Correlates and outcomes of depressed out-patients with greater and fewer anxious symptoms: a CO-MED report

Abstract

The objective of this paper was to determine whether the presence of more vs. fewer anxious symptom features, at baseline, are associated with other clinical features and treatment outcomes in out-patients with major depressive disorder (MDD). This single-blind, randomized trial enrolled 665 MDD out-patients to compare the efficacy of two antidepressant medication combinations against escitalopram after 12-wk acute treatment and follow-up (total 28 wk). The sample was divided into those with greater (vs. fewer) anxiety features using the anxiety/somatization subscale of the baseline 17-item Hamilton Rating Scale for Depression. Baseline sociodemographic and clinical features, treatment features and outcomes compared these two groups. Overall, 74.7% of participants met the threshold for ‘anxious features’. They were more likely to be female, have other concurrent anxiety disorders, more severe depression, more lethargic and melancholic features and poorer cognitive and physical functioning, quality of life and work and social adjustment. In acute treatment, participants with anxious features received comparatively higher doses of mirtazapine and venlafaxine and reported more side-effects. The groups with and without anxious features did not differ in treatment outcomes and side-effect burden. Despite being associated with a distinct clinical profile, baseline anxious features were not clinically useful in predicting acute treatment outcomes or differential treatment response.

Introduction

Anxiety, nervousness and other somatic symptoms are common among patients with major depressive disorder (MDD) (Fawcett & Kravitz, 1983), as are anxiety disorders (Zimmerman et al.2002). Anxious features have much in common with MDD features. For example, the 17-item Hamilton Rating Scale for Depression (HAMD₁₇; Cleary & Guy, 1977) contains six anxiety/somatization items: psychic anxiety; somatic anxiety; gastrointestinal somatic symptoms; general somatic symptoms; hypochondriasis; insight.

When high levels of anxiety symptoms occur in the context of MDD, they have been associated with greater severity of depressive illness, greater functional impairment (Joffe et al.1993), greater chronicity (van Valkenburg et al.1984) and an increased risk of suicidality (Tollefson et al.1994). Patients with anxious features have also been found to have greater unemployment rates and less education (Fava et al.2004, 2006).

Patients with MDD and a high level of anxious features may be less likely to respond to antidepressant treatment than patients with fewer anxious features in most (Davidson et al.2002; Fava et al.1997, 2008; Flint & Rifat, 1997) but not all (Russell et al.2001; Tollefson et al.1994) studies, regardless of medication type. Furthermore, greater anxious features may be associated with a delayed response to treatment or greater side-effect burden (Fava et al.2008).

Aims of the study

This report evaluates whether anxious symptom features are associated with any baseline sociodemographic or clinical features in out-patients with non-psychotic, recurrent or chronic MDD and whether anxious features divided into those with more vs. fewer anxious features are associated with treatment outcomes or side-effect burden for the full sample, or with outcomes or side-effect burden among three antidepressant medication options (a single medication and two different medication combinations).

Method

Study overview

This study was conducted using a large sample obtained from the Combining Medications to Enhance Depression Outcomes (CO-MED) trial (Rush et al.2011). CO-MED was a 7-month, single-blind, randomized trial that compared the efficacy of each of two different antidepressant medication combinations vs. escitalopram (Escit)+placebo (Pbo) (1:1:1 ratio) as a first-step MDD treatment, including acute (12 wk) and long-term continuation treatment (total 28 wk). Out-patient participants with non-psychotic MDD were recruited from six primary care and nine psychiatric care sites across the United States. Study details and methodology are available elsewhere (Rush et al.2011).

Broad inclusion and minimal exclusion criteria ensured a reasonably representative participant sample. Out-patient enrollees aged 18–75 yr met DSM-IV TR (APA, 2000) criteria for either recurrent [⩾1 prior major depressive episode (MDE)] or chronic (current MDE for ⩾2 yr) MDD based on a clinical interview, which was confirmed by a DSM-IV MDD symptom checklist completed by the Clinical Research Coordinator. Eligible participants had to be in the index episode for ⩾2 months and they had to have a score ⩾16 on the HAMD₁₇ (Hamilton, 1960). Those with a history of any psychotic illness, bipolar disorder or in need of acute hospitalization were excluded. For a full listing of exclusion criteria, see www.co-med.org.

