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Original Investigation |

Prevention of Depression With Escitalopram in Patients Undergoing Treatment for Head and Neck Cancer:  Randomized, Double-blind, Placebo-Controlled Clinical Trial FREE

William M. Lydiatt, MD1; Diane Bessette, PA2; Kendra K. Schmid, PhD3; Harlan Sayles, MS3; William J. Burke, MD2
[+] Author Affiliations
1Department of Otolaryngology–Head and Neck Surgery, College of Medicine, Nebraska Methodist Hospital, University of Nebraska Medical Center, Omaha, Nebraska
2Department of Psychiatry, College of Medicine, University of Nebraska Medical Center, Omaha, Nebraska
3Department of Biostatistics, College of Public Health, University of Nebraska Medical Center, Omaha, Nebraska
JAMA Otolaryngol Head Neck Surg. 2013;139(7):678-686. doi:10.1001/jamaoto.2013.3371.
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Published online

Importance  Major depressive disorder develops in up to half the patients undergoing treatment for head and neck cancer, resulting in significant morbidity; therefore, preventing depression during cancer treatment may be of great benefit.

Objective  To determine whether prophylactic use of the antidepressant escitalopram oxalate would decrease the incidence of depression in patients receiving primary therapy for head and neck cancer.

Design, Setting, and Participants  A randomized, double-blind, placebo-controlled trial of escitalopram vs placebo was conducted in a group of nondepressed patients diagnosed as having head and neck cancer who were about to enter cancer treatment. Patients were stratified by sex, site, stage (early vs advanced), and primary modality of treatment (radiation vs surgery).

Main Outcome and Measure  The primary outcome measure was the number of participants who developed moderate or greater depression (scores on the Quick Inventory of Depressive Symptomology–Self Rated of ≥11).

Results  From January 6, 2008, to December 28, 2011, 148 patients were randomized. Significantly fewer patients receiving escitalopram developed depression (24.6% in the placebo group vs 10.0% in the escitalopram group; stratified log-rank test, P = .04). A Cox proportional hazards regression model compared the 2 treatment groups after controlling for age, baseline smoking status, and stratification variables. The hazard ratio of 0.37 (95% CI, 0.14-0.96) demonstrated an advantage of escitalopram (P = .04). Patients undergoing radiotherapy as the initial modality were significantly more likely to develop depression than those undergoing surgery (radiotherapy compared with surgery group; hazard ratio, 3.6; 95% CI, 1.38-9.40; P = .009). Patients in the escitalopram group who completed the study and were not depressed rated their overall quality of life as significantly better for 3 consecutive months after cessation of drug use.

Conclusions and Relevance  In nondepressed patients undergoing treatment for head and neck cancer, prophylactic escitalopram reduced the risk of developing depression by more than 50%. In nondepressed patients who completed the trial, quality of life was also significantly better for 3 consecutive months after cessation of drug use in the escitalopram group. These findings have important implications for the treatment of patients with head and neck cancer.

Trial Registration  clinicaltrials.gov Identifier: NCT00536172

Figures in this Article

Head and neck cancer (HNC) accounts for 4% of all cancers in the United States and is the fifth most common type of cancer worldwide.1 The term HNC is the collective name for cancers that affect the oral cavity, paranasal sinuses, pharynx, larynx, skin, and salivary glands, 95% of which are epidermoid carcinomas. The incidence of HNC of the oropharynx is increasing worldwide because of the epidemic of human papillomavirus-associated cancer and is increasing the global burden and importance of this disease.2 Curative treatment consists of either surgery or radiation as the primary modality for early-stage disease.3 For more advanced disease, combination therapies using surgery, radiation, and chemotherapy are used.47 The burden of treatment is extensive and frequently includes dysphagia, disfigurement, voice alterations, mucositis, need for tracheostomy and feeding tubes, fatigue, and depression.8,9 Mitigation of these adverse effects and enhancement of survivorship are important goals of caregivers and researchers alike.

Psychiatric complications associated with HNC and its treatment are frequent, underdiagnosed, and often untreated.10 Major depressive disorder (MDD) occurs in 11% to 52% of patients with HNC, typically in the first 2 to 3 months after diagnosis of cancer.1114 Major depressive disorder substantially affects patients with HNC by adversely affecting length of hospital stay, adherence to treatment, self-care abilities, and quality of life.1214 Suicide is of particular concern in patients with HNC, with rates among the highest of all medically ill patients.1519 Compounding this problem, many oncologists are not adept at diagnosing and treating depression or identifying the overlap of signs and symptoms of depression with cancer treatment–related adverse effects. In addition, there is often limited time in the clinical setting to delve into psychiatric symptoms. Patients with depression during HNC treatment have a lower survival rate,20 yet there remains a scarcity of data about treatment of depression in patients with cancer.

Prevention of illness is a major focus of modern health care (eg, aspirin use to prevent stroke).21 Antidepressants can prevent recurrent depressive episodes in persons with major depression, depression after stroke, and depression associated with interferon alfa treatment.2225 A small pilot trial by our group suggested that citalopram hydrobromide might have a role in preventing depression in patients with HNC who were about to undergo treatment for cancer.26 However, no adequately powered randomized trial has demonstrated depression prevention in a cancer population.

The hypothesis for the Prevention of Depression in Patients Being Treated for Head and Neck Cancer Trial (PROTECT) was that prophylactic escitalopram would decrease the incidence of depression in patients receiving primary therapy for HNC. To test the hypothesis, this randomized, double-blind, placebo-controlled trial was conducted. To maximize safety, patients were removed from the trial if they reached a predefined score on a self-rated depression measure (the primary outcome) or 1 of 3 other clinician-rated measures. A secondary aim was to assess quality of life in the patients before, during, and after cancer treatment and study drug therapy.

Patients

The study was conducted at 2 sites: the University of Nebraska Medical Center (UNMC) and the Nebraska Methodist Cancer Center (NMCC), a community hospital. Institutional approval was obtained from both sites. Patients were approached by one of the head and neck surgeons and given an overview of the study, including the risks, benefits, and alternatives to participation. A delayed study consent process was used, allowing the patients ample opportunity to review the study plan and consent form, ask questions, or decline to participate with no influence on their subsequent care.

Patients were eligible if they were older than 18 years with newly diagnosed or recurrent stage II to IV epidermoid cancer of the head and neck. Patients were excluded if they were cognitively impaired; had advanced cancer or other conditions that limited life expectancy to less than 6 months; met diagnostic criteria for psychosis, schizophrenia, or MDD; were receiving treatment for depression or anxiety; had a persistent inability to verbally communicate; had uncontrolled pain; were currently participating in another research study involving a therapeutic intervention; or were females of childbearing age who were pregnant, nursing, or not practicing a reliable method of birth control.

Choice of Prevention Method

Pharmacotherapy was selected as the modality for prevention based on its effectiveness in the treatment of depression, comfort level of the clinicians, ease of administration, ability to be compared with placebo control, and ease of use in this population of patients in which many are quite ill and have significant impairments in speech.

Data about antidepressant use in patients with HNC are limited, and cancer patients are typically excluded from depression trials. The selective serotonin reuptake inhibitor escitalopram was selected as the study medication based on evidence of its efficacy, safety, favorable adverse effect profile, ease of discontinuing treatment, ease of administration as a single daily dose, safety in older adults and in medically fragile patients, few dosage adjustment steps, ability to be given through a nasogastric or percutaneous endoscopic gastrostomy, and minimal drug interaction potential. In our pilot study, citalopram was well tolerated. The S-stereoisomer of citalopram, escitalopram, was used in this trial because of the availability of a matching placebo tablet from the manufacturer.

Study Design and Intervention

This randomized, double-blind, placebo-controlled trial of escitalopram vs placebo was conducted in a group of nondepressed patients diagnosed as having stage II to IV epidermoid HNC. Patients were stratified by site (UNMC or NMCC), sex, stage (early [stage II] vs advanced [stage III/IV]), and primary modality of treatment (radiation with or without chemotherapy vs surgery [not biopsy] with or without radiation). The trial design was developed to maximize safety; therefore, patients were removed from the study if they met the primary end point of depression to avoid risk of untreated depression in this population at high risk of suicide and morbidity from MDD. Patients would also be withdrawn from the study if they exhibited other depression indicators, including significant suicidal ideation or intent or a diagnosis of depression on the Mini-International Neuropsychiatric Interview (MINI) depression module, a brief, structured, diagnostic interview.27

After giving informed consent, patients were randomized by a pharmacist with no involvement in the evaluation in a 1:1 ratio to either escitalopram or matching placebo according to a randomization table prepared by the study statistician. Study medication was dosed at 1 tablet for the first week (either placebo or escitalopram, 10 mg/d) and then increased to 2 tablets per day (2 placebo pills or 2 escitalopram pills, 10 mg/d) until week 16 (the acute phase). The dosage of the study medication was decreased to 1 tablet per day for an adverse event. Tablet counts were performed at the end of weeks 4, 8, 12, and 16. At 16 weeks, all patients taking 2 tablets daily had their dose reduced to 1 tablet daily for 1 week and then stopped. Those who were taking only 1 tablet had their medication use stopped at the end of 16 weeks.

In the follow-up phase, patients who completed the acute phase were assessed at 20, 24, and 28 weeks to gauge potential longer-term outcomes of the acute phase intervention. All patients received standard clinical psychosocial interventions throughout the study, primarily education and counseling performed by the physicians and nurses as needed. Per the standard practice of our clinic, patients were offered the opportunity to join a monthly support group but did not receive formal psychotherapy.

Measurement Tools

The assessment measures chosen for this study reflected the needs of the unique population of patients with HNC. These tools were (1) not burdensome to the patient (primary treatment of cancer is arduous), (2) could be self-rated (given the difficulties with verbal communication some of these patients experience), and (3) allowed for remote assessment (given the distance many of the patients live from the research clinic). The Quick Inventory of Depressive Symptomatology (QIDS) scales were initially developed to improve on available clinician and patient ratings by providing equivalent weightings for each depressive symptom and to provide clear anchors for each item. The self-rated version of the QIDS (QIDS-SR) was chosen as the primary outcome measure.28 The QIDS-SR was administered at baseline and at weeks 2, 4, 6, 8, 10, 12, 16, 20, 24, and 28. This trial used a score of 11 or higher as indicative of moderate or greater depression.

At baseline, patients were screened for psychiatric illness using the MINI.27 At subsequent visits, the MINI depression and suicide modules were administered as an additional way to monitor patient safety. Likewise, the clinician version of the QIDS (QIDS-C) was conducted at each rating period.

Quality of life was assessed throughout the study using the University of Washington Quality of Life Scale (UW-QOL).29 The UW-QOL is a self-administered scale designed specifically for patients with HNC. It consists of 9 categories, including pain, disfigurement, activity, recreation/entertainment, employment, eating/chewing, eating/swallowing, speech, and shoulder disability. Because it is concise and specific to the illness, the UW-QOL has been reported to have excellent psychometric properties and acceptability to patients in the midst of treatment for HNC.29

Adverse effects were monitored closely. The Frequency, Intensity, and Burden of Side Effects Rating (FIBSER) is a self-report measure that focuses on the last 7 days and is composed of 3 global ratings that encompass all adverse effects to study treatment.30

Study Oversight

An independent data and safety monitoring committee was composed of UNMC faculty with knowledge and experience relevant to the conduct of this study but not involved in the study as either an investigator or participating clinician. Formal interim analyses conducted by the data and safety monitoring committee reviewed the data at the 25% and 50% study completion time points.

The study was designed to have 80% power (testing at the .05 level of statistical significance [2-sided]) to detect a difference in depression rates at week 16 of 20%. Thus, assuming a 20% loss to follow-up rate, we planned to randomize 188 patients to achieve 150 patients not lost to follow-up. In this context, patients lost to follow-up were patients for whom no postrandomization follow-up observations were available. Because of slower than expected accrual, the study closed to enrollment on December 31, 2011, with 148 patients randomized and 125 evaluable.

Statistical Analysis

The stratified log-rank test was used to compare the groups on the primary end point (moderate or greater depression) defined as a QIDS-SR score of 11 or higher. A Cox proportional hazard regression model was used to compare the 2 treatment groups after adjusting for age, baseline smoking status, and stratification factors. Health-related quality of life was descriptively summarized, by treatment group at each time point, as the percentage reporting good, very good, or outstanding during the past 7 days. Patients rated their adverse effects using the FIBSER, which includes 3 questions, each with a 7-point scale. The FIBSER responses were dichotomized because of small cell counts (frequency: 0%-25% vs >25%; intensity: none, trivial, mild vs moderate, or greater; burden: none to mild impairment vs moderate or greater impairment), and differences between treatment groups were assessed using the Fisher exact test.

Patient Characteristics

From January 6, 2008, to December 28, 2011, 298 patients were screened, with 160 (53.7%) agreeing to participate (Figure 1). Although patients were not specifically asked why they did not participate, 42.0% volunteered a reason. The 2 most common reasons for nonparticipation were unwillingness in taking a study medicine and lack of time. Demographics did not differ between the screened population and the randomized population.

Place holder to copy figure label and caption
Figure 1.
Patient Enrollment

MINI indicates Mini-International Neuropsychiatric Interview; QID-C, Quick Inventory of Depressive Symptomatology–Clinician; and QID-SR, Quick Inventory of Depressive Symptomatology–Self Rated.

Graphic Jump Location

Twelve patients (7.5%) did not meet eligibility criteria. Nine had a QIDS-SR or QIDS-C score of 11 or higher. One patient was not willing or able to return to the clinic for follow-up visits at 16 and 28 weeks. One patient was not diagnosed as having epidermoid cancer and also met criteria for MDD at baseline. The remaining patient had received another antidepressant in the prior week (Figure 1).

The demographics and stratification for the 148 patients randomized are listed in Table 1. Per protocol, patients were not evaluable if they went off study for reasons other than the study end point or only completed the baseline visit. Patients were considered evaluable if they had at least one visit after baseline. Sixty-five of 74 patients (87.8%) were evaluable in the placebo arm and 60 of 74 (81.1%) in the treatment arm. Reasons for dropouts other than study end point are depicted in Figure 1. Adverse effects as reported by the patients were the primary reason for dropout in 5 patients in the placebo group and 14 in the treatment group. The proportion of evaluable patients was not significantly different between the placebo and treatment arms (χ21 = 1.29, P = .26) or for the proportion who dropped out because of adverse effects (χ21 = 3.39, P = .07). Although not statistically different, there were more patients in the treatment group listing adverse effects as a reason for dropping out. Table 2 lists the responses to the FIBSER questionnaire by treatment assignment. No significant difference was found in the proportion reporting frequency of adverse effects more than 25% of the time (3.3% in the placebo group vs 8.8% in the escitalopram group; P = .26), the proportion reporting moderate or greater intensity of adverse effects (4.8% in the placebo group vs 14.0% in the escitalopram group; P = .12), or the proportion reporting moderate or greater impairment because of adverse effects (3.2% in the placebo group vs 5.3% in the escitalopram group; P = .67) between treatment and placebo groups. Furthermore, Table 2 indicates that 91.2% of the escitalopram groups and 96.7% of the placebo group reported adverse effects 25% of the time or less, and 95.2% and 86.0% of placebo and escitalopram groups, respectively, reported adverse effects to be of mild or less impairment. Together, adverse effects were not statistically significantly different between the groups, although more patients dropped out of the treatment group than the placebo group.

Table Graphic Jump LocationTable 1.  Baseline Characteristics of Randomized Study Participants by Treatment Group
Table Graphic Jump LocationTable 2.  Maximum Reported Frequency, Intensity, and Adverse Effect Burden as Rated by the FIBSER by Treatment Assignment

The stratified log-rank test used to compare the 2 treatment groups revealed a significant difference in depression rates (QIDS-SR score ≥11) for patients taking escitalopram compared with placebo (10.0% vs 24.6%, P = .04). The difference in depression rates between treatment assignments is 14.6% (95% CI, 1.1%-27.5%), and the relative risk reduction is 59.4% (95% CI, 3.0%-83.0%). Figure 2A compares the product limit estimates.

Place holder to copy figure label and caption
Figure 2.
Product Limit Estimates

A, Kaplan-Meier curve depicting depression-free survival by treatment assignment (P = .42). B, Comparison of mean depression rates for placebo vs escitalopram oxalate by initial cancer treatment. Error bars indicate SDs.

Graphic Jump Location

Table 3 lists the results of a Cox proportional hazard regression model comparing the 2 treatment groups after controlling for age, sex, baseline smoking status, study site, stage of disease, and initial treatment. The hazard ratio of 0.37 (95% CI, 0.14-0.96, P = .04) demonstrates that escitalopram was superior to placebo even after controlling for possible confounders.

Table Graphic Jump LocationTable 3.  Results of Cox Proportional Hazards Regression Model Comparing Treatment Groups After Adjustment for Age, Baseline Smoking, and Stratification Variables

The only stratification variable significantly related to depression was the initial treatment for HNC. Those receiving radiation as primary treatment were more likely to reach the primary end point than those undergoing surgery (hazard ratio, 3.6; 95% CI, 1.38-9.40; P = .009). On subgroup analysis, 38.7% of placebo patients vs 13.8% of escitalopram patients in the radiation group developed depression compared with 11.8% of placebo patients vs 6.5% of escitalopram patients who developed depression in the surgery group (Figure 2B). The number needed to treat for treatment vs placebo is 6.8. Suicidality was not reported by any participant after baseline on the suicidality module of the MINI.

Investigations of differences between treatment groups in quality of life over time revealed that patients taking escitalopram report better health-related quality of life compared with those taking placebo at each time point throughout the study (Table 4).

Table Graphic Jump LocationTable 4.  Percentage of Study Participants Reporting Good, Very Good, or Outstanding Health-Related QOL at Each Time Point

This study has 3 important findings. First, prophylactic escitalopram reduced the rate of depression in patients with HNC undergoing treatment. Second, the rate of developing depression was significantly higher in patients receiving radiation as their primary therapy compared with those undergoing surgery. Third, those who received escitalopram reported better overall and health-related quality of life throughout the trial than the placebo group and during the 3 consecutive months after drug cessation.

Prevention of depression in a large oncology trial has not been demonstrated previously. Only 10.0% of the patients who received escitalopram reached our depression threshold compared with 24.6% in the placebo group. This represents a number needed to treat to show benefit of 6.8, similar to the number needed to treat of 7.2 that Robinson et al23 reported for depression prevention with escitalopram in patients with acute stroke.

These findings have important implications for treatment recommendations in HNC and potentially other cancers. Determining which cancer patients will become depressed is nebulous. Social support, sex, and history of depression are all potential predictors of MDD; however, they are not consistent and are not exclusive. Because of the lack of a clear method to predict who will become depressed, the use of a prevention paradigm seems to offer considerable benefit at an acceptable risk.

Failing to identify depressed patients until they have blatant manifestations could be perilous given that patients with HNC have a risk of suicide 3 times greater than the general population and 1.5 times the risk of the average patient with cancer.18 In this study no patient exhibited suicidality. This surprising result is likely attributable to the study design whereby patients were carefully assessed every 2 weeks for the development of suicidality and depression. If either developed, the patient was removed from the study and referred to psychiatric care. This type of overview does not happen in clinical practice and suggests that prevention strategies might help reduce suicidality.

There are downsides to treating all patients with HNC with escitalopram, including the potential for adverse effects and additional costs. Adverse effects sufficient to cause withdrawal from the study were substantially more common in the treatment group. This is an important consideration for the clinician because patients in both groups cited adverse effects as the reason for dropping out, which may somewhat limit the use of this approach. Patients did not detail the specific adverse effects but merely reported the general category as the reason for study cessation. This difference likely reflects, in part, our decision to use the maximum recommended daily dose of escitalopram in this proof-of-concept trial. The common clinical use of a 10-mg dose may have been better tolerated because adverse effects are dose related. We also used a rapid ramp-up of 1 week as opposed to the common practice of 1 month. However, the burden of adverse effects was generally minor. In addition, stopping use of the drug will result in cessation of the adverse effects. Future trials or clinical use should allow more flexibility in dosing. Depression is considered to have the greatest associated disability of any medical illness and has an array of costs associated with it.31 Although there are many costs associated with adopting a prevention strategy for patients with HNC, the availability of low-cost generic antidepressants (including escitalopram) reduces cost as a potential barrier. The 16-week cost of escitalopram should not be a barrier because the drug is now available as a generic. A 90-day prescription of generic escitalopram ranges from $100 to $150.

This study was not designed to look at quality of life. Because quality of life was only measured in those patients continuing in the study and not in those who dropped out, it is impossible to get a full appreciation of the magnitude of difference between the 2 groups. However, overall quality of life was rated as better in the escitalopram-treated group throughout the study and achieved statistical significance during the 3 consecutive months after cessation of drug therapy. Osborn et al32 also observed improved long-term quality of life in a meta-analysis of psychosocial interventions in patients with cancer. Quality of life has been demonstrated as a predictor of survival in patients with HNC and thus represents an important end point.33 Depression has been demonstrated to lower self-care abilities, decrease quality of life, and potentially lead to increased treatment delay.34 The importance of maintaining and recovering quality of life is essential for healthy survivorship. The fact that improved quality of life was observed in nondepressed patients in this trial suggests a benefit to therapy that may extend beyond prevention of depression.

The mechanism by which escitalopram prevents depression is unknown. In an animal model, exposure to inescapable stress results in subsequent behavioral depression termed learned helplessness.35 Prophylactic administrations of selective serotonin reuptake inhibitors can prevent or decrease learned helplessness in animals. In these experiments, cortical serotonin levels and stress-induced depletion of serotonin in proportion to prevention of stress-induced depressive behavior has been seen. Thus, this may be one mechanism in humans that mitigates the onset of depression. Recent research in rodents suggests that neuritin, also known as the CPG15 gene, and the protein it encodes may be factors in chronic, unpredictable, stress-associated depression.36 Antidepressant use has been reported to increase neuritin expression in the rat brain.37 The evidence for better overall quality of life seen after use of the study drug was stopped may reflect these long-term changes.

Treatment of HNC can be an extremely stressful process, likened to the learned helplessness model in animals. The higher incidence of depression in the cohort receiving radiation suggests that radiation represents a greater and longer duration stress event than surgery. Radiation may also generate greater inflammatory cytokines during treatment, which could contribute to the higher rate.3840 Surgery, on the other hand, is a discreet, one-time event in which maximal morbidity occurs in one setting and typically improves from that point forward. The patient is able to begin adjusting to the mental and physical alteration immediately, lessening the stress response. Depression as the result of radiation therapy has been previously observed in patients with oral cavity cancer.41 The observed relationship between radiation dose and development of depression in this study suggests a direct link between radiation and depression. Even though this study was not powered to detect differences in depression rates for placebo compared with escitalopram within the surgery or radiation group, we observed that fewer patients taking escitalopram developed depression in both groups, and the difference was larger in the radiation group. The mechanism behind these differences in rate will require further investigation.

Although these findings are significant for the treatment of patients with HNC, they must be interpreted in the context of the study design. All patients came from a single group of clinicians practicing in 2 settings: an academic and a community hospital. The population served by these clinicians is essentially ethnically and racially homogenous (ie, primarily white). Replication in a broader population will address this issue.

In conclusion, this study found that prophylactic use of escitalopram is effective in reducing the rate of depression in patients undergoing HNC treatment independent of stage, sex, or primary cancer treatment modality. In addition, the quality of life of patients who continued in the trial and did not develop depression was better in those who received escitalopram for the 3 months after cessation of study drug. Finally, the rate of depression was higher in the group who received radiation as the primary modality, but the intervention reduced rates of depression in both. Adverse effects may limit the use somewhat, but the significant benefit of this approach warrants careful consideration. Prophylactic use of escitalopram should be strongly considered in patients who fit the inclusion criteria for this study. These finding deserve confirmation in a multicenter trial.

Corresponding Author: William M. Lydiatt, MD, Department of Otolaryngology–Head and Neck Surgery, University of Nebraska, 981225 Nebraska Medical Center, Omaha, NE 68198-1225 (wmlydiat@unmc.edu).

Submitted for Publication: October 26, 2012; final revision received April 3, 2013; accepted April 17, 2013.

Published Online: June 20, 2013. doi:10.1001/jamaoto.2013.3371.

Author Contributions: Drs Lydiatt and Burke had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Lydiatt, Schmid, Burke.

Acquisition of data: Bessette, Burke.

Analysis and interpretation of data: Lydiatt, Schmid, Sayles, Burke.

Drafting of the manuscript: Lydiatt, Schmid, Burke.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Schmid, Sayles, Burke.

Obtained funding: Lydiatt, Burke.

Administrative, technical, and material support: Lydiatt, Bessette.

Study supervision: Lydiatt.

Conflict of Interest Disclosures: Dr Lydiatt is on the head and neck panel for guideline development for the National Comprehensive Cancer Network but does not receive honorarium for participation in guideline development. Dr Burke has received grant support for his institution from Forest Research Institute and has served as a consultant to Forest and on their speakers’ bureau.

Funding/Support: The project described was supported by grant R01 MH079420 from the National Institute of Mental Health. Additional support was provided by a research support fund grant from the Nebraska Medical Center and the UNMC.

Role of the Sponsor: Forest Research Institute provided matching placebo and drug. Forest Research Institute had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Mental Health or the National Institutes of Health.

Previous Presentations: This study was presented as an oral presentation at the American Head and Neck Society and Combined Otolaryngology Spring Meetings; April 11, 2013; Orlando, Florida. Some of the data were also presented at the American Psychosocial Oncology Society Annual Meeting; February 14, 2013; Huntington Beach, California.

Additional Contributions: This manuscript is presented on behalf of the PROTECT study team: Mary Morris, BSN, James C. Lynch, PhD, Jonathan D. Beck, PharmD, Daniel D. Lydiatt, MD, Oleg N. Militsakh, MD, Alan T. Richards, MD, Russell B. Smith, MD, Aaron M. Wieland, MD, Katerina Goldman, PA-C, Jennelea R. Montanez, PA-C, Lora L. Dosen, BSN, Nikie Herrera, RN, Jane Hill, LPN, Sheryl Jungbluth, BSN, Danya O'Brien, RN, Nicole R. Strohman, BSN, Matthew Egbert, MD, Christopher J. Kratochvil, MD, Ashish Sharma, MD, Jane Theobald, MD, Steven P. Wengel, MD, Paula Danekas, PharmD, Randy Rasmussen, PharmD, Barbara L. Bayer, MSN, Micki T. Bethea, BS, Deborah S. Heimes, BS, Delores A. McArthur-Miller, MA, and Rosella Squires, BS. The data safety monitoring committee was chaired by James Anderson, PhD, with Charles A. Enke, MD, Mark H. Fleisher, MD, Donald Leopold, MD, Fredrick Petty, PhD, Toby L. Schonfeld, PhD, and Weining Zhen, MD.

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Hammerlid  E, Ahlner-Elmqvist  M, Bjordal  K,  et al.  A prospective multicentre study in Sweden and Norway of mental distress and psychiatric morbidity in head and neck cancer patients. Br J Cancer. 1999;80(5-6):766-774.
PubMed   |  Link to Article
Hammerlid  E, Silander  E, Hörnestam  L, Sullivan  M.  Health-related quality of life three years after diagnosis of head and neck cancer: a longitudinal study. Head Neck. 2001;23(2):113-125.
PubMed   |  Link to Article
Yousaf  U, Christensen  ML, Engholm  G, Storm  HH.  Suicides among Danish cancer patients 1971-1999. Br J Cancer. 2005;92(6):995-1000.
PubMed   |  Link to Article
Yu  GP, Mehta  V, Branovan  D, Huang  Q, Schantz  SP.  Non–cancer-related deaths from suicide, cardiovascular disease, and pneumonia in patients with oral cavity and oropharyngeal squamous carcinoma. Arch Otolaryngol Head Neck Surg. 2012;138(1):25-32.
PubMed   |  Link to Article
Hem  E, Loge  JH, Haldorsen  T, Ekeberg  O.  Suicide risk in cancer patients from 1960 to 1999. J Clin Oncol. 2004;22(20):4209-4216.
PubMed   |  Link to Article
Misono  S, Weiss  NS, Fann  JR, Redman  M, Yueh  B.  Incidence of suicide in persons with cancer. J Clin Oncol. 2008;26(29):4731-4738.
Link to Article
Sharma  PS.  High suicide rate among cancer patients fuels prevention discussions. J Natl Cancer Inst. 2008;100(24):1750-1752.
PubMed   |  Link to Article
Lazure  KE, Lydiatt  WM, Denman  D, Burke  WJ.  Association between depression and survival or disease recurrence in patients with head and neck cancer enrolled in a depression prevention trial. Head Neck. 2009;31(7):888-892.
PubMed   |  Link to Article
Becattini  C, Agnelli  G, Schenone  A,  et al; WARFASA Investigators.  Aspirin for preventing the recurrence of venous thromboembolism. N Engl J Med. 2012;366(21):1959-1967.
PubMed   |  Link to Article
Kocsis  JH, Thase  ME, Trivedi  MH,  et al.  Prevention of recurrent episodes of depression with venlafaxine ER in a 1-year maintenance phase from the PREVENT Study. J Clin Psychiatry. 2007;68(7):1014-1023.
PubMed   |  Link to Article
Robinson  RG, Jorge  RE, Moser  DJ,  et al.  Escitalopram and problem-solving therapy for prevention of poststroke depression: a randomized controlled trial. JAMA. 2008;299(20):2391-2400.
PubMed   |  Link to Article
Musselman  DL, Lawson  DH, Gumnick  JF,  et al.  Paroxetine for the prevention of depression induced by high-dose interferon alfa. N Engl J Med. 2001;344(13):961-966.
PubMed   |  Link to Article
Schaefer  M, Sarkar  R, Knop  V,  et al.  Escitalopram for the prevention of peginterferon-2a–associated depression in hepatitis C virus–infected patients without previous psychiatric disease: a randomized trial. Ann Intern Med. 2012;157(2):94-103.
PubMed   |  Link to Article
Lydiatt  WM, Denman  D, McNeilly  DP, Puumula  SE, Burke  WJ.  A randomized, placebo-controlled trial of citalopram for the prevention of major depression during treatment for head and neck cancer. Arch Otolaryngol Head Neck Surg. 2008;134(5):528-525.
PubMed   |  Link to Article
Sheehan  DV, Lecrubier  Y, Sheehan  KH,  et al.  The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10J Clin Psychiatry. 1998;59(suppl 20):22-57.
PubMed
Rush  AJ, Trivedi  MH, Ibrahim  HM,  et al.  The 16-Item Quick Inventory of Depressive Symptomatology (QIDS), clinician rating (QIDS-C), and self-report (QIDS-SR): a psychometric evaluation in patients with chronic major depression. Biol Psychiatry. 2003;54(5):573-583.
PubMed   |  Link to Article
Hassan  SJ, Weymuller  EA  Jr.  Assessment of quality of life in head and neck cancer patients. Head Neck. 1993;15(6):485-496.
PubMed   |  Link to Article
Wisniewski  SR, Rush  AJ, Balasubramani  GK, Trivedi  MH, Nierenberg  AA; STARD Investigators.  Self-rated global measure of the frequency, intensity, and burden of side effects. J Psychiatr Pract. 2006;12(2):71-79.
PubMed   |  Link to Article
National Institute of Mental Health website. http://www.nimh.nih.gov/statistics/2LIDD.shtml. Accessed May 14, 2013.
Osborn  RL, Demoncada  AC, Feuerstein  M.  Psychosocial interventions for depression, anxiety, and quality of life in cancer survivors: meta-analyses. Int J Psychiatry Med. 2006;36(1):13-34.
PubMed   |  Link to Article
Oskam  IM, Verdonck-de Leeuw  IM, Aaronson  NK,  et al.  Quality of life as predictor of survival: a prospective study on patients treated with combined surgery and radiotherapy for advanced oral and oropharyngeal cancer. Radiother Oncol. 2010;97(2):258-262.
PubMed   |  Link to Article
McDaniel  JS, Musselman  DL, Porter  MR, Reed  DA, Nemeroff  CB.  Depression in patients with cancer: diagnosis, biology, and treatment. Arch Gen Psychiatry. 1995;52(2):89-99.
PubMed   |  Link to Article
Petty  F, Kramer  G, Wilson  L.  Prevention of learned helplessness: in vivo correlation with cortical serotonin. Pharmacol Biochem Behav. 1992;43(2):361-367.
PubMed   |  Link to Article
Son  H, Banasr  M, Choi  M,  et al.  Neuritin produces antidepressant actions and blocks the neuronal and behavioral deficits caused by chronic stress [published online June 25, 2012]. Proc Natl Acad Sci U S A. 2012;109(28):11378-11383.
PubMed   |  Link to Article
Alme  MN, Wibrand  K, Dagestad  G, Bramham  CR.  Chronic fluoxetine treatment induces brain region-specific upregulation of genes associated with BDNF-induced long-term potentiation. Neural Plast. 2007;2007:26496.
PubMed   |  Link to Article
Dantzer  R, O’Connor  JC, Freund  GG, Johnson  RW, Kelley  KW.  From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci. 2008;9(1):46-56.
PubMed   |  Link to Article
Chen  Z, Malhotra  PS, Thomas  GR,  et al.  Expression of proinflammatory and proangiogenic cytokines in patients with head and neck cancer. Clin Cancer Res. 1999;5(6):1369-1379.
PubMed
Seruga  B, Zhang  H, Bernstein  LJ, Tannock  IF.  Cytokines and their relationship to the symptoms and outcome of cancer. Nat Rev Cancer. 2008;8(11):887-899.
PubMed   |  Link to Article
Chen  SC, Lai  YH, Liao  CT, Lin  CC, Chang  JT.  Changes of symptoms and depression in oral cavity cancer patients receiving radiation therapy. Oral Oncol. 2010;46(7):509-513.
PubMed   |  Link to Article

Figures

Place holder to copy figure label and caption
Figure 1.
Patient Enrollment

MINI indicates Mini-International Neuropsychiatric Interview; QID-C, Quick Inventory of Depressive Symptomatology–Clinician; and QID-SR, Quick Inventory of Depressive Symptomatology–Self Rated.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.
Product Limit Estimates

A, Kaplan-Meier curve depicting depression-free survival by treatment assignment (P = .42). B, Comparison of mean depression rates for placebo vs escitalopram oxalate by initial cancer treatment. Error bars indicate SDs.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1.  Baseline Characteristics of Randomized Study Participants by Treatment Group
Table Graphic Jump LocationTable 2.  Maximum Reported Frequency, Intensity, and Adverse Effect Burden as Rated by the FIBSER by Treatment Assignment
Table Graphic Jump LocationTable 3.  Results of Cox Proportional Hazards Regression Model Comparing Treatment Groups After Adjustment for Age, Baseline Smoking, and Stratification Variables
Table Graphic Jump LocationTable 4.  Percentage of Study Participants Reporting Good, Very Good, or Outstanding Health-Related QOL at Each Time Point

References

Goon  PKC, Stanley  MA, Ebmeyer  J,  et al.  HPV and head and neck cancer: a descriptive update. Head Neck Oncol. 2009;1:36.
Link to Article
Simard  EP, Ward  EM, Siegel  R, Jemal  A.  Cancers with increasing incidence trends in the United States: 1999 through 2008. CA Cancer J Clin. 2012;62(4):118-128.
PubMed   |  Link to Article
Shah  JP, Lydiatt  W.  Treatment of cancer of the head and neck. CA Cancer J Clin. 1995;45(6):352-368.
PubMed   |  Link to Article
Bernier  J, Domenge  C, Ozsahin  M,  et al; European Organization for Research and Treatment of Cancer Trial 22931.  Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. N Engl J Med. 2004;350(19):1945-1952.
PubMed   |  Link to Article
Cooper  JS, Pajak  TF, Forastiere  AA,  et al; Radiation Therapy Oncology Group 9501/Intergroup.  Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck. N Engl J Med. 2004;350(19):1937-1944.
PubMed   |  Link to Article
Brizel  DM, Lydiatt  W, Colevas  AD.  Controversies in the locoregional management of head and neck cancer. J Natl Compr Canc Netw. 2011;9(6):653-662.
PubMed
Pfister  DG, Ang  KK, Brizel  DM,  et al; National Comprehensive Cancer Network.  Head and neck cancers. J Natl Compr Canc Netw. 2011;9(6):596-650.
PubMed
Frampton  M.  Psychological distress in patients with head and neck cancer: review. Br J Oral Maxillofac Surg. 2001;39(1):67-70.
PubMed   |  Link to Article
de Leeuw  JRJ, de Graeff  A, Ros  WJ, Blijham  GH, Hordijk  G-J, Winnubst  JAM.  Prediction of depressive symptomatology after treatment of head and neck cancer: the influence of pre-treatment physical and depressive symptoms, coping, and social support. Head Neck. 2000;22(8):799-807.
PubMed   |  Link to Article
Lydiatt  WM, Moran  J, Burke  WJ.  A review of depression in the head and neck cancer patient. Clin Adv Hematol Oncol. 2009;7(6):397-403.
PubMed
Hammerlid  E, Mercke  C, Sullivan  M, Westin  T.  A prospective quality of life study of patients with oral or pharyngeal carcinoma treated with external beam irradiation with or without brachytherapy. Oral Oncol. 1997;33(3):189-196.
PubMed   |  Link to Article
Paula  JM, Sonobe  HM, Nicolussi  AC, Zago  MM, Sawada  NO.  Symptoms of depression in patients with cancer of the head and neck undergoing radiotherapy treatment: a prospective study. Rev Lat Am Enfermagem. 2012;20(2):362-368.
PubMed   |  Link to Article
Hammerlid  E, Ahlner-Elmqvist  M, Bjordal  K,  et al.  A prospective multicentre study in Sweden and Norway of mental distress and psychiatric morbidity in head and neck cancer patients. Br J Cancer. 1999;80(5-6):766-774.
PubMed   |  Link to Article
Hammerlid  E, Silander  E, Hörnestam  L, Sullivan  M.  Health-related quality of life three years after diagnosis of head and neck cancer: a longitudinal study. Head Neck. 2001;23(2):113-125.
PubMed   |  Link to Article
Yousaf  U, Christensen  ML, Engholm  G, Storm  HH.  Suicides among Danish cancer patients 1971-1999. Br J Cancer. 2005;92(6):995-1000.
PubMed   |  Link to Article
Yu  GP, Mehta  V, Branovan  D, Huang  Q, Schantz  SP.  Non–cancer-related deaths from suicide, cardiovascular disease, and pneumonia in patients with oral cavity and oropharyngeal squamous carcinoma. Arch Otolaryngol Head Neck Surg. 2012;138(1):25-32.
PubMed   |  Link to Article
Hem  E, Loge  JH, Haldorsen  T, Ekeberg  O.  Suicide risk in cancer patients from 1960 to 1999. J Clin Oncol. 2004;22(20):4209-4216.
PubMed   |  Link to Article
Misono  S, Weiss  NS, Fann  JR, Redman  M, Yueh  B.  Incidence of suicide in persons with cancer. J Clin Oncol. 2008;26(29):4731-4738.
Link to Article
Sharma  PS.  High suicide rate among cancer patients fuels prevention discussions. J Natl Cancer Inst. 2008;100(24):1750-1752.
PubMed   |  Link to Article
Lazure  KE, Lydiatt  WM, Denman  D, Burke  WJ.  Association between depression and survival or disease recurrence in patients with head and neck cancer enrolled in a depression prevention trial. Head Neck. 2009;31(7):888-892.
PubMed   |  Link to Article
Becattini  C, Agnelli  G, Schenone  A,  et al; WARFASA Investigators.  Aspirin for preventing the recurrence of venous thromboembolism. N Engl J Med. 2012;366(21):1959-1967.
PubMed   |  Link to Article
Kocsis  JH, Thase  ME, Trivedi  MH,  et al.  Prevention of recurrent episodes of depression with venlafaxine ER in a 1-year maintenance phase from the PREVENT Study. J Clin Psychiatry. 2007;68(7):1014-1023.
PubMed   |  Link to Article
Robinson  RG, Jorge  RE, Moser  DJ,  et al.  Escitalopram and problem-solving therapy for prevention of poststroke depression: a randomized controlled trial. JAMA. 2008;299(20):2391-2400.
PubMed   |  Link to Article
Musselman  DL, Lawson  DH, Gumnick  JF,  et al.  Paroxetine for the prevention of depression induced by high-dose interferon alfa. N Engl J Med. 2001;344(13):961-966.
PubMed   |  Link to Article
Schaefer  M, Sarkar  R, Knop  V,  et al.  Escitalopram for the prevention of peginterferon-2a–associated depression in hepatitis C virus–infected patients without previous psychiatric disease: a randomized trial. Ann Intern Med. 2012;157(2):94-103.
PubMed   |  Link to Article
Lydiatt  WM, Denman  D, McNeilly  DP, Puumula  SE, Burke  WJ.  A randomized, placebo-controlled trial of citalopram for the prevention of major depression during treatment for head and neck cancer. Arch Otolaryngol Head Neck Surg. 2008;134(5):528-525.
PubMed   |  Link to Article
Sheehan  DV, Lecrubier  Y, Sheehan  KH,  et al.  The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10J Clin Psychiatry. 1998;59(suppl 20):22-57.
PubMed
Rush  AJ, Trivedi  MH, Ibrahim  HM,  et al.  The 16-Item Quick Inventory of Depressive Symptomatology (QIDS), clinician rating (QIDS-C), and self-report (QIDS-SR): a psychometric evaluation in patients with chronic major depression. Biol Psychiatry. 2003;54(5):573-583.
PubMed   |  Link to Article
Hassan  SJ, Weymuller  EA  Jr.  Assessment of quality of life in head and neck cancer patients. Head Neck. 1993;15(6):485-496.
PubMed   |  Link to Article
Wisniewski  SR, Rush  AJ, Balasubramani  GK, Trivedi  MH, Nierenberg  AA; STARD Investigators.  Self-rated global measure of the frequency, intensity, and burden of side effects. J Psychiatr Pract. 2006;12(2):71-79.
PubMed   |  Link to Article
National Institute of Mental Health website. http://www.nimh.nih.gov/statistics/2LIDD.shtml. Accessed May 14, 2013.
Osborn  RL, Demoncada  AC, Feuerstein  M.  Psychosocial interventions for depression, anxiety, and quality of life in cancer survivors: meta-analyses. Int J Psychiatry Med. 2006;36(1):13-34.
PubMed   |  Link to Article
Oskam  IM, Verdonck-de Leeuw  IM, Aaronson  NK,  et al.  Quality of life as predictor of survival: a prospective study on patients treated with combined surgery and radiotherapy for advanced oral and oropharyngeal cancer. Radiother Oncol. 2010;97(2):258-262.
PubMed   |  Link to Article
McDaniel  JS, Musselman  DL, Porter  MR, Reed  DA, Nemeroff  CB.  Depression in patients with cancer: diagnosis, biology, and treatment. Arch Gen Psychiatry. 1995;52(2):89-99.
PubMed   |  Link to Article
Petty  F, Kramer  G, Wilson  L.  Prevention of learned helplessness: in vivo correlation with cortical serotonin. Pharmacol Biochem Behav. 1992;43(2):361-367.
PubMed   |  Link to Article
Son  H, Banasr  M, Choi  M,  et al.  Neuritin produces antidepressant actions and blocks the neuronal and behavioral deficits caused by chronic stress [published online June 25, 2012]. Proc Natl Acad Sci U S A. 2012;109(28):11378-11383.
PubMed   |  Link to Article
Alme  MN, Wibrand  K, Dagestad  G, Bramham  CR.  Chronic fluoxetine treatment induces brain region-specific upregulation of genes associated with BDNF-induced long-term potentiation. Neural Plast. 2007;2007:26496.
PubMed   |  Link to Article
Dantzer  R, O’Connor  JC, Freund  GG, Johnson  RW, Kelley  KW.  From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci. 2008;9(1):46-56.
PubMed   |  Link to Article
Chen  Z, Malhotra  PS, Thomas  GR,  et al.  Expression of proinflammatory and proangiogenic cytokines in patients with head and neck cancer. Clin Cancer Res. 1999;5(6):1369-1379.
PubMed
Seruga  B, Zhang  H, Bernstein  LJ, Tannock  IF.  Cytokines and their relationship to the symptoms and outcome of cancer. Nat Rev Cancer. 2008;8(11):887-899.
PubMed   |  Link to Article
Chen  SC, Lai  YH, Liao  CT, Lin  CC, Chang  JT.  Changes of symptoms and depression in oral cavity cancer patients receiving radiation therapy. Oral Oncol. 2010;46(7):509-513.
PubMed   |  Link to Article

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