA elementary schools during the 2007-2008 influenza season. Children in five intervention schools received training in hand and respiratory hygiene, and were provided and encouraged to use hand sanitizer regularly. Children in five schools acted as controls. Children with influenza-like illness were tested for influenza A and B by RT-PCR.
3360 children participated. Using RT-PCR, 54 cases of influenza A and 50 cases of influenza B were detected. We found no significant effect of the intervention on the primary study outcome of all laboratory confirmed influenza cases (IRR 0.81 95% CI 0.54, 1.23). However, we did find statistically significant differences in protocol-specified ancillary outcomes. Children in intervention schools had significantly fewer laboratory-confirmed influenza A infections than children in control schools, with an adjusted IRR of 0.48 (95% CI 0.26, 0.87). Total absent episodes were also significantly lower among the intervention group than among the control group; adjusted IRR 0.74 (95% CI 0.56, 0.97).
Non-pharmaceutical interventions (respiratory hygiene education and the regular use of hand sanitizer) did not reduce total laboratory confirmed influenza. However the interventions did reduce school total absence episodes by 26% and laboratory-confirmed influenza A infections by 52%. Our results suggest that NPIs can be an important adjunct to influenza vaccination programs to reduce the number of influenza A infections among children.
PMCID: PMC3470868  PMID: 21691245
Influenza; Non-pharmaceutical Interventions; School-aged Children; Randomized Controlled Trial; Hand Sanitizer; Absence Surveillance; Laboratory Testing
20.  Suicide and Suicide Attempts in the Systematic Treatment Enhancement Program for Bipolar Disorder 
Journal of affective disorders  2011;133(3):423-427.
The current report describes individuals with bipolar disorder who attempted or completed suicide while participating in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study.
Baseline and course features of individuals with suicide events are described.
Among the 4360 people with bipolar disorder enrolled, 182 individuals made 270 prospectively observed suicidal acts, including 8 completed suicides. This represents a suicide rate of .014 per 100 person years in STEP-BD, which included frequent clinical visits, evidence based care, and standardized assessment at each patient contact. Approximately 1/3 of those who attempted suicide had more than one attempt during study participation. Those who completed suicide tended to do so early in study participation, and half of them did so on their first attempt.
While this study is limited to description of individuals and precipitants of completed suicides and attempts in STEP-BD, further analyses are planned to explore risk factors and potential interventions for prevention of suicidal acts in persons with bipolar disorder.
Persons with bipolar disorder are at high risk for suicide. Overall rates of suicide events in STEP-BD were lower than expected, suggesting that the combination of frequent clinical visits (i.e., access to care), standardized assessment, and evidence-based treatment were helpful in this population.
PMCID: PMC3163014  PMID: 21601286
bipolar disorder; suicide; suicide attempt
21.  Sensitivity, specificity, and predictive power of the “Brief Risk-resilience Index for SCreening,” a brief pan-diagnostic web screen for emotional health 
Brain and Behavior  2012;2(5):576-589.
Few standardized tools are available for time-efficient screening of emotional health status across diagnostic categories, especially in primary care. We evaluated the 45-question Brief Risk-resilience Index for SCreening (BRISC) and the 15-question mini-BRISC in identifying poor emotional health and coping capacity across a range of diagnostic groups – compared with a detailed clinical assessment – in a large sample of adult outpatients. Participants 18–60 years of age (n = 1079) recruited from 12 medical research and clinical sites completed the computerized assessments. Three index scores were derived from the full BRISC and the mini-BRISC: one for risk (negativity–positivity bias) and two for coping (resilience and social capacity). Summed answers were converted to standardized z-scores. BRISC scores were compared with detailed health assessment and diagnostic interview (for current psychiatric, psychological, and neurological conditions) by clinicians at each site according to diagnostic criteria. Clinicians were blinded to BRISC scores. Clinical assessment stratified participants as having “clinical” (n = 435) or “healthy” (n = 644) diagnostic status. Receiver operating characteristic analyses showed that a z-score threshold of −1.57 on the full BRISC index of emotional health provided an optimal classification of “clinical” versus “healthy” status (sensitivity: 81.2%, specificity: 92.7%, positive predictive power: 80.2%, and negative predictive power: 93.1%). Comparable findings were revealed for the mini-BRISC. Negativity–positivity bias index scores contributed the most to prediction. The negativity–positivity index of emotional health was most sensitive to classifying major depressive disorder (100%), posttraumatic stress disorder (95.8%), and panic disorder (88.7%). The BRISC and mini-BRISC both offer a brief, clinically useful screen to identify individuals at risk of disorders characterized by poor emotion regulation, from those with good emotional health and coping.