The study protocol and all consent and study procedures were approved by the Institutional Review Boards at the National Coordinating Center (The University of Texas Southwestern Medical Center at Dallas), the University of Pittsburgh Data Coordinating Center, each participating regional centre and all relevant clinical sites.

Baseline data

Sociodemographic and clinical features were gathered at baseline. A score of ⩾7 on the anxiety/somatization subscale of the baseline HAMD₁₇ established the presence of anxious features (Fava et al.2008). The self-report Psychiatric Diagnostic Screening Questionnaire (PDSQ) (Zimmerman & Mattia, 2001a, b) established the presence of current Axis I disorders (Rush et al.2005). The Self-administered Comorbidity Questionnaire (Sangha et al.2003) established the presence, severity and functional impact of a wide range of common general medical comorbidities (GMCs). The presence of lethargic, melancholic and atypical features was ascertained on the basis of specific item scores on the 30-item Inventory of Depressive Symptomatology – Clinician-rated (IDS-C₃₀; Rush et al.2003). Similarly, the presence of sleep disturbances was ascertained on the basis of specific item scores on the IDS-C₃₀.

Antidepressant treatment

A 12-wk study period was chosen for the primary analysis. Treatment visits were planned at baseline and weeks 1, 2, 4, 6, 8, 10, 12 and at weeks 16, 20, 24 and 28. Dosage adjustments were guided by the CO-MED Operations Manual (available at www.co-med.org), which utilized measurement-based care to provide personally tailored and vigorous dosing (Trivedi & Daly, 2007; Trivedi et al.2007), with dosage adjustments based on the 16-item Quick Inventory of Depressive Symptomatology – Clinician-rated (QIDS-C₁₆) (Rush et al.2003, 2006), which was extracted from the IDS-C₃₀, the Frequency, Intensity and Burden of Side Effects Rating (FIBSER; Wisniewski et al.2006) and the measurement of participant adherence obtained at each treatment visit.

Treatment was randomly assigned, stratified by clinical site using a Web-based randomization system (Wisniewski et al.2004). Random block sizes of three and six were used to minimize the probability of identifying the next treatment assignment. Dosing schedules were based on prior reports (Fava, 2001; Leuchter et al.2008; McGrath et al.2006). Doses were increased only in the context of acceptable side-effects. Details of the dosing schedule are available elsewhere (Rush et al.2011). Participants could exit the study if unacceptable or intolerable side-effects occurred that could not be resolved with dose reduction or medication treatment.

Medication blinding

One medication in each treatment group was open (participant and study personnel unblinded), while the second medication was blinded (participant only). Thus, all participants took two types of ‘pills’. Specifically, in the Escit+Pbo group, the Pbo medication was blinded; in the bupropion-sustained release (Bup-SR)+Escit group, Escit was blinded; and in the venlafaxine-extended release (Ven-XR)+mirtazapine (Mirt) group, Mirt was blinded.

Concurrent treatments

Only protocol antidepressant medications were allowed. Treatments with possible antidepressant effects were proscribed, as were anxiolytics, sedative hypnotics and depression-targeted, empirically validated psychotherapies for depression. Other therapies (e.g. supportive, couples, occupational therapy) were allowed, as were medications for any GMC. Given the Bup-SR inhibition of the 2D6 isoenzyme, we alerted clinicians to recognize non-protocol medications (e.g. type 1C antiarrhthmics, β blockers, etc.) for which serum levels or dose adjustments might be needed. Medications to treat antidepressant medication side-effects were allowed (clinician judgement) in order to mimic clinical practice and enhance retention.

