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1.  Biomarkers and the Future of Treatment for Depression 
Editor’s note:
Doctors have a variety of drug options for treatment of depression. But there is currently no way to determine which antidepressant will work best for a given patient, which means that many people continue to suffer while their doctors try a series of medications. As Marisa Toups and Madhukar H. Trivedi write, however, many researchers have focused their efforts on developing biomarkers for depression—tests for aspects of a patient’s physiology that can predict a clinical outcome. In the future, doctors may be able to screen patients to determine which treatment options will work for them, reducing the time a patient must continue to live with the effects of depression.
PMCID: PMC3574808  PMID: 23447792
2.  Relationship Between Obesity and Depression: Characteristics and Treatment Outcomes with Antidepressant Medication 
Psychosomatic medicine  2013;75(9):863-872.
Objective
Obesity and Major Depressive Disorder (MDD) often co-occur. However, differences between obese and normal-weight depressed patients and the moderating effect of obesity on antidepressant treatment outcome have not been well studied.
Methods
662 subjects in the COmbining Medications to Enhance Depression Outcomes (COMED) were randomized to treatment with escitalopram plus placebo, bupropion plus escitalopram, or venlafaxine plus mirtazapine for a 12 week primary treatment phase and 16 week follow-up. Body Mass Index (BMI) was calculated at baseline. Subjects were divided into BMI classes according to World Health Organization criteria: 1) normal (and low) weight (NW), 2) overweight (OW), 3) obese I (OB1) and 4) obese II+ (OB2). Clinical characteristics were compared using Chi-squared or Kruskall-Wallis testing. Outcomes were assessed using a repeated effects model, unadjusted and adjusted for baseline variables differing across BMI classes.
Results
31.4% of the subjects were normal weight; 46.2% were obese. Higher BMI was associated with greater medical illness (p<0.001), social phobia (p=0.003) and bulimia (p=0.026). Lower BMI was associated with higher rates of Post Traumatic Stress Disorder (p=0.002) and drug abuse. Treatment outcomes, including remission, did not differ across classes. However, lower BMI was associated with more frequent (p=0.024, unadjusted, 0.053 adjusted) and more severe (p=0.008 unadjusted, 0.053 adjusted) side effects.
Conclusions
We found a high rate of obesity compared to the general population and significant differences in presentation and comorbidity, but not medication use and antidepressant outcomes, in subjects across BMI classes. Lower BMI classes had higher rates of comorbidities associated with poor outcome, which may have obscured outcome differences.
Trial Registration
clinicaltrials.gov Identifier: NCT 00270647
doi:10.1097/PSY.0000000000000000
PMCID: PMC3905462  PMID: 24163386
Depression; Obesity; Treatment Resistance
3.  Rationale for Using Exercise in the Treatment of Stimulant Use Disorders 
The journal of global drug policy and practice  2012;6(1):http://ctndisseminationlibrary.org/display/825.htm.
Novel approaches to the treatment of stimulant abuse and dependence are needed. Clinical data examining the use of exercise as a treatment for the abuse of nicotine, alcohol, and other substances suggest that exercise may be a beneficial treatment for stimulant abuse. In addition, exercise has been associated with improvements in many other health-related areas that may be adversely affected by stimulant use or its treatment, such as sleep disturbance, cognitive function, mood, weight, quality of life, and anhedonia. Neurobiological evidence provides plausible mechanisms by which exercise could positively affect treatment outcomes in stimulant abuse. The National Institute on Drug Abuse (NIDA) Clinical Trials Network (CTN) CTN-0037 Stimulant Reduction Intervention using Dosed Exercise (STRIDE) study is a multisite randomized clinical trial that compares exercise to health education as potential treatments for stimulant abuse or dependence. If effective, exercise may provide an additional approach to the treatment of stimulant use disorders.
PMCID: PMC4214380  PMID: 25364477
stimulant abuse; stimulant dependence; exercise; health education; behavioral intervention
4.  Pro-Inflammatory Cytokines as Predictors of Antidepressant Effects of Exercise in Major Depressive Disorder 
Molecular psychiatry  2012;18(10):1119-1124.
Exercise is an efficacious treatment for Major Depressive Disorder (MDD) and has independently been shown to have anti-inflammatory effects in non depressed subjects. Patients with MDD have elevated inflammatory cytokines but it is not known if exercise affects inflammation in MDD patients and whether these changes are clinically relevant. In the TReatment with Exercise Augmentation for Depression (TREAD) study, participants who were partial responders to a Selective Serotonin Reuptake Inhibitor (SSRI) were randomized to receive one of two doses of exercise: 16 kilocalories per kilogram of body weight (KKW), or 4 KKW for 12 weeks.
Blood samples were collected before initiation and again at the end of the 12-week exercise intervention. Serum was analyzed using a multiplexed ELISA for Interferon-γ (IFN-γ), Interleukin 1-β (IL-1β), Interleukin-6 (IL-6), and Tumor Necrosis Factor-α (TNF-α).