PMCID: PMC3489810  PMID: 23139903
Depression and anxiety; emotional well-being; Internet; mental health screen; risk and resilience; sensitivity and specificity
22.  Sleep Disturbances in Depressed and Non-Depressed Pregnant Women 
Depression and anxiety  2011;28(8):676-685.
Sleep disturbances and symptoms of depression are common during pregnancy. Both are independent and interrelated risk factors for adverse outcomes. It is unclear the degree to which sleep differs between depressed and non-depressed pregnant women. We sought to 1), describe and compare sleep disturbances in depressed pregnant and non-depressed pregnant women, 2) determine the impact of selective serotonin reuptake inhibitors (SSRI) treatment on sleep, and 3)evaluate whether sleep at 20 weeks is associated with increased depressive symptoms and major depressive disorder (MDD) in later pregnancy.
Pregnant women (N = 240) were recruited in the second trimester (20 weeks gestation) and assigned to depressed (N = 59) and non-depressed (N = 181) groups based on a SCID diagnosis of major depressive disorder. The Structured Interview Guide for the Hamilton Rating Scale with Atypical Depression Supplement (SIGH-ADS) was administered at 20, 30 and 36 weeks gestation from which the sleep variables were obtained.
Depressed women had more fragmented sleep at each assessment (p values ≤ .05). However, the frequency of insomnia symptoms was greater for depressed women only at 20 weeks gestation. SSRI use, regardless of MDD status, did significantly affect several sleep variables. Among the non-depressed women, those with short or longer sleep duration, symptoms of insomnia and long periods of nocturnal waketime had higher SIGH-ADS scores later in pregnancy (p values = < .05).
At 20 and 30 weeks gestation sleep was more disturbed in depressed pregnant women compared to non-depressed pregnant women. At 36 weeks, sleep was disturbed regardless of depression status or SSRI use. Among the non-depressed women, disturbed sleep in conjunction with SSRI use was associated with higher depressive symptoms.
PMCID: PMC3145808  PMID: 21608086
Sleep; depression; pregnancy; women; SIGH-ADS; insomnia; SSRI
23.  Local Spatial and Temporal Processes of Influenza in Pennsylvania, USA: 2003–2009 
PLoS ONE  2012;7(3):e34245.
Influenza is a contagious respiratory disease responsible for annual seasonal epidemics in temperate climates. An understanding of how influenza spreads geographically and temporally within regions could result in improved public health prevention programs. The purpose of this study was to summarize the spatial and temporal spread of influenza using data obtained from the Pennsylvania Department of Health's influenza surveillance system.
Methodology and Findings
We evaluated the spatial and temporal patterns of laboratory-confirmed influenza cases in Pennsylvania, United States from six influenza seasons (2003–2009). Using a test of spatial autocorrelation, local clusters of elevated risk were identified in the South Central region of the state. Multivariable logistic regression indicated that lower monthly precipitation levels during the influenza season (OR = 0.52, 95% CI: 0.28, 0.94), fewer residents over age 64 (OR = 0.27, 95% CI: 0.10, 0.73) and fewer residents with more than a high school education (OR = 0.76, 95% CI: 0.61, 0.95) were significantly associated with membership in this cluster. In addition, time series analysis revealed a temporal lag in the peak timing of the influenza B epidemic compared to the influenza A epidemic.