Research outcomes

Outcome assessments were collected at baseline and at all subsequent treatment visits. The primary outcome, symptom remission, was based on the 16-item Quick Inventory of Depressive Symptomatology – Self-Report (QIDS-SR₁₆; Rush et al.2003, 2006; Trivedi et al.2007). Remission was ascribed a priori based on the last two consecutive measurements obtained during the 12-wk acute trial to ensure that a single ‘good week’ was not falsely signalling remission. At least one of these ratings had to be <6, while the other had to be <8. If participants exited before 12 wk, their last two consecutive QIDS-SR₁₆ scores were used to ascribe remission. Those who exited before having two post-baseline measures were considered not remitted.

Participants could exit the study if they had received a maximally tolerated dose(s) for ⩾4 wk by week 8 without receiving a ⩾30% reduction in baseline QIDS-C₁₆. They could enter continuation treatment (weeks 12–28) if they had received an acceptable benefit (defined as a QIDS-C₁₆ ⩽9 by week 12) or if they reached a QIDS-C₁₆ of 10–13 with clinician and participant judging the benefit to be substantial enough to indicate a treatment continuation. Thus, virtually all participants entering the continuation phase had at least a 40% reduction in baseline QIDS-C₁₆.

Additional baseline measures included the IDS-C₃₀ (Rush et al.1996, 2000, 2003), of which 28 items are rated 0–3 (range 0–84, with higher numbers indicating more severe depression), the Work and Social Adjustment Scale (Mundt et al.2002), (five items; range 0–40; higher numbers indicate greater impairment) and the Quality of Life Inventory (Frisch, 1994; Frisch et al.1992, 2005) (overall life satisfaction is calculated as the mean of 17 weighted items resulting in a possible score ranging from −6 to +6). Cognition, fatigue, sleepiness and anhedonia were measured using the Cognitive and Physical Functioning Questionnaire (Fava et al.2009), a unifactorial scale consisting of seven questions with ratings from 1–6, and side-effect burden was measured using the FIBSER.

Statistical analyses

Descriptive statistics, including measures of central tendency and dispersion, were computed for continuous data. Frequency distributions were estimated for categorical data. The appropriate parametric (e.g. t test) or nonparametric test (e.g. χ², Wilcoxon tests) were used to ensure a balanced distribution of the sociodemographic, psychiatric and medical characteristics among those with and without anxious depression.

At 12 and 28 wk, unadjusted and adjusted treatment features and outcomes were compared among those with and without anxious depression using regression models. The type of regression models varied by outcome and included linear regression, logistic regression, ordinal logistic regression and negative binomial regression models. Potential confounders were identified using a stepwise logistic regression model with an indicator of anxious depression as the outcome and all other baseline characteristics as independent variables. Those variables that remained in the final stepwise model were considered as potential confounders in the adjusted models. The moderating effect of anxious depression on treatment was evaluated on two outcomes, severity of depression (QIDS-SR₁₆) and side-effect burden (FIBSER burden), both at 12 and 28 wk. For severity of depression a linear regression model was fit, and for side-effect burden an ordinal logistic regression model was fit. Both models included main effects for treatment and anxious depression. The moderating effect of anxiety and treatment on time to remission (QIDS-SR₁₆ ⩽5) was examined using Kaplan–Meir curves and a log-rank test to determine if the curves were significantly different. All analyses are considered to be exploratory in nature and a type I error or a p value <0.05 was used as a threshold to identify statistical significance. No adjustments were made for multiple comparisons, so results should be interpreted accordingly.

Results

A total of 835 out-patients were offered consent to be screened for the study (Fig. 1). Of these, 734 (87.9%) signed consent. Of those screened, 665 (90.6%) were eligible and were enrolled and randomly assigned to one of the three treatment groups. Of these, 497/665 (74.7%) met the criterion for anxious features.

A larger percentage of those with more anxious features were women compared with those with fewer anxious features (71.4% vs. 57.7%; p=0.0010) (Table 1). Slightly more participants with more anxious features reported sexual abuse before age 18 than those with fewer anxious features (23.6% vs. 16.8%, p=0.0651) (Table 2).

At baseline, participants with more anxious features had higher rates of concurrent agoraphobia (p<0.0001), panic disorder (p=0.0002), generalized anxiety disorder (p<0.0001), post-traumatic stress disorder (p=0.0043) and social phobia (p=0.0006), and more psychiatric disorders overall (p<0.0001) than the less anxious group. The two groups did not differ in the number of concurrent GMCs at baseline (Table 3).