Higher baseline levels of TNF-α were associated with greater decrease in depression symptoms over the 12 week exercise period (p = 0.0023). In addition, a significant positive correlation between change in IL-1β and change in depression symptom scores was observed (p=0.0441). There were no significant changes in mean level of any cytokine following the 12-week intervention, and no significant relationship between exercise dose and change in mean cytokine level.
Results suggest that high TNF-α may differentially predict better outcomes with exercise treatment as opposed to antidepressant medications for which high TNF-α is linked to poor response. Our results also confirm findings from studies of antidepressant medications that tie decreasing IL-1β to positive depression treatment outcomes.
doi:10.1038/mp.2012.125
PMCID: PMC3511631  PMID: 22925832
exercise; physical activity; depression; inflammation; cytokines
5.  What Are the Clinical Implications of New Onset or Worsening Anxiety During the First Two Weeks of SSRI Treatment for Depression? 
Depression and anxiety  2011;29(2):10.1002/da.20917.
Objective
To evaluate the prevalence of new onset or worsening of anxiety symptoms, as well as their clinical implications, during the first two weeks of Selective Serotonin Reuptake Inhibitor (SSRI) pharmacotherapy for depression.
Method
Adult outpatients with non-psychotic major depressive disorder were enrolled in an 8-week acute phase SSRI treatment trial at 15 clinical sites across the US. Worsening anxiety was defined as a greater than 2 point increase on the Beck Anxiety Inventory (BAI) between baseline and Week 2. New onset of anxiety symptoms was ascribed when the BAI baseline rating was 0 and the Week 2 value was greater or equal to 2 points on the BAI.
Results
Overall, after two weeks of treatment, 48.8% (98 of 201 participants) reported improvement in anxiety symptoms, 36.3% (73 of 201) reported minimal symptom change, and 14.9% (30 of 201) reported worsening of anxiety symptoms. No association was found between change in anxiety symptoms within the first two weeks and change in depressive symptoms or remission at the end of 8 weeks of treatment. For participants with clinically meaningful anxiety symptoms at baseline, however, worsening of anxiety during the first two weeks of treatment was associated with worsening depressive symptoms by 8 weeks (p = .054).
Conclusions
The trajectory of anxiety symptom change early in SSRI treatment is an important indicator of eventual outcome for outpatients with major depression and baseline anxiety symptoms.
doi:10.1002/da.20917
PMCID: PMC3860362  PMID: 22147631
anxiety; change; depression; SSRI; outcome
6.  Determining the Primary Endpoint for a Stimulant Abuse Trial: Lessons Learned from STRIDE (CTN 0037) 
Background
No consensus is available for identifying the best primary outcome for substance abuse trials. While abstinence is the most desirable outcome for substance use interventions, a wide variety of other endpoints have been used to evaluate efficacy trials.
Objectives
This report provides a framework for determining an optimal primary endpoint and the relevant measurement approach for substance use disorder treatment trials. The framework was developed based on a trial for stimulant abuse using exercise as an augmentation treatment, delivered within the NIDA Clinical Trials Network. The use of a common primary endpoint across trials will facilitate comparisons of treatment efficacy.
Methods
Primary endpoint options in existing substance abuse studies were evaluated. This evaluation included surveys of the literature for endpoints and measurement approaches, followed by assessment of endpoint choices against study design issues, population characteristics, tests of sensitivity and tests of clinical meaningfulness.
Conclusion
We concluded that the best current choice for a primary endpoint is percent days abstinent, as measured by the Time Line Follow Back (TLFB) interview conducted three times a week with recall aided by a take-home Substance Use Diary. To further improve the accuracy of the self-reported drug use, an algorithm will be applied to reconcile the results from the TLFB with the results of qualitative urine drug screens.
Scientific Significance
There is a need for a standardized endpoint in this field to allow for comparison across treatment studies, and we suggest that the recommended endpoint be considered for use in this field.
doi:10.3109/00952990.2011.598589
PMCID: PMC3274420  PMID: 21854276
cocaine abuse; methamphetamine abuse; measurement; abstinence endpoint; exercise
7.  Telephone-based Assessments to Minimize Missing Data in Longitudinal Depression Trials: A Project IMPACTS Study Report 
Contemporary Clinical Trials  2008;30(1):13-19.
Purpose
Missing data in clinical efficacy and effectiveness trials continue to be a major threat to the validity of study findings. The purpose of this report is to describe methods developed to ensure completion of outcome assessments with public mental health sector subjects participating in a longitudinal, repeated measures study for the treatment of major depressive disorder. We developed longitudinal assessment procedures that included telephone-based clinician interviews in order to minimize missing data commonly encountered with face-to-face assessment procedures.
Methods
A pre-planned, multi-step strategy was developed to ensure completeness of data collection. The procedure included obtaining multiple pieces of patient contact information at baseline, careful education of both staff and patients concerning the purpose of assessments, establishing good patient rapport, and finally being flexible and persistent with phone appointments to ensure the completion of telephone-based follow-up assessments. A well-developed administrative and organizational structure was also put in place prior to study implementation.
