Nmd21310 807.810

Changes in Depressive Symptoms and Social Functioning in the Sequenced Treatment Alternatives to Relieve Depression Study John W. Denninger, MD, PhD,* Adrienne O. van Nieuwenhuizen, MSc,* Stephen R. Wisniewski, PhD,Þ James F. Luther, MSc,Þ Madhukar H. Trivedi, MD,þ A. John Rush, MD,§ Jackie K. Gollan, PhD, Diego A. Pizzagalli, PhD,¶ and Maurizio Fava, MD* antidepressants, social functioning often does not return to baseline Abstract: Major depressive disorder (MDD) profoundly affects social func- (Weissman, 2000). A small number of studies have investigated long- tioning, including the ability to enjoy social activities with peers, friends, and term social functioning impairments during or after treatment using family members. We sought to compare changes in social functioning and antidepressants; these suggest that long-term impairments in social depressive symptoms in the first level of the Sequenced Treatment Alterna- functioning may persist even in patients whose depression is deter- tives to Relieve Depression (STAR*D) study. Adult outpatients (N = 2876) mined to be in clinical remission (Kennedy et al., 2007). In level 1 of with diagnoses of MDD were treated using flexible doses of citalopram for the STAR*D trial, greater baseline symptom severity was associated up to 14 weeks. We compared the change over the course of treatment in the with lower health-related quality of life as assessed across multiple social activities item of the Work and Social Adjustment Scale to the change domains (Trivedi et al., 2006b). Interestingly, Rapaport et al. (2005) in individual items of the Quick Inventory of Depressive SymptomsYSelf- found that symptom measures in mood and anxiety disorders were Rated (QIDS-SR). Improvement in social functioning was modestly positively associated with baseline quality of life; however, the symptom mea- correlated with improvement in sad mood, concentration/decision making, in- sures accounted for only a small proportion of the variance in quality volvement, and energy/fatigability. Only 16% to 22% of the variance in the change in social functioning was accounted for by these symptoms, and only We sought to make a similar comparison for social function- 32% was accounted for by the total QIDS-SR score. In this large real-world ing in a large sample of patients with MDD before and after selective sample of outpatients treated using citalopram, changes in depressive symptoms serotonin reuptake inhibitor treatment. To this end, we compared do not entirely explain improvements in social functioning.
changes in social functioning as measured by the social leisure activ- Key Words: Major depressive disorder, citalopram, social adjustment.
ities item of the Work and Social Adjustment Scale (WSAS), withchanges in depression symptoms in level 1 of STAR*D trial (Mundt (J Nerv Ment Dis 2011;199: 807Y810) et al., 2002). We hypothesized that changes in symptom measuresduring citalopram treatment would be associated with changes in so-cial functioning measures but would account for only a small propor- Psychosocial and functional impairments are common in major tion of thevariance in the improvements in social functioning.
depressive disorder (MDD) and are likely to result in negative psychosocial outcomes, including unemployment and decreased so-cial contacts (Hirschfeld et al., 2002; Weissman, 2000). However, the exact nature of the relationship between MDD symptoms and defi- The rationale, design, and detailed methods for the first level cits in psychosocial functioning remains to be established. Although of STAR*D have been previously described (Rush et al., 2004; there is a modest association between decreases in clinical symptoms Trivedi et al., 2006a). The study protocol was approved by individual and improvements in social functioning during acute treatment using institutional review boards, and all patients provided written informedconsent. The generalizability of our results was increased by limitingeligibility to patients who sought care as part of routine medical orpsychiatric treatment (i.e., patients were not recruited through ad- *Depression Clinical and Research Program, Massachusetts General Hospital, vertising) and by having broad inclusion and minimal exclusion cri- Boston, MA; †Epidemiology Data Center, Graduate School of Public Health, teria. Outpatients aged 18 to 75 years diagnosed with nonpsychotic University of Pittsburgh, Pittsburgh, PA; ‡Department of Psychiatry, University MDD with a baseline 17-item Hamilton Depression Rating Scale of Texas Southwestern Medical Center, Dallas, TX; §Office of Clinical Sci-ences, Duke-National University of Singapore, Singapore; Department of (Hamilton, 1960; Hamilton, 1967) score of 14 or greater were eligi- Psychiatry and Behavioral Sciences, Northwestern University Feinberg School ble. Eligible patients (n = 2876) were treated with the selective se- of Medicine, Chicago, IL; and ¶Department of Psychology, Harvard University, rotonin reuptake inhibitor citalopram for up to 14 weeks. Citalopram Cambridge, MA.