Participants with more anxious features had greater baseline depressive severity than the less anxious based on the HAMD₁₇, QIDS-SR₁₆, QIDS-C₁₆, and the IDS-C₃₀ (all p<0.0001) and the more anxious were more likely to have melancholic (p<0.0001) or lethargic (p<0.0001) depressive symptom features at baseline. Worse cognitive function (p=0.0001), lower quality of life (p=0.0008) and poorer work and worse social adjustment (p=0.0017) at baseline characterized the more anxious group (Table 4).

Early termination rates did not distinguish the two groups defined by baseline anxious features. Severity of depression did not differentiate between the two groups at weeks 12 or 28, nor did quality-of-life scores. At week 12, participants with more anxious features had greater side-effect burden than those with less anxious features (p=0.0049). The more anxious participants were prescribed higher doses of venlafaxine (p=0.0485) and Mirt (p=0.0444) than the less anxious participants. At week 28 participants with greater baseline anxiety still had a greater side-effect burden than the less anxious (p=0.0009), but doses of antidepressant medications were not different (Table 5).

The two groups (more or less anxious) did not differ in time to response to any of the three treatments at either 12 wk or 28 wk (Fig. 2). In addition, more vs. fewer anxious features was unrelated to treatment outcomes or side-effect burden among the three treatment options (Table 6).

To further evaluate the relevance of baseline anxiety on outcomes, we divided the whole group into those with vs. those without any formal anxiety disorder based on the PDSQ. Of those with a formal anxiety disorder 46.5% (120/258) responded and 27.9% (73/262) remitted. Of those who were deemed ‘less anxious’, but who had one or more formal anxiety disorders by PDSQ, 50% (25/50) responded (p=0.651) and 32.0% (16/50) remitted (p=0.5527).

Turning to those without a formal anxiety disorder, of those considered to be ‘more anxious’, 57.9% (129/223) responded, and 48.1% (113/235) remitted. On the other hand, those without a formal anxiety disorder and fewer anxious features, 53.7% (60/112) responded (p=0.466) and 45.8% (45/118) remitted (p=0.6801).

Discussion

About three out of four participants in this study met the threshold for more anxious symptoms, which is higher than the 44–46% found in the depressed out-patient sample of our earlier Sequenced Treatment Alternatives to Relieve Depression study (STAR*D; Fava et al.2004, 2006) and the 51.2% found in a recent depressed inpatient sample (Wiethoff et al.2010). CO-MED required that participants have either recurrent or chronic depression and that the index episode had to exceed 2 months in duration. Anxious features are more common among participants with a chronic index episode of depression (Gilmer et al.2008). Perhaps the inclusion criteria in the current study account for the high rate of more anxious participants.

Those with more anxious features were more likely to be female (>70%) than the less anxious (57%), reported elsewhere (Fava et al.2004, 2006). There were no significant differences between the two groups in employment status, educational level or household income, although some studies have found that those with more anxious features have lower educational attainment, greater unemployment and poorer social circumstances (Fava et al.2004, 2006; Wiethoff et al.2010). In addition, we did not find an earlier onset of illness, greater suicidality or greater duration of illness in the more anxious compared with the less anxious group. Childhood sexual, physical or emotional abuses are known risk factors for the development of anxiety and depressive disorders in adults (Gibb et al.2007; Young et al.1997). In this study, such childhood adversities did not differentiate those with more vs. less anxious features.

Participants with more anxious features had more concurrent formal anxiety disorders based on the PDSQ and more psychiatric disorders overall – including agoraphobia, generalized anxiety disorder, panic disorder, post-traumatic stress disorder and social phobia – which is consistent with prior reports (Fava et al.2004, 2006). Thus, anxiety symptom features (as a dimension) are highly related to the likelihood of syndromal diagnoses of various anxiety disorders.