Results
The assessment completion rate for the primary outcome for 310 of 504 subjects who enrolled and completed 52 weeks (at the time of manuscript) of telephone-based follow-up assessments was 96.8%.
Conclusion
By utilizing telephone-based follow-up procedures and adapting our easy-to-use pre-defined multi-step approach, researchers can maximize patient data retention in longitudinal studies.
doi:10.1016/j.cct.2008.08.001
PMCID: PMC3268227  PMID: 18761427
telephone assessments; follow-up strategies; rapport; longitudinal study; retention; patient contact; appointment adherence; compliance
8.  Research staff training in a multisite randomized clinical trial: Methods and recommendations from the Stimulant Reduction Intervention using Dosed Exercise (STRIDE) trial 
Addiction research & theory  2013;22(5):407-415.
Background
Descriptions of and recommendations for meeting the challenges of training research staff for multisite studies are limited despite the recognized importance of training on trial outcomes. The STRIDE (STimulant Reduction Intervention using Dosed Exercise) study is a multisite randomized clinical trial that was conducted at nine addiction treatment programs across the United States within the National Drug Abuse Treatment Clinical Trials Network (CTN) and evaluated the addition of exercise to addiction treatment as usual (TAU), compared to health education added to TAU, for individuals with stimulant abuse or dependence. Research staff administered a variety of measures that required a range of interviewing, technical, and clinical skills.
Purpose
In order to address the absence of information on how research staff are trained for multisite clinical studies, the current manuscript describes the conceptual process of training and certifying research assistants for STRIDE.
Methods
Training was conducted using a three-stage process to allow staff sufficient time for distributive learning, practice, and calibration leading up to implementation of this complex study.
Results
Training was successfully implemented with staff across nine sites. Staff demonstrated evidence of study and procedural knowledge via quizzes and skill demonstration on six measures requiring certification. Overall, while the majority of staff had little to no experience in the six measures, all research assistants demonstrated ability to correctly and reliably administer the measures throughout the study.
Conclusions
Practical recommendations are provided for training research staff and are particularly applicable to the challenges encountered with large, multisite trials.
doi:10.3109/16066359.2013.868446
PMCID: PMC4217528  PMID: 25379036
training recommendations; research staff training; multisite trials; training; certification
9.  Assessing Physicians' Use of Treatment Algorithms: Project IMPACTS Study Design and Rationale 
Contemporary clinical trials  2006;28(2):192-212.
Effective treatments for major depressive disorder have been available for 35 years, yet inadequate pharmacotherapy continues to be widespread leading to suboptimal outcomes. Evidence-based medication algorithms have the potential to bring much-needed improvement in effectiveness of antidepressant treatment in “real-world” clinical settings. Project IMPACTS (Implementation of Algorithms using Computerized Treatment Systems) addresses the critical question of how best to facilitate integration of depression treatment algorithms into routine care. It tests an algorithm implemented through a computerized decision support system using a measurement-based care approach for depression against a paper-and-pencil version of the same algorithm and nonalgorithm-based, specialist-delivered usual care. This paper reviews issues related to the Project IMPACTS study rationale, design, and procedures. Patient outcomes include symptom severity, social and work function, and quality of life. The economic impact of treatment is assessed in terms of health care utilization and cost. Data collected on physician behavior include degree of adherence to guidelines and physician attitudes about the perceived utility, ease of use, and self-reported effect of the use of algorithms on workload. Novel features of the design include a two-tiered study enrollment procedure, which initially enrolls physicians as subjects, and then following recruitment of physicians, enrollment of subjects takes place based initially on an independent assessment by study staff to determine study eligibility. The study utilizes brief, easy-to-use symptom severity measures that facilitate physician decision making, and it employs a validated, phone-based, follow-up assessment protocol in order to minimize missing data, a problem common in public sector and longitudinal mental health studies. IMPACTS will assess the success of algorithm implementation and subsequent physician adherence using study-developed criteria and related statistical approaches. These new procedures and data points will also allow a more refined assessment of algorithm-driven treatment in the future.
doi:10.1016/j.cct.2006.08.005
PMCID: PMC2793279  PMID: 16997636
depression; measurement-based care (MBC); treatment algorithms; physician decision support; electronic medical records; medical information technology
10.  Measurement-Based Care for Refractory Depression: A Clinical Decision Support Model for Clinical Research and Practice 
Drug and alcohol dependence  2007;88(Suppl 2):S61-S71.