was started at 20 mg/day and titrated to a target dose of 60 mg/day The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study was supported by the NIMH through the N01 MH-90003 contract. The content by week 6, with flexibility to titrate more slowly if necessary.
of this publication does not necessarily reflect the views or policies of the The WSAS is a five-item scale used to assess work, home Department of Health and Human Services, nor does the mention of trade management, social leisure activities, private leisure activities, and names, commercial products, or organizations imply endorsement by the US close relationships; Cronbach > measure of internal consistency for This report represents secondary analyses of the STAR*D trial. The STAR*D study the scale ranges from 0.70 to 0.94, and test-retest correlation is 0.73 is registered at Clinical Trials as Sequenced Treatment Alternatives to Relieve (Mundt et al., 2002). In STAR*D, the WSAS was administered using Depression (STAR*D; http://clinicaltrials.gov/ct2/home; NCT00021528).
an interactive voice response (IVR) system, which has been shown Preliminary results were previously presented in poster form at NCDEU: New Research to correlate highly (0.81 Approaches for Mental Health Interventions, Phoenix, AZ, May 28, 2008.
Y0.86) with the clinician-administered ver- Send reprint requests to John W. Denninger, MD, PhD, Massachusetts General sion (Mundt et al., 2002). The current analysis focused on the social Hospital, 151 Merrimac St, Ste. 400, Boston, MA 02114-4717.
activities item: ‘‘3. Because of my [disorder], my social leisure ac- tivities (with other people, such as parties, bars, clubs, outings, visits, Copyright * 2011 by Lippincott Williams & Wilkins dating, home entertainment) are impaired,'' which was rated using a scale ranging from 0 (‘‘not at all'') to 8 (‘‘very severely impaired'').
The Journal of Nervous and Mental Disease & Volume 199, Number 10, October 2011 Copyright 2011 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Denninger et al.
The Journal of Nervous and Mental Disease & Volume 199, Number 10, October 2011 The QIDS-SR is a well-validated 16-item self-rated scale of depres-sive symptoms (Rush et al., 2003), which captures the nine criteria TABLE 2. Pearson Product Moment Correlation (r) andProportion of Variance Accounted for (R2) Between Change used to diagnose major depressive episode in the DSM-IV. It was in WSAS Item 3 and Individual QIDS-SR Items or Total QIDS-SR also administered using the IVR system. Scores for individual items Score for the Entire Sample (n = 1846) range from 0 to 3; the score for the entire instrument ranges from0 to 27.
Patients who had QIDS-SR and WSAS scores for entry and exit Sleep-onset insomnia (n = 1846) were included in this post hoc analysis. We compared Midnocturnal insomnia the change (exitYentry) in the social activities item of the WSAS (item Early-morning insomnia 3) to the change in individual items of the QIDS-SR. The Pearson product-moment correlation was computed between the change inWSAS item 3 and the change in each QIDS-SR item (for a total of 16 separate correlations); for these correlations, > was adjusted using the Bonferroni correction, yielding an > of 0.003 (= 0.05/16). In addition, the Pearson product-moment correlation was computed be- tween the change in WSAS Item 3 and the change in total QIDS-SR score. Proportion of variance was calculated as the square of Pearson r.
Suicidal ideation The STAR*D level 1 analyzable sample of 2876 has been Psychomotor slowing reported elsewhere (Trivedi et al., 2006a). Of these 2876 patients, Psychomotor agitation 1846 had both baseline and exit assessments of the WSAS. Table 1 shows the baseline characteristics of the 1846 patients included in this Bonferroni-corrected > = 0.003.
analysis; these were not significantly different from the characteristics QIDS-SR indicates Quick Inventory of Depressive SymptomatologyYSelf-report; of the full sample (n = 2876).
WSAS, Work and Social Adjustment Scale.