Comorbid depression is a well-known feature of chronic medical illnesses such as asthma (Eisner et al.2005), coronary artery disease (Spertus et al.2000) and congestive heart failure (Rumsfield et al.2003). In this study, however, anxious features were not associated with greater rates of concurrent, comorbid general medical illnesses, although up to half of the depressed participants had at least one comorbid health problem.

The participants with more anxious features were more severely depressed and they displayed more lethargic and melancholic features than the less anxious – although not more atypical features – which fits previous findings (Rush et al.2006; Trivedi et al.2006). Given the greater severity and psychiatric comorbidity in the more anxious, it is not surprising that greater impairment in cognitive and physical functioning, lower quality of life and greater difficulty in work and social adjustment was also present.

Contrary to expectation, the two groups (more vs. less anxious) did not differ in terms of depressive symptom outcomes at either 12 or 28 wk, nor did they differ in drop-out rates (early terminations). Our finding that those with more anxious features did not have a worse depression outcome than those with fewer anxious features at baseline is contrary to some (Davidson et al.2002; Fava et al.1997, 2008; Flint & Rifat, 1997) but not all (Russell et al.2001; Tollefson et al.1994) prior reports. It could be due to: (1) the risk that all of these reports (this one included) are secondary analyses, which risk false positive findings; (2) the sample herein is one in which over half of the participants were in the index episode for at least two (and in many cases several more) years; and/or (3) the requirement of at least 6 months than the current episode or other factors. It should be noted, however, that we did not have a Pbo comparison. Thus, there could be a drug–Pbo response difference within either or both the more and less anxious groups.

At the end of acute treatment (week 12), participants with more anxious features reported higher side-effect burden than the less anxious participants. This finding could be due to the higher doses of MIRT and venlafaxine prescribed in acute treatment for the more anxious (vs. less) participants. Previous reports with other treatments (Fava et al.2008) have also found that participants with more anxious features have a greater frequency, intensity and burden of side-effects during treatment compared with less anxious depressed participants. Thus, baseline anxiety features may put patients at greater risk for side-effect burden, due to the use of larger doses of medication or to a heightened focus on bodily symptoms or greater sympathetic nervous system arousal.

However, at week 28, participants with more anxious features reported higher side-effect burden even when there was no difference in medication dosage. A large-scale study of >50 000 participants (Haug et al.2004) has shown that when both anxiety and depression are present, there is a higher prevalence of somatic symptoms than when anxiety or depression alone are present. It has been suggested that the threshold for experiencing somatic symptoms may be lower in participants with concurrent anxiety and depression (Katon et al.1991). Thus, the use of the self-report FIBSER to measure side-effect burden may have detected participants with residual anxious depression who are somatizing rather than actually experiencing side-effects.

When we compared the three treatment options in this study, membership in the more or less anxious group was unrelated to treatment outcomes or side-effect burden. Thus, anxious features did not moderate outcomes among the three treatment options in this study, which is similar to findings in STAR*D (Rush et al.2008). However, STAR*D found that, overall, those with more anxious features had poorer outcomes than those with fewer anxious features.

This study had several limitations. We did not utilize a clinician-administered structured diagnostic interview, which could have provided a more accurate diagnostic picture. Also, the results can only be generalized to out-patients with chronic or recurrent MDD, in which the index episode is at least 2 months in duration. Most of the assessment tools relied on participant self-assessment.

In summary, this single-blind, randomized trial found anxious features to be highly prevalent in these nonpsychotic depressed out-patients, over half of whom were in a chronic episode. Anxious features were more common in women than in men. Baseline anxious features were associated with a distinct clinical profile but, in this study, we found no association between anxious features at baseline and overall outcome or with differential treatment outcomes among the three antidepressant medication options.

Acknowledgements

This project was funded by the National Institute of Mental Health under Contract N01MH90003 to UT Southwestern Medical Center at Dallas (PIs A. J. Rush, M. H. Trivedi). The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. The NIMH had no role in the drafting or review of the manuscript, nor in the collection or analysis of the data. We appreciate the support of Forest Pharmaceuticals Inc., GlaxoSmithKline, Organon Inc. and Wyeth Pharmaceuticals in providing medications at no cost for this trial. We acknowledge the administrative support of the Research and Development Service at the participating VA Medical Centers. We also acknowledge the editorial support of Jon Kilner, MS, MA (Pittsburgh, PA). The authors are entirely responsible for the scientific content of the paper.