Despite years of antidepressant drug development and patient and provider education, suboptimal medication dosing and duration of exposure resulting in incomplete remission of symptoms remains the norm in the treatment of depression. Additionally, since no one treatment is effective for all patients, optimal implementation focusing on the measurement of symptoms, side effects, and function is essential to determine effective sequential treatment approaches. There is a need for a paradigm shift in how clinical decision making is incorporated into clinical practice and for a move away from the trial-and-error approach that currently determines the “next best” treatment. This paper describes how our experience with the Texas Medication Algorithm Project (TMAP) and the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial has confirmed the need for easy-to-use clinical support systems to ensure fidelity to guidelines. To further enhance guideline fidelity, we have developed an electronic decision support system that provides critical feedback and guidance at the point of patient care. We believe that a measurement-based care (MBC) approach is essential to any decision support system, allowing physicians to individualize and adapt decisions about patient care based on symptom progress, tolerability of medication, and dose optimization. We also believe that successful integration of sequential algorithms with MBC into real-world clinics will facilitate change that will endure and improve patient outcomes. Although we use major depression to illustrate our approach, the issues addressed are applicable to other chronic psychiatric conditions including comorbid depression and substance use disorder as well as other medical illnesses.
doi:10.1016/j.drugalcdep.2007.01.007
PMCID: PMC2793274  PMID: 17320312
Measurement-Based Care; Decision Support Systems; Adaptive Treatment Strategies; Depression
11.  What moderator characteristics are associated with better prognosis for depression? 
A retrospective data analysis was conducted to evaluate the usefulness of baseline characteristics in predicting treatment response to antidepressant medication in 97 outpatients with nonpsychotic major depression treated for up to sixteen weeks with nefazodone. Baseline demographics (gender), illness features (symptom severity, length of illness, length of current episode, number of episodes, age of onset, longitudinal subtype, endogenicity, melancholia, family history of mood disorders), and social features (living status) were evaluated. Response to treatment was defined as a ≥ 50% reduction in the 17-item Hamilton Rating Scale for Depression (HRSD17) score. The results of a survival analysis indicated that patients with shorter histories of illness (< 4 years), a negative family history of depression, and those who were either married or were living with someone were more likely to have a positive outcome during the acute phase treatment of depression. The main findings are consistent with extensive previous literature indicating a better short-term outcome of depression where illness is shorter, where there is no family history, and where there is better social support.
PMCID: PMC2426815  PMID: 18568124
antidepressant; treatment predictor; social support; major depression
12.  Course and Severity of Maternal Depression: Associations with Family Functioning and Child Adjustment 
Journal of youth and adolescence  2008;37(8):906-916.
Number of lifetime episodes, duration of current episode, and severity of maternal depression were investigated in relation to family functioning and child adjustment. Participants were the 151 mother–child pairs in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) child multi-site study. Mothers were diagnosed with Major Depressive Disorder; children (80 males and 71 females) ranged in age from 7 to 17 years. Measures of child adjustment included psychiatric diagnoses, internalizing and externalizing symptoms, and functional impairment. Measures of family functioning included family cohesion, expressiveness, conflict, organization, and household control; parenting measures assessed maternal acceptance and psychological control. Children of mothers with longer current depressive episodes were more likely to have internalizing and externalizing symptoms, with this association being moderated by child gender. Mothers with more lifetime depressive episodes were less likely to use appropriate control in their homes.
doi:10.1007/s10964-007-9216-0
PMCID: PMC4086840  PMID: 25013241
Maternal depression; Family functioning; Child adjustment; Gender
13.  The Clinical Relevance of Self-Reported Premenstrual Worsening of Depressive Symptoms in the Management of Depressed Outpatients: A STAR*D Report 
Journal of Women's Health  2013;22(3):219-229.
Abstract
Objective
To determine the incidence, clinical and demographic correlates, and relationship to treatment outcome of self-reported premenstrual exacerbation of depressive symptoms in premenopausal women with major depressive disorder who are receiving antidepressant medication.
Method
This post-hoc analysis used clinical trial data from treatment-seeking, premenopausal, adult female outpatients with major depression who were not using hormonal contraceptives. For this report, citalopram was used as the first treatment step. We also used data from the second step in which one of three new medications were used (bupropion-SR [sustained release], venlafaxine-XR [extended release], or sertraline). Treatment-blinded assessors obtained baseline treatment outcomes data. We hypothesized that those with reported premenstrual depressive symptom exacerbation would have more general medical conditions, longer index depressive episodes, lower response or remission rates, and shorter times-to-relapse with citalopram, and that they would have a better outcome with sertraline than with bupropion-SR.
Results
At baseline, 66% (n=545/821) of women reported premenstrual exacerbation. They had more general medical conditions, more anxious features, longer index episodes, and shorter times-to-relapse (41.3 to 47.1 weeks, respectively). Response and remission rates to citalopram, however, were unrelated to reported premenstrual exacerbation. Reported premenstrual exacerbation was also unrelated to differential benefit with sertraline and bupropion-SR.
Conclusions
Self-reported premenstrual exacerbation has moderate clinical utility in the management of depressed patients, although it is not predictive of overall treatment response. Factors that contribute to a more chronic or relapsing course may also play a role in premenstrual worsening of major depressive disorder (MDD).
doi:10.1089/jwh.2011.3186
PMCID: PMC3634137  PMID: 23480315
14.  Do Menopausal Status and Use of Hormone Therapy Affect Antidepressant Treatment Response? Findings from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) Study 
Journal of Women's Health  2013;22(2):121-131.