For WSAS Item 3, mean change (exitYentry) was j1.9 T 2.8 (n = 1846, p G 0.0001), with change values ranging from j8 (im-provement) to 8 (worsening). For the 16-item QIDS-SR, total meanchange (exitYentry) was j6.3 T 6.7 (n = 1846, p G 0.0001), with was modestly correlated with 4 of the 14 individual QIDS-SR items: change values ranging from j25 (improvement) to 13 (worsening).
sad mood (r = 0.48, p G 0.001), concentration/decision making (r = Table 2 shows Pearson product moment correlation (r) and the 0.44, p G 0.001), involvement (r = 0.42, p G 0.001) and energy/ proportion of the variance (r2) in WSAS item 3 accounted for by the fatigability (r = 0.40, p G 0.001). As Table 2 shows, however, only change in individual QIDS-SR items. Change in social functioning 16% to 23% of the variance in the change in social functioningwas accounted for by each of these items individually. The remain-der of the items each explained 10% or less of the variance in thechange in social functioning. Although the change in the WSAS so- TABLE 1. Patient Sample Descriptive Characteristics cial activities item was more highly correlated with the change intotal QIDS-SR score (r = 0.58, p G 0.001), the change in depressive symptoms overall only accounted for 34% of the variance in the Age (mean T SD), yrs change in social functioning.
Female sex (n, %) Rapaport et al. (2005) compared baseline symptom measures with baseline quality of life measures in an array of mood and anxiety disorders and found that ‘‘illness-specific symptoms'' accounted for only a small to modest proportion of the variance in quality of life, Years of education (mean T SD) leading them to conclude that quality of life is a ‘‘related but semi- Employment status (n, %) independent component of DSM-IV syndromes'' (p. 1176). In thisstudy, we sought to determine the extent to which improvements in social functioning, as opposed to the broader concept of quality of life, were related to improvements in MDD symptoms.
In this large (n = 1846), real-world sample of outpatients, Monthly household income (mean T SD) all QIDS-SR items (except for the infrequently reported increased Medical insurance (n, %) appetite and weight gain) were significantly correlated (Bonferroni- corrected > = 0.003) with change in the social activities item of the WSAS (Table 2). However, even the most highly correlated items (sad mood, concentration/decision making, involvement, and energy/ Marital status (n, %) fatigability) individually account for only 16% to 23% of the variance in social functioning. The less highly correlated items (sleep onsetinsomnia, self-outlook, suicidal ideation, psychomotor slowing, mid- nocturnal insomnia, decreased appetite, psychomotor agitation, early morning insomnia, hypersomnia, decreased weight, and increased appetite) individually account for only 1% to 10% of the variance.
Psychiatric care (n, %) Even the change in total QIDS-SR score accounted for only 34% * 2011 Lippincott Williams & Wilkins Copyright 2011 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
The Journal of Nervous and Mental Disease & Volume 199, Number 10, October 2011 MDD Symptoms and Social Functioning of the variance in the change in WSAS item 3. It should be noted, Bristol-Myers Squibb Company, Cephalon Inc, Cyberonics Inc, Eli Lilly as well, that the wording of the WSAS instructions (which explicitly & Company, Evotec, Fabre-Kramer Pharmaceuticals Inc, Forest ask subjects to evaluate the effect of their disorder on their social Pharmaceuticals, GlaxoSmithKline, Janssen Pharmaceutica Products, functioning) would be expected to bias subjects into linking social LP, Johnson & Johnson PRD, Meade Johnson, Medtronic, Neuronetics, functioning and depression symptoms. As such, the proportion of Otsuka Pharmaceuticals, Parke-Davis Pharmaceuticals Inc, Pfizer Inc, variance in social functioning accounted for by depression symp- Sepracor, SHIRE Development, Solvay Pharmaceuticals, VantagePoint, toms, which we report here, is likely to be an overestimate.
and Wyeth-Ayerst Laboratories. He receives research support from Similar to the results here, our analysis of changes in social the Agency for Healthcare Research and Quality (AHRQ), Corcept functioning and depression symptoms in a double-blind, randomized, Therapeutics Inc, Cyberonics Inc, Merck, National Alliance for Re- placebo-controlled trial comparing Hypericum perforatum to sertra- search in Schizophrenia and Depression, NIMH, National Institute on line showed that only 25% of the variance in the change in social Drug Abuse, Novartis, Pharmacia & Upjohn, Predix Pharmaceuticals functioning, measured using the Sheehan Disability Scale (Sheehan (Epix), Solvay Pharmaceuticals Inc, and Targacept. A. John Rush et al., 1996), was accounted for by the variance in the change in reports receiving royalties from UT Southwestern, speaking fees from depression symptoms during the 8-week acute phase (Denninger Otsuka Pharamaceuticals, and consultant fees from Best Practices.