[Trial Registry Name: ClinicalTrials.gov (Registration identification number: NCT00590863) URL for the registry: http://www.clinicaltrials.gov/ct2/show/NCT00590863?term=CO-MED&rank=1].

Statement of Interest

Dr Davis has received research support (no personal income) from Abbott Laboratories, Inc.; AstraZeneca; Bristol-Myers Squibb Company (BMS); Eisai Pharmaceuticals; Janssen; VA, NIMH, Shire; AstraZeneca; Southwestern Oncology Group, Department of Defense (DoD). She has done advising/consulting for Cyberonics; Abbott; Shire; Constella; Eli Lilly, has done speaking engagements for Abbott Laboratories; Cyberonics; Sanofi-Aventis; and AstraZeneca and has equity holdings in Pfizer (until 2009). Dr Fava has received research support from Abbott Laboratories; Alkermes; Aspect Medical Systems; Astra-Zeneca; Bristol-Myers Squibb Company; Cephalon; Forest Pharmaceuticals Inc.; GlaxoSmithKline; J & J Pharmaceuticals; Lichtwer Pharma GmbH; Eli Lilly & Company; Lorex Pharmaceuticals; Novartis; Organon Inc.; PamLab, LLC; Pfizer Inc.; Pharmavite; Roche; Sanofi/Synthelabo; Solvay Pharmaceuticals, Inc.; Wyeth-Ayerst Laboratories. He has provided advisory/consulting services to Aspect Medical Systems; Astra-Zeneca; Bayer AG; Biovail Pharmaceuticals, Inc.; BrainCells, Inc.; Bristol-Myers Squibb Company; Cephalon; Compellis; Cypress Pharmaceuticals; Dov Pharmaceuticals; EPIX Pharmaceuticals; Fabre-Kramer Pharmaceuticals, Inc.; Forest Pharmaceuticals Inc.; GlaxoSmithKline; Grunenthal GmBH; J & J Pharmaceuticals; Janssen Pharmaceutica; Jazz Pharmaceuticals; Knoll Pharmaceutical Company; Eli Lilly & Company; Lundbeck; MedAvante, Inc.; Novartis; Nutrition 21; Organon Inc.; PamLab, LLC; Pfizer Inc.; PharmaStar; Pharmavite; Roche; Sanofi/Synthelabo; Sepracor; Solvay Pharmaceuticals, Inc.; Somerset Pharmaceuticals; Wyeth-Ayerst Laboratories. He has been on speaking bureaus for Astra-Zeneca; Bristol-Myers Squibb Company; Cephalon; Forest Pharmaceuticals Inc.; GlaxoSmithKline; Eli Lilly & Company; Novartis; Organon Inc.; Pfizer Inc.; PharmaStar; Wyeth-Ayerst Laboratories. Dr Fava has equity holdings (excluding mutual funds/blinded trusts) with Compellis and MedAvante. Dr Friedman has received grant/research support: Aspect Medical Systems; Indevus; AstraZeneca; Bristol-Myers Squibb; Pfizer; Sanofi-Aventis; Wyeth-Ayerst; Cyberonics; Novartis; NorthStar/St. Jude Medical; Medtronics; Repligen. He has been on speaker bureaus or advisory boards for AstraZeneca; GlaxoSmithKline; Pfizer; Wyeth-Ayerst. Dr Gaynes has received grant/research from the National Institute of Mental Health; Agency for Healthcare Research and Quality; and M-3 Information. Dr Nierenberg is a full time employee of the Massachusetts General Hospital (MGH). He has served as a consultant to the American Psychiatric Association (only travel expenses paid) and Appliance Computing Inc. (Mindsite), Brandeis University. Through the MGH Clinical Trials Network and Institute, he has consulted for Brain Cells, Inc Dianippon Sumitomo/Sepracor Novartis, PGx Health, Shire, Schering-Plough, Targacept and Takeda/lundbeck Pharmaceuticals. He received grant/research support through MGH from NIMH, Pam labs, Pfizer Pharmaceuticals and Shire. He received honoraria from Belvior Publishing, University of Texas Southwestern