These findings illustrate a distinct spatial cluster of cases in the South Central region of Pennsylvania. Further examination of the regional transmission dynamics within these clusters may be useful in planning public health influenza prevention programs.
PMCID: PMC3314628  PMID: 22470544
24.  Irritability is associated with anxiety and greater severity, but not bipolar spectrum features, in major depressive disorder 
Acta Psychiatrica Scandinavica  2009;119(4):282-289.
Irritability is common during major depressive episodes, but its clinical significance and overlap with symptoms of anxiety or bipolar disorder remains unclear. We examined clinical correlates of irritability in a confirmatory cohort of Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study participants with major depressive disorder (MDD).
Logistic regression was used to identify features associated with presence of irritability on the clinician-rated Inventory of Depressive Symptomatology.
Of 2,307 study participants, 1067(46%) reported irritability at least half the time during the preceding week; they were more likely to be female, to be younger, to experience greater depression severity and anxiety, and to report poorer quality of life, prior suicide attempts, and suicidal ideation. Bipolar spectrum features were not more common among those with irritability.
Irritable depression is not a distinct subtype of MDD, but irritability is associated with greater overall severity, anxiety comorbidity, and suicidality.
PMCID: PMC3312008  PMID: 19207123
major depressive disorder; bipolar disorder; diagnosis; irritability; anger; suicide
25.  α-Synuclein Levels Are Elevated in Cerebrospinal Fluid following Traumatic Brain Injury in Infants and Children: The Effect of Therapeutic Hypothermia 
Developmental Neuroscience  2010;32(5-6):385-395.
α-Synuclein is one of the most abundant proteins in presynaptic terminals. Normal expression of α-synuclein is essential for neuronal survival and it prevents the initiation of apoptosis in neurons through covalent cross-linking of cytochrome c released from mitochondria. Exocytosis of α-synuclein occurs with neuronal mitochondrial dysfunction, making its detection in cerebrospinal fluid (CSF) of children after severe traumatic brain injury (TBI) a potentially important marker of injury. Experimental therapeutic hypothermia (TH) improves mitochondrial function and attenuates cell death, and therefore may also affect CSF α-synuclein concentrations. We assessed α-synuclein levels in CSF of 47 infants and children with severe TBI using a commercial ELISA for detection of monomeric protein. 23 patients were randomized to TH based on published protocols where cooling (32–33°C) was initiated within 6–24 h, maintained for 48 h, and then followed by slow rewarming. CSF samples were obtained continuously via an intraventricular catheter for 6 days after TBI. Control CSF (n = 9) was sampled from children receiving lumbar puncture for CSF analysis of infection that was proven negative. Associations of initial Glasgow Coma Scale (GCS) score, age, gender, treatment, mechanism of injury and Glasgow Outcome Scale (GOS) score with CSF α-synuclein were compared by multivariate regression analysis. CSF α-synuclein levels were elevated in TBI patients compared to controls (p = 0.0093), with a temporal profile showing an early, approximately 5-fold increase on days 1–3 followed by a delayed, >10-fold increase on days 4–6 versus control. α-Synuclein levels were higher in patients treated with normothermia versus hypothermia (p = 0.0033), in patients aged <4 years versus ≥4 years (p < 0.0001), in females versus males (p = 0.0007), in nonaccidental TBI versus accidental TBI victims (p = 0.0003), and in patients with global versus focal injury on computed tomography of the brain (p = 0.046). Comparisons of CSF α-synuclein levels with initial GCS and GOS scores were not statistically significant. Further studies are needed to evaluate the conformational status of α-synuclein in CSF, and whether TH affects α-synuclein aggregation.
PMCID: PMC3073758  PMID: 21124000
Nonaccidental head injury; Abusive head injury; Synaptic dysfunction; Apoptosis; Mitochondrial injury; Cell death; Oxidative stress; Secondary injury

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