Abstract
Background
Menopausal status and use of hormonal contraception or menopausal hormone therapy (HT) may affect treatment response to selective serotonin reuptake inhibitors (SSRIs). This report evaluates whether menopausal status and use of hormonal contraceptives or menopausal HT affect outcome in women treated with citalopram.
Methods
In the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, 896 premenopausal and 544 postmenopausal women were treated with citalopram for 12–14 weeks. Baseline demographic and clinical characteristics were used in adjusted analysis of the effect of menopausal status and use of hormonal contraceptives or menopausal HT on outcomes. Remission was defined as final Hamilton Rating Scale for Depression-17 (HRSD17) ≤7 or Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR16) score ≤5 and response as ≥50% decrease from the baseline QIDS-SR16 score.
Results
Premenopausal and postmenopausal women differed in multiple clinical and demographic baseline variables but did not differ in response or remission rates. Premenopausal women taking hormonal contraceptives had significantly greater unadjusted remission rates on the HRSD17 and the QIDS-SR16 than women not taking contraception. Response and remission rates were not different between postmenopausal women taking vs. not taking HT. Adjusted results showed no significant difference in any outcome measure across menopause status in women who were not taking contraception/HT. There were no significant differences in adjusted results across HT status in premenopausal or postmenopausal women.
Conclusions
In this study, citalopram treatment outcome was not affected by menopausal status. Hormonal contraceptives and HT also did not affect probability of good outcome.
doi:10.1089/jwh.2012.3479
PMCID: PMC3613168  PMID: 23398127
15.  Does Duloxetine Improve Cognitive Function Independently of Its Antidepressant Effect in Patients with Major Depressive Disorder and Subjective Reports of Cognitive Dysfunction? 
Introduction. Cognitive deficits are commonly reported by patients with major depressive disorder (MDD). Duloxetine, a dual serotonin/noradrenaline reuptake inhibitor, may improve cognitive deficits in MDD. It is unclear if cognitive improvements occur independently of antidepressant effects with standard antidepressant medications. Methods. Thirty participants with MDD who endorsed cognitive deficits at screening received 12-week duloxetine treatment. Twenty-one participants completed treatment and baseline and posttreatment cognitive testing. The Cambridge Neuropsychological Test Automated Battery was used to assess the following cognitive domains: attention, visual memory, executive function/set shifting and working memory, executive function/spatial planning, decision making and response control, and verbal learning and memory. Results. Completers showed significant cognitive improvements across several domains on tasks assessing psychomotor function and mental processing speed, with additional improvements in visual and verbal learning and memory, and affective decision making and response control. Overall significance tests for executive function tasks were also significant, although individual tasks were not, perhaps due to the small sample size. Most notably, cognitive improvements were observed independently of symptom reduction on all domains except verbal learning and memory. Conclusions. Patients reporting baseline cognitive deficits achieved cognitive improvements with duloxetine treatment, most of which were independent of symptomatic improvement. This trial is registered with NCT00933439.
doi:10.1155/2014/627863
PMCID: PMC3915915  PMID: 24563781
16.  Rationale and Design of the Chronic Kidney Disease Antidepressant Sertraline Trial (CAST) 
Contemporary clinical trials  2012;34(1):136-144.
Major depressive disorder (MDD) affects one in five patients with Chronic Kidney Disease (CKD) and is an independent risk factor for hospitalization and death before and after dialysis initiation. However, it remains an under-recognized and under-treated problem, in part due to the lack of well-controlled studies that support or refute the efficacy and safety of antidepressant medications in CKD patients. Major trials of antidepressant treatment excluded patients with stages 3–5 CKD, precisely those at higher risk for both depression and increased mortality. The Chronic Kidney Disease Antidepressant Sertraline Trial (CAST) is a randomized, double-blinded, placebo-controlled trial of sertraline, a selective serotonin reuptake inhibitor (SSRI). It will enroll 200 adults with stages 3–5 CKD and MDD excluding kidney transplant and chronic dialysis patients. Sertraline will be administered at an initial dose of 50 mg once daily or matching placebo followed by a dose escalation strategy consisting of 50 mg increments at 2 weeks intervals (as tolerated) to a maximum dose of 200 mg. The primary outcome is improvement in depression symptom severity measured by the Quick Inventory of Depressive Symptomatology scale. Secondary outcomes include safety endpoints and improvement in quality of life. Changes in cognitive function, adherence to medications, nutritional status, inflammation, and platelet function will be explored as potential mechanisms by which depression may mediate poor outcomes. We discuss the rationale and design of the CAST study, the largest placebo-controlled trial aimed to establish safety and efficacy of a SSRI in the acute phase treatment of CKD patients with MDD.
doi:10.1016/j.cct.2012.10.004
PMCID: PMC3525806  PMID: 23085503
depression; chronic kidney disease; sertraline; randomized trial; treatment
17.  Assessing Rates and Predictors of Tachyphylaxis During the Prevention of Recurrent Episodes of Depression With Venlafaxine ER for Two Years (PREVENT) Study 
Psychopharmacology bulletin  2009;42(3):5-20.