et al., 2008). These and our current results seem to support the con- Jackie Gollan has received research support from NIMH, National clusion by Rapaport et al. (2005) that quality of life measures cap- Alliance for Research in Schizophrenia and Depression, and Amer- ture a component of mood and anxiety disorders partially distinct ican Foundation of Suicide Prevention. She has received royalties from symptom measures.
from American Psychological Association and Guilford Press. She Our study has several limitations. First, our use of WSAS item has owned shares of Pfizer and Bristol-Myers Squibb stock. She has 3 as a proxy measure of social functioning may define social func- received a speaker honoria from AstraZeneca. She is a consultant for tioning too narrowly, given that item 3 refers only to social leisure Prevail Inc. Diego Pizzagalli has received consulting fees from ANT activities. Second, there are no studies, to our knowledge, correlating North America Inc (Advanced Neuro Technology) and AstraZeneca WSAS item 3 scores to total scores on other validated social func- and honoraria from AstraZeneca. Maurizio Fava has received re- tioning scales. Finally, we have not controlled for comorbid anxiety search support from Abbott Laboratories, Alkermes Inc, Aspect disorders, symptoms of which can also contribute to deficits in so- Medical Systems, AstraZeneca, BioResearch, BrainCells Inc, Bristol- cial functioning and quality of life (Rapaport et al., 2005).
Myers Squibb, Cephalon Inc, Clinical Trials Solutions LLC, Covidien,Eli Lilly and Company, EnVivo Pharmaceuticals Inc, Forest Pharma-ceuticals Inc, Ganeden Biotech Inc, GlaxoSmithKline, Johnson &Johnson Pharmaceutical Research & Development, Lichtwer Pharma GmbH, Lorex Pharmaceuticals, Novartis AG, Organon Pharmaceu- In sum, the current results support the idea that social func- ticals, PamLab LLC, Pfizer Inc, Pharmavite LLC, Roche, RTC Logic tioning measures capture a component of MDD that is distinct from LLC, Sanofi-Aventis US LLC, Shire, Solvay Pharmaceuticals Inc, symptom-based measures. Social functioning measures may provide a Synthelabo, and Wyeth-Ayerst Laboratories. Dr. Fava has received window into patients' recovery that incompletely overlaps with mea- advisory/consulting fees from Abbott Laboratories, Affectis Pharma- sures of depression symptoms. Further research is needed to deter- ceuticals AG, Amarin Pharma Inc, Aspect Medical Systems, mine the optimal way to track and directly remediate quality of life AstraZeneca, Auspex Pharmaceuticals, Bayer AG, Best Practice and social functioning deficits.
Project Management Inc, BioMarin Pharmaceuticals Inc, BiovailCorporation, BrainCells Inc, Bristol-Myers Squibb, CeNeRx Bio-Pharma, Cephalon Inc, Clinical Trials Solutions LLC, CNS Response Inc, Compellis Pharmaceuticals, Cypress Pharmaceutical Inc, Dov John Denninger has received or is receiving salary support Pharmaceuticals Inc, Eisai Inc, Eli Lilly and Company, EPIX Phar- from the National Institutes of Health, the Centers for Disease Con- maceuticals Inc, Euthymics Bioscience Inc, Fabre-Kramer Pharma- trol, the Kaplen Foundation, Massachusetts General Hospital, and the Massachusetts General Hospital Physicians Organization, as GlaxoSmithKline, Gruenthal GmbH, Janssen Pharmaceutica, Jazz well as (through fellowships funded by unrestricted educational Pharmaceuticals Inc, Johnson & Johnson Pharmaceutical Research & grants) from AstraZeneca, Bristol-Meyers Squibb, Cephalon, Janssen, Development LLC., Knoll Pharmaceuticals Corp., Labopharm Inc, Lilly, Merck, Pfizer, and Wyeth. Dr. Denninger has also received hon- Lorex Pharmaceuticals, Lundbeck Inc, MedAvante Inc, Merck & Co.
oraria (through unrestricted educational grants) from AstraZeneca, Inc, Methylation Sciences, Neuronetics Inc, Novartis AG, Nutrition 21, Bristol-Meyers Squibb, Cephalon, Eli Lilly, Janssen, Pfizer, and Wyeth.
Organon Pharmaceuticals, PamLab LLC, Pfizer Inc, PharmaStar, Dr. Denninger and/or the Depression Clinical and Research Program Pharmavite LLC, Precision Human Biolaboratory, Prexa Pharmaceu- of Massachusetts General Hospital have received or are receiving ticals Inc, PsychoGenics, Psylin Neurosciences Inc, Ridge Diagnostics research support from Abbott, Alkermes, Aspect Medical Systems, Inc, Roche, RCT Logic LLC, Sanofi-Aventis US LLC., Sepracor Inc, AstraZeneca, Bristol-Myers Squibb, Cephalon, Eli Lilly, Forest Labo- Schering-Plough Corporation, Solvay Pharmaceuticals Inc, Somaxon ratories, GlaxoSmithKline, Johnson & Johnson, Lichtwer Pharma Pharmaceuticals Inc, Somerset Pharmaceuticals Inc, Synthelabo, GmbH, Lorex Pharmaceuticals, Novartis, Organon, Pamlab, Pfizer, Takeda Pharmaceutical Company Limited, Tetragenex Pharmaceu- Pharmavite, Roche, Sanofi-Synthelabo, Solvay, and Wyeth. Adrienne ticals Inc, TransForm Pharmaceuticals Inc, Transcept Pharmaceuticals van Nieuwenhuizen reported no biomedical financial interests or po- Inc, Vanda Pharmaceuticals Inc, and Wyeth-Ayerst Laboratories.
tential conflicts of interest. Stephen Wisniewski reports having received Dr. Fava also reports receiving speaking/publishing fees from Adamed consulting fees from Cyberonic Inc (2005Y2009), ImaRx Therapeutics, Co, Advanced Meeting Partners, American Psychiatric Association, Inc (2006), Bristol-Myers Squibb Company (2007Y2008), Organon American Society of Clinical Psychopharmacology, AstraZeneca, (2007), Case-Western University (2007), and the Singapore Clinical Belvoir Media Group, Boehringer Ingelheim GmbH, Bristol-Myers Research Institute (2009). James Luther reported no biomedical fi- Squibb, Cephalon Inc, Eli Lilly and Company, Forest Pharmaceuticals nancial interests or potential conflicts of interest. Madhukar Trivedi is a Inc, GlaxoSmithKline, Imedex LLC, MGH Psychiatry Reed/Primedia, consultant to or is on a speakers' bureau for Abbott Laboratories Inc, MGH Psychiatry Academy/Reed Elsevier, Novartis AG, Organon Abdi Ibrahim, Akzo (Organon Pharmaceuticals Inc), AstraZeneca, Pharmaceuticals, Pfizer Inc, PharmaStar, United BioSource Corp, and * 2011 Lippincott Williams & Wilkins Copyright 2011 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Denninger et al.
The Journal of Nervous and Mental Disease & Volume 199, Number 10, October 2011 Wyeth-Ayerst Laboratories. Dr. Fava has equity holdings in Compellis, Mundt JC, Marks IM, Shear MK, Greist JH (2002) The Work and Social Adjustment and receives royalty/patent or other income from the following: patent Scale: A simple measure of impairment in functioning. Br J Psychiatry. 180:461Y464.
for the Sequential Parallel Comparison Design and patent applicationfor a combination of azapirones and bupropion in MDD, copyright Rapaport MH, Clary C, Fayyad R, Endicott J (2005) Quality-of-life impairment in depressive and anxiety disorders. Am J Psychiatry. 162:1171Y1178.
royalties for the Massachusetts General Hospital Cognitive andPhysical Functioning Questionnaire, Sexual Functioning Inventory, Rush AJ, Fava M, Wisniewski SR, Lavori PW, Trivedi MH, Sackeim HA, Thase ME, Nierenberg AA, Quitkin FM, Kashner TM, Kupfer DJ, Rosenbaum JF, Antidepressant Treatment Response Questionnaire, Discontinuation Alpert J, Stewart JW, McGrath PJ, Biggs MM, Shores-Wilson K, Lebowitz BD, Emergent Signs and Symptoms, and the State vs Trait, Assessability, Ritz L, Niederehe G; STAR*D Investigators Group (2004) Sequenced treatment Face Validity, Ecological Validity, and Rule of Three P's Criteria.
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