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A Randomized, Placebo-Controlled Trial
of Citalopram for the Prevention of Major
Depression During Treatment
for Head and Neck Cancer

William M. Lydiatt, MD; David Denman, MD; Dennis P. McNeilly, PsyD;Susan E. Puumula, MS; William J. Burke, MD Objective: To determine whether prophylactic treat-
Results: The numbers of subjects who met predefined
ment with the antidepressant citalopram hydrobro- cutoff criteria for depression during the 12 weeks of ac- mide, compared with placebo, could prevent major de- tive study were 5 of 10 (50%) taking placebo and 2 of 12 pressive disorder in patients undergoing therapy for head (17%) taking citalopram (Fisher exact test, P = .17). No patients in the citalopram group became suicidal, com-pared with 2 in the placebo group. Global mood state at Design: Prospective, randomized, placebo-controlled
the conclusion of the study as measured by the CGI-S scale was rated as at least mildly ill in 15% of those re-ceiving citalopram compared with 60% in the placebo Setting: Academic medical center.
group (Fisher exact test, P = .04). Quality of life, mea-sured by the UW-QOL, deteriorated in both groups from Patients: Thirty-six subjects were randomized, and 23
completed the study.
baseline but less so in the citalopram group.
Interventions: Subjects were randomized to receive 40
Conclusions: This study reports data from the first de-
mg of citalopram hydrobromide or matching placebo pression prevention trial in HNC and suggests that pro- (hereinafter, citalopram group and placebo group, re- phylactic treatment may decrease the incidence of de- spectively) for 12 weeks with a final visit at 16 weeks.
pression during HNC therapy. The clinical significanceof the reduction in depression was best demonstrated by Main Outcome Measures: The Hamilton Depres-
the CGI-S scale, which showed a notable difference in sion Rating Scale, psychiatric interview, and the Univer- global psychiatric and physical well-being.
sity of Washington Quality of Life (UW-QOL) and Cli-nician Global Impression–Severity (CGI-S) scales.
Arch Otolaryngol Head Neck Surg. 2008;134(5):528-535 TREATMENTFORHEADAND cityofdataontreatmentofMDDinpa-
tients with cancer in general and those with tients with HNC, alternative strategies for the surveillance and treatment of MDD must be considered. One proactive approach wor- thy of consideration is prophylactic treat- Author Affiliations:
within the first 3 months of diagnosis.6 Un- Departments ofOtolaryngology–Head and Neck fortunately, MDD is rarely identified and lactic treatment of medical disease is gain- almost never treated in these patients.1,2 ing in popularity and acceptability. The role The reasons are myriad and include a lack of ␤-blockers in prevention of myocardial damage following myocardial infarction and vention in atrial fibrillation has become well established.14,15 Likewise, ongoing or inter- treating psychiatric illness, limited time mittent use of antidepressants is established available in the clinical setting, and thera- as an important means of preventing recur- Surgical Oncology, NebraskaMethodist Hospital rences of MDD, as is intermittent use in the MDD therapy.7-13 Finally, there is a pau- prevention of premenstrual syndrome.16-18 (REPRINTED) ARCH OTOLARYNGOL HEAD NECK SURG/ VOL 134 (NO. 5), MAY 2008 2008 American Medical Association. All rights reserved.
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With this background, the possibility of prophylactic treat- Tumor- and treatment-specific information was given as per ment of MDD in patients with HNC was considered.
the usual standard in the head and neck clinic. For additional The hypothesis was that the frequency and/or severity background information about HNC and its treatment, sub- of MDD could be reduced using a prophylactic antidepres- jects also received the book Cancers of the Mouth and Throat: A sant started soon after the cancer diagnosis and just prior Patient’s Guide to Treatment.8 Each subject received supportivecare in the usual fashion as needed by clinical staff, and each to initiation of HNC treatment. The goal was to minimize was invited to join the HNC support group. Subjects were asked and prevent MDD by initiating treatment intervention soon not to enter into formal psychotherapy or to take other anti- after the diagnosis of cancer was made, thus avoiding many depressants during the active portion of this trial.
of the problems that can result from the development of Cancer therapy was delivered in the usual manner and con- clinical depression. The additional hope was that quality sisted of surgery and radiation therapy with or without che- of life (QOL) might thereby be better preserved. To test this motherapy as per the standard care of our head and neck clinic hypothesis, a randomized, prospective, double-blind, pla- and generally according to the National Comprehensive Can- cebo-controlled trial of the antidepressant citalopram hy- cer Network guidelines.20 Subjects began their cancer therapy drobromide was conducted to evaluate whether MDD could and baseline study visit concurrently.
be prevented in patients undergoing treatment for HNC.