Background
Antidepressant tachyphylaxis describes the return of apathetic depressive symptoms, such as fatigue and decreased motivation, despite continued use of a previously effective treatment.
Methods
Data were collected from a multiphase, double-blind, placebo-controlled study that assessed the efficacy of venlafaxine extended release (ER) during 2 sequential 1-year maintenance phases (A and B) in patients with recurrent major depressive disorder (MDD). The primary outcome was the cumulative probability of tachyphylaxis in patients receiving venlafaxine ER, fluoxetine, or placebo. Tachyphylaxis was defined as Rothschild Scale for Antidepressant Tachyphylaxis (RSAT) scored ≥ 7 in patients with prior satisfactory therapeutic response. A Kaplan-Meier estimate of the cumulative probability of not experiencing tachyphylaxis, and a 2-sided Fisher exact test was used to assess the relationship between tachyphylaxis and recurrence.
Results
The maintenance phase A population was comprised of 337 patients (venlafaxine ER [n = 129], fluoxetine [n = 79], placebo [n = 129]), whereas 128 patients (venlafaxine ER [n = 43], fluoxetine [n = 45], placebo [n = 40]) were treated during maintenance phase B. No difference in the probability of experiencing tachyphylaxis were observed between the active treatment groups during either maintenance phase; however, a significant difference between venlafaxine ER and placebo was observed at the completion of maintenance phase A. A significant relationship between tachyphylaxis and recurrence was observed.
Limitations
Despite demonstrating psychometric validity and reliability, the current definition of tachyphylaxis has not been widely studied
Conclusions
Although no significant differences were observed in the probability of tachyphylaxis among patients receiving active treatment, the relationship between tachyphylaxis and recurrence suggests that tachyphylaxis may be a predrome of recurrence.
PMCID: PMC3806307  PMID: 19752838
loss of antidepressant response; psychopharmacology; major depressive disorder; serotonin norepinephrine reuptake inhibitor; Rothschild Scale for Antidepressant Tachyphylaxis
18.  Association Between Bipolar Spectrum Features and Treatment Outcomes in Outpatients With Major Depressive Disorder 
Archives of general psychiatry  2010;68(4):351-360.
Context
It has been suggested that patients with major depressive disorder (MDD) who display pretreatment features suggestive of bipolar disorder or bipolar spectrum features might have poorer treatment outcomes.
Objective
To assess the association between bipolar spectrum features and antidepressant treatment outcome in MDD.
Design
Open treatment followed by sequential randomized controlled trials.
Setting
Primary and specialty psychiatric outpatient centers in the United States.
Participants
Male and female outpatients aged 18 to 75 years with a DSM-IV diagnosis of nonpsychotic MDD who participated in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study.
Interventions
Open treatment with citalopram followed by up to 3 sequential next-step treatments.
Main Outcome Measures
Number of treatment levels required to reach protocol-defined remission, as well as failure to return for the postbaseline visit, loss to follow-up, and psychiatric adverse events. For this secondary analysis, putative bipolar spectrum features, including items on the mania and psychosis subscales of the Psychiatric Diagnosis Screening Questionnaire, were examined for association with treatment outcomes.
Results
Of the 4041 subjects who entered the study, 1198 (30.0%) endorsed at least 1 item on the psychosis scale and 1524 (38.1%) described at least 1 recent manic-like/hypomaniclike symptom. Irritability and psychotic-like symptoms at entry were significantly associated with poorer outcomes across up to 4 treatment levels, as were shorter episodes and some neurovegetative symptoms of depression. However, other indicators of bipolar diathesis including recent maniclike symptoms and family history of bipolar disorder as well as summary measures of bipolar spectrum features were not associated with treatment resistance.
Conclusion
Self-reported psychoticlike symptoms were common in a community sample of outpatients with MDD and strongly associated with poorer outcomes. Overall, the data do not support the hypothesis that unrecognized bipolar spectrum illness contributes substantially to antidepressant treatment resistance.
doi:10.1001/archgenpsychiatry.2010.179
PMCID: PMC3794668  PMID: 21135313
19.  Decline in Cardiorespiratory Fitness and Odds of Incident Depression 
Background
Studies of physical activity and incidence of physician-diagnosed depression have been limited to a single estimate of self-reported physical activity exposure, despite follow-up periods lasting many years.
Purpose
To examine longitudinal change in cardiorespiratory fitness, an objective marker of habitual physical activity, and incident depression complaints made to a physician.
Methods
Cardiorespiratory fitness assessed at four clinic visits between 1971 and 2006, each separated by an average of 2–3 years, was used to objectively measure cumulative physical activity exposure in cohorts of 7936 men and 1261 women, aged 20–85 years, from the Aerobics Center Longitudinal Study who did not complain of depression at their first clinic visit in 1971–2003. Data were analyzed in August 2010.