Dallas, Hillside Hospital, American Drug Utilization Review, American Society for Clinical Psychopharmacology, Baystate Medical Center, Columbia University, IMEDEX, MJ Consulting, New York State, MBl Publishing, Physicians Postgraduate Press, SUNY Buffalo, University of Wisconsin and the University of Pisa. Dr Nierenberg is a presenter for the Massachusetts General Hospital Psychiatry Academy (MGHPA). The education programs conducted by the MGHPA were supported through Independent Medical Education (IME) grants from the following pharmaceutical companies in 2008: Astra Zeneca, Eli Lilly and Janssen Pharmaceuticals; in 2009 Astra Zeneca, Eli Lilly and Bristol-Myers Squibb. No speaker bureaus or boards since 2003. He is on the advisory boards of Appliance Computing, Inc., Brain Cells, Inc., Eli Lilly and Company and Takeda/lundbeck and Targacept. Dr Nierenberg owns stock options in Appliance Computing, Inc. and Brain Cells, Inc. Through MGH, he is named for copyrights to the Clinical Positive Affect Scale and the MGH Structured Clinical Interview for the Montgomery Asberg Depression Scale exclusively licensed to the MGH Clinical Trials Network and Institute (CTNI). Also, through MGH, Dr Nierenberg has a patent extension application for the combination of buspirone, bupropion and melatonin for the treatment of depression. Dr Rush has received consultant fees from University of Michigan, Brain Resource; speaking fees from Otsuka Pharmaceuticals; research support from National Institute of Mental Health and royalties from Guilford Publications and the University of Texas Southwestern Medical Center. Dr Trivedi has been a consultant for Abbott Laboratories, Inc.; Akzo (Organon Pharmaceuticals Inc.); AstraZeneca; Bayer; Bristol-Myers Squibb Company; Cephalon, Inc.; Cyberonics, Inc.; Eli Lilly & Company; Fabre-Kramer Pharmaceuticals, Inc. Forest Pharmaceuticals; GlaxoSmithKline; Janssen Pharmaceutica Products, LP; Johnson & Johnson PRD; Eli Lilly & Company; Meade Johnson; Neuronetics; Parke-Davis Pharmaceuticals, Inc.; Pfizer, Inc.; Pharmacia & Upjohn; Sepracor; Solvay Pharmaceuticals, Inc.; VantagePoint; and Wyeth-Ayerst Laboratories. He has served on speakers bureaus for Abdi Brahim; Akzo (Organon Pharmaceuticals Inc.); Bristol-Myers Squibb Company; Cephalon, Inc.; Cyberonics, Inc.; Forest Pharmaceuticals; GlaxoSmithKline; Janssen Pharmaceutica Products, LP; Eli Lilly & Company; Pharmacia & Upjohn; Solvay Pharmaceuticals, Inc.; and Wyeth-Ayerst Laboratories. He has also received grant support from Bristol-Myers Squibb Company; Cephalon, Inc.; Corcept Therapeutics, Inc.; Cyberonics, Inc.; Eli Lilly & Company; Forest Pharmaceuticals; GlaxoSmithKline; Janssen Pharmaceutica; Merck; National Institute of Mental Health; National Alliance for Research in Schizophrenia and Depression; Novartis; Pfizer Inc.; Pharmacia & Upjohn; Predix Pharmaceuticals; Solvay Pharmaceuticals, Inc.; and Wyeth-Ayerst Laboratories. Dr Wisniewski has been a consultant for: Cyberonic Inc. (2005–2009), ImaRx Therapeutics, Inc. (2006), Bristol-Myers Squibb Company (2007–08), Organon (2007), Case-Western University (2007), Singapore Clinical Research Institute (2009), Dey Pharmaceuticals (2010), Venebio (2010), Dey (2010).

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