A medical history was taken and physical examination per- formed by a head and neck surgeon or physician’s assistant ateach visit, noting abnormal findings related to either cancer PATIENTS
University of Nebraska Medical Center (Omaha) institutional re- A baseline power analysis was conducted. The study was de- view board approval was sought and secured. Inclusion criteria signed to have 80% power (testing at the 5% level of statistical included an age of 19 years or older and newly diagnosed or re- significance) to detect a difference of 0.5 standard deviation (SD) current cancers of the oral cavity, larynx, pharynx, neck, and pa- in the time-averaged differences in the mean scores between ranasal sinuses requiring more than limited excision. Subjects were the 2 treatment groups. Given the expected mean value of the excluded if they had a Mini-Mental State Examination (MMSE) various scales in this population, a difference of 0.5 SD trans- score of less than 24; if they were suicidal; met diagnostic crite- lates into a difference of about 15%. Assuming a correction of ria for MDD, psychosis, or schizophrenia; were currently taking 0.5 between observations from the same individuals, a sample an antidepressant medication; or had a contraindication to tak- size of 68 (34 per treatment) would provide the necessary power.
ing citalopram. Subjects were approached by 1 of the participat- Because up to 15% to 20% of subjects could be lost to follow- ing surgeons (W.M.L.) and given a detailed explanation of the up, the total sample size was set at 80 to assure the sufficient study. A delayed consent process was used, which allowed sub- power. The study was stopped early because of personnel jects time to review the study plan and consent form and then changes, making adequate accrual unlikely.
return to the research clinic at a later date to complete the con-sent process and for the baseline interview.
Baseline evaluations performed to evaluate psychiatric and cog-nitive status included the Mini-International Neuropsychiatric In- There are almost no data on the use of antidepressants in patients terview I (MINI) and MMSE.21,22 The MINI is a brief, structured with HNC. Citalopram was selected as the study medication based psychiatric diagnostic interview for use in clinical and research on evidence of its efficacy; safety; favorable adverse effect profile; settings.22 The MINI provides broad coverage of psychiatric di- ease of discontinuing treatment; ease of administration as a single agnoses according to the Diagnostic and Statistical Manual of Men- daily dose as a pill, liquid, or via nasogastric tube; safety in older tal Disorders, fourth edition (DSM-IV),23 and has been used very adults and in medically fragile patients; ease of titration; and mini- widely in psychiatric research.22 The MINI covers a variety of psy- mal drug interaction potential.16,19 It is a member of the class of chiatric disorders of particular interest to this study, including selective serotonin reuptake inhibitors (SSRIs).
major depressive episode (current and past), suicidality (in pastmonth), and alcohol abuse or dependence (past 12 months). The TREATMENT AND FOLLOW-UP
MINI was used at baseline to identify any exclusionary psychi-atric diagnoses, and the depression and suicide modules of the A physical examination and mental status examination were per- MINI were repeated at each subsequent visit.
formed to verify that subjects were eligible to participate. Sub- The primary outcome measure was the number of subjects jects were randomized in the University of Nebraska pharmacy who developed depression according to the Hamilton Rating Scale by coin toss in a 1:1 fashion to receive placebo or citalopram (here- for Depression (HRSD) (the predefined cutoff for depression was inafter, placebo group and citalopram group, respectively). Sub- Ն15). The HRSD is a standard, physician-administered, assess- jects were randomized to receive active drug or placebo for 12 ment tool used to measure depression severity in efficacy evalu- weeks. Each subject received identical capsules either contain- ations of antidepressants.24 The HRSD, which consists of 21 items ing citalopram hydrobromide, 20 mg, or a matching placebo and that quantify depressive symptoms, was administered at each of were asked to begin with 1 pill per day for 1 week and increase the 5 visits. Higher scores on the HRSD indicate higher levels the dosage to 2 pills per day until the 12th week when they were asked to take 1 pill per day for 1 week and stop. Subject visits The physician-administered MINI depression module served were performed every 4 weeks throughout the intervention pe- as a secondary measure of depression. A global assessment of riod. A follow-up visit off study medication was then performed depression severity, the Clinical Global Impression–Severity at 16 weeks. Pill counts were performed at each visit to verify at (CGI-S) scale, was also obtained at each visit. The CGI-S pro- least 80% compliance. At baseline, each subject underwent thy- vides an overall rating of the severity of depression on a simple roid function studies to verify the euthyroid state.