Results
Across subsequent visits, there were 446 incident cases in men and 153 cases in women. After adjustment for age, time between visits, BMI at each visit, and fitness at Visit 1, each 1-minute decline in treadmill endurance (i.e., a decline in cardiorespiratory fitness of approximately 1 half-MET) between ages 51 and 55 years in men and ages 53 and 56 years in women, increased the odds of incident depression complaints by approximately 2% and 9.5%, respectively. The increased odds remained significant but were attenuated to 1.3% and 5.4% after further adjustment at each visit for smoking, alcohol use, chronic medical conditions, anxiety, and sleep problems.
Conclusions
Maintenance of cardiorespiratory fitness during late middle-age, when decline in fitness typically accelerates, helps protect against the onset of depression complaints made to a physician.
doi:10.1016/j.amepre.2012.06.011
PMCID: PMC3478961  PMID: 22992353
20.  Predictors of attrition with buprenorphine/naloxone treatment in opioid dependent youth☆ 
Addictive behaviors  2012;37(9):1046-1053.
Background
In opioid dependent youth there is substantial attrition from medication-assisted treatment. If youth at risk for attrition can be identified at treatment entry or early in treatment, they can be targeted for interventions to help retain them in treatment.
Methods
Opioid dependent adolescents and young adults (n=152), aged 15–21, were randomized to 12 weeks (BUP, n=74) or 2 weeks of detoxification (DETOX, n=78) with buprenorphine/naloxone (Bup/Nal), both in combination with 12 weeks of psychosocial treatment. Baseline and early treatment related predictors of treatment attrition were identified in each group using bivariate and multivariate logistic regression.
Results
In the DETOX group 36% left between weeks 2 and 4, at the end of the dose taper, while in the BUP group only 8% left by week 4. In the BUP group, early adherence to Bup/Nal, early opioid negative urines, use of any medications in the month prior to treatment entry, and lifetime non-heroin opioid use were associated with retention while prior 30-day hallucinogen use was associated with attrition. In the DETOX group, only use of sleep medications was associated with retention although not an independent predictor. A broad range of other pre-treatment characteristics was unrelated to attrition.
Conclusions
Prompt attention to those with early non-adherence to medication or an early opioid positive urine, markers available in the first 2 weeks of treatment, may improve treatment retention. Extended Bup/ Nal treatment appeared effective in improving treatment retention for youth with opioid dependence across a wide range of demographics, and pre-treatment clinical characteristics.
doi:10.1016/j.addbeh.2012.04.011
PMCID: PMC3691698  PMID: 22626890
Retention; Adherence; Opioid dependence; Youth; Adolescents; Buprenorphine
21.  Assessing anxious features in depressed outpatients 
Both the 17-item Hamilton Rating Scale for Depression (HRSD17) and 30-item Inventory of Depressive Symptomatology – Clinician-rated (IDS-C30) contain a subscale that assesses anxious symptoms. We used classical test theory and item response theory methods to assess and compare the psychometric properties of the two anxiety subscales (HRSDANX and IDS-CANX) in a large sample (N = 3453) of outpatients with non-psychotic major depressive disorder in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. Approximately 48% of evaluable participants had at least one concurrent anxiety disorder by the self-report Psychiatric Diagnostic Screening Questionnaire (PDSQ). The HRSDANX and IDS-CANX were highly correlated (r = 0.75) and both had moderate internal consistency given their limited number of items (HRSDANX Cronbach’s alpha = 0.48; IDS-CANX Cronbach’s alpha = 0.58). The optimal threshold for ascribing the presence/absence of anxious features was found at a total score of eight or nine for the HRSDANX and seven or eight for the IDS-CANX. It would seem beneficial to delete item 17 (loss of insight) from the HRSDANX as it negatively correlated with the scale’s total score. Both the HRSDANX and IDS-CANX subscales have acceptable psychometric properties and can be used to identify anxious features for clinical or research purposes.
doi:10.1002/mpr.353
PMCID: PMC3708141  PMID: 22057975
depression; anxiety; rating scales; STAR*D; measurement-based care
22.  Psychosocial outcomes in patients with recurrent major depressive disorder during 2 years of maintenance treatment with venlafaxine extended release 
Journal of affective disorders  2010;126(3):420-429.
Background
Psychosocial outcomes from the Prevention of Recurrent Episodes of Depression with Venlafaxine ER for Two Years (PREVENT) study were evaluated.
Methods
Adult outpatients with recurrent major depressive disorder (MDD) and response or remission following 6-month continuation treatment with venlafaxine extended release (ER) were randomized to receive venlafaxine ER or placebo for 1 year. Patients without recurrence on venlafaxine ER during year 1 were randomized to venlafaxine ER or placebo for year 2. Psychosocial functioning was assessed using the Quality of Life Enjoyment and Satisfaction Questionnaire—Short Form (Q-LES-Q), Life EnjoymentScale—Short Version (LES-S), Social Adjustment Scale—Self-Report (SAS-SR) total and individual factors, Short Form Health Survey (SF-36) (vitality, social functioning, and role function-emotional items), and Longitudinal Interval Follow-up Evaluation (LIFE).
Results
At year 1 end, better overall psychosocial functioning was seen among patients randomly assigned to venlafaxine ER (n=129) vs placebo (n=129), with significant differences at end point on SF-36 role function-emotional, Q-LES-Q, and SAS-SR total, and work, house work, social/leisure, and extended-family factor scores (p≤0.05). At year 2 end, significant differences favored venlafaxine ER (n=43) vs placebo (n=40)on SF-36 vitality and rolefunction-emotional, Q-LES-Q, LES-S, LIFE, and SAS-SR total, social/leisure, and extended-family factor scores (p≤0.05).
Limitations
Patients with chronic MDD or treatment resistance were excluded and long-term specialist care was a financial incentive for treatment compliance. Discontinuation-related adverse events may have compromised the integrity of the treatment blind.
Conclusions
For patients with recurrent MDD, 2 years’ maintenance therapy with venlafaxine ER may improve psychosocial functioning vs placebo.
doi:10.1016/j.jad.2010.04.011
PMCID: PMC3705737  PMID: 20510459
Venlafaxine extended release; Psychosocial outcomes; Major depressive disorder; Maintenance treatment
23.  Faster Remission of Chronic Depression With Combined Psychotherapy and Medication Than With Each Therapy Alone 
The main aim of the present novel reanalysis of archival data was to compare the time to remission during 12 weeks of treatment of chronic depression following antidepressant medication (n = 218), psychotherapy (n = 216), and their combination (n = 222). Cox regression survival analyses revealed that the combination of medication and psychotherapy produced full remission from chronic depression more rapidly than either of the single modality treatments, which did not differ from each other. Receiver operating characteristic curve analysis was used to explore predictors (treatment group, demographic, clinical, and psychosocial) of remission. For those receiving the combination treatment, the most likely to succeed were those with low baseline depression (24-item Hamilton Rating Scale for Depression [HRSD; M. Hamilton, 1967] score < 26) and those with high depression scores but low anxiety (HRSD ≥ 26 and Hamilton Anxiety Rating Scale [M. Hamilton, 1959] <14). Both profiles were associated with at least 40% chance of attaining full remission. The model did not identify predictors for those receiving medication or psychotherapy alone, and it did not distinguish between the 2 monotherapies. The authors conclude that combined antidepressant medications and psychotherapy result in faster full remission of chronic forms of major depressive disorder.
doi:10.1037/0022-006X.76.3.459
PMCID: PMC3694578  PMID: 18540739
chronic depression; remission; psychotherapy; antidepressant medications; combined treatments
24.  Concordance between clinician and patient ratings as predictors of response, remission, and recurrence in major depressive disorder 
Journal of psychiatric research  2010;45(1):96-103.
We conducted a secondary analysis of data from the Prevention of Recurrent Episodes of Depression With Venlafaxine Extended Release (ER) for Two Years (PREVENT) trial to evaluate whether discrepancies between clinician and patient ratings of depression severity were predictive of response, remission, and recurrence during treatment for a depressive episode. Patients who self-rated depression severity in concordance with the clinician (“concordant patients”) were defined as having a standardized patient-rated Inventory of Depressive Symptoms-Self Report (IDS-SR30) score minus standardized clinician-rated Hamilton Rating Scale for Depression (HAM-D17) score <1 SD from mean. Non-concordant patients (“underrating patients” [−1 SD], “overrating patients” [+1 SD]) were identified. Cohorts were compared for remission and response on the HAM-D17, Clinician Global Impression–Severity (CGI-S), and IDS-SR30 during acute and continuation therapy and time to recurrence during maintenance therapy. During acute treatment female patients were more likely to overrate their depression severity compared to the clinician; older age predicted overrating during continuation treatment. Overrating patients had a slower onset of response on the HAM-D17 during acute treatment (P = 0.004). There were no differences between cohorts for remission or response on the HAM-D17 or CGI-S. Overrating patients at week 10 had lower remission and response rates on the IDS-SR30 during continuation therapy (32% and 50%, respectively; P ≤ 0.001) compared with underrating patients (76%, 77%) or concordant patients (64%, 78%). Patient concordance at the end of continuation therapy did not predict recurrence during maintenance therapy, indicating that patient rating scales may be useful in tracking recurrence during maintenance therapy. Poor agreement between patient- and clinician-ratings of depression severity is primarily a state phenomenon, although it is trait-like for some patients.
doi:10.1016/j.jpsychires.2010.04.032
PMCID: PMC3677164  PMID: 20537348
Depression; Psychiatric status rating scales; Reliability and validity; Outcome assessment; Treatment outcome; Anxiety
25.  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.
doi:10.1097/JCP.0b013e31820ebd2c
PMCID: PMC3677201  PMID: 21346613
depression; STAR*D; residual; symptoms; treatment response

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