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also used to compare the frequency of a diagnosis of MDD on theMINI and the frequency of having a global illness rating of “mildly ill” or greater on the CGI-S. The Wilcoxon rank-sum test com-pared change in QOL from baseline with week 12 and week 16 between the treatment groups. All analyses were conducted using Enrollment
SAS statistical software for Windows (version 9.1; SAS Inc, Cary, PATIENT CHARACTERISTICS
From July 2002 through April 2005, 36 subjects were ran- domized (see Figure 1 for details). Five were ineligible
owing to baseline depression (HRSD scores were Ն15 [base
rate of MDD preintervention=14%]), and 1 was ineligible owing to a low MMSE score. The ineligible subject shouldnot have been randomized and was done so through an er-ror. Those with baseline depression were randomized, butin retrospect our eligibility criteria should have excluded these subjects. Two subjects failed to make baseline visits after randomization but prior to allocation of the drug.
Twenty-eight subjects began medication; 2 in the cital- opram group quit because of adverse events (1 each, ow-ing to diarrhea and nausea), and 1 in the placebo group failed to return for visit 1. Twenty-five subjects com- pleted the first visit. Two subjects in the placebo group dropped out after the first visit; 1 did so after week 4 ow-ing to hospitalization for severe MDD, the other be- cause she was placed in a care facility for the duration of her cancer treatment. Twenty-two subjects were evalu-ated at week 12 of the study, and 23 completed the study Figure 1. This diagram demonstrates the flow of subjects from original
(13 in the citalopram group, and 10 in the placebo group).
presentation in the study, through randomization, and to completion of the One subject in the citalopram group was not available study. It demonstrates where and why subjects left the study. MMSE for the week 12 visit because of travel difficulties but did indicates Mini-Mental State Examination.
return for the follow-up visit at week 16.
Twelve men and 11 women, with a mean (SD) age of Health-related QOL was assessed with the University of Washington Disease-Specific Quality of Life Questionnaire (UW- 61.0 (10.6), completed the study. Subjects did not signifi- QOL), which was developed to assess QOL in patients with cantly differ according to age, sex, tumor grade, type, or HNC. It is self-administered and includes 9 categories empha- location (Table 1). However, there was a trend toward
sizing important areas of daily living frequently affected by HNC more women in the placebo group (60% vs 38%). There or its treatment.26 A score of 100 represents the highest level were no notable differences in the number of HNC treat- of function, and zero indicates the lowest level of function.
ment modalities received (ie, surgery, chemotherapy, ra- The tested domains include pain, disfigurement, activity, rec- diation, either individually or in combination).
reation/entertainment, employment, eating/chewing, eating/swallowing, speech, and shoulder disability.
All assessments were performed in a blinded fashion. Nei- ther the investigators nor the subjects knew whether they werereceiving active drug or placebo. Unblinding did not occur un- The primary outcome measure was the number of sub- til the last subject had completed the final assessments.
jects who met the predefined cutoff (Ն15) on the HRSD
(Figure 2). The numbers who met this criteria for clini-
cally significant MDD at any time during the 12 weeksof active study were 5 of 10 (50%) in the placebo group Analyses used a modified intent-to-treat sample that included all and 2 of 12 (17%) in the citalopram group (Fisher exact subjects who provided informed consent, were not depressed test, P = .17; Figure 2). The percentage whose HRSD was (HRSD Ͻ15 at baseline), and were available for evaluation at the at least 15 stayed roughly at 15% in the citalopram group first postrandomization visit (4 weeks). Subjects with HDRS scores throughout the study but increased to 50% in the pla- of at least 15 at baseline were continued in the study because data on the treatment vs the natural history of untreated MDD havealso not been studied in HNC. They were excluded from the pri- The secondary measure of MDD was the number of mary analysis of MDD prevention because, by definition, MDD subjects who met the criteria for MDD on the depres- was already present. The Fisher exact test was used to compare sion module of the MINI (Figure 3). The number of sub-
the frequency of MDD in the 2 treatment groups at weeks 12 and jects who met criteria at any visit was 5 of 10 (50%) in 16 as well as at any time during the study. Fisher exact tests were the placebo group and 4 of 13 (31%) in the citalopram (REPRINTED) ARCH OTOLARYNGOL HEAD NECK SURG/ VOL 134 (NO. 5), MAY 2008 2008 American Medical Association. All rights reserved.
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Table 1. Demographics of Subjects Completing Visit 1a
Placebo Group
Group (N = 13)
Figure 3. Percentage of patients with a diagnosis of major depressive
disorder (MDD). Results of the Mini-International Neuropsychiatric Interview are expressed as a percentage of the total group comparing the citalopramhydrobromide group with the placebo group. The asterisk indicates the Fisher exact P value, P = .42.
a Data are given as numbers, except where indicated.
Figure 4. Percentage of subjects with a Clinical Global Impression–Severity
rating of at least mildly ill at 4, 8, 12, and 16 weeks, indicating a significant difference between how the subjects were perceived by the examiner. The placebo group seemed markedly more ill compared with the citalopram hydrobromide group. The asterisk indicates the Fisher exact P value, P = .04.
Figure 2. Results of the Hamilton Depression Rating Scale (HDRS) at weeks
4, 8, 12, 16, or at any visit indicating a trend toward significant differences
between the placebo and citalopram hydrobromide groups (an HDRS score
group had a CGI-S rating worse than “mildly ill” at any point of Ն15). The asterisk indicates the Fisher exact value, P=.17.
during the study compared with 30% in the placebo group.
The treatment group showed improvement at 16 weekscompared with worsening scores in the placebo group.
group (Fisher exact test, P=.42; Figure 3). After 12 weeks Table 2 reports the summary of results for primary and
of participation in the study, 40% of the placebo group secondary outcomes. Table 3 demonstrates confidence
vs 17% of the citalopram group had MDD. On the fol- intervals for 1 primary and 2 secondary outcomes.
low-up visit, 1 subject from the citalopram group devel-oped MDD after stopping the drug. No patients in the QUALITY OF LIFE
citalopram group exhibited suicidal ideation (suicide mod-ule of the MINI) during the 16 weeks of study, com- The UW-QOL deteriorated in both groups from baseline pared with 2 in the placebo group. No subjects in either but less so in the citalopram group (Figure 5). The me-
dian UW-QOL change from baseline to week 12 was 18 Overall severity of depression, as estimated by CGI-S points in the citalopram group and 30 points in the placebo rating, was “mildly ill” or worse in 25% of citalopram- group (P=.60). At week 16, the decline was 7 points in the treated participants at week 12 and 15% at week 16 com- citalopram group and 32 points in the placebo group (Wil- pared with 50% and 60% of the placebo-treated patients, coxon rank-sum test, P=.14). The placebo group contin- respectively (Figure 4) (Fisher exact test: at week 12,
ued to decline at follow-up, whereas the citalopram group P=.38; at week 16, P =.40). No patient in the citalopram (REPRINTED) ARCH OTOLARYNGOL HEAD NECK SURG/ VOL 134 (NO. 5), MAY 2008 2008 American Medical Association. All rights reserved.
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Table 2. Summary of Results and the Estimated Effect Sizea
Hydrobromide Group
Placebo Group
Difference, %
End Point
(95% CI)c
P Value
CGI-S rating of at least mildly ill at any visit CGI-S rating of at least mildly ill at 12 wk CGI-S rating of at least mildly ill at follow-up Abbreviations: CGIS, Clinical Global Impression–Severity; CI, confidence interval; HDRS, Hamilton Rating Scale for Depression; MDD, major depressive a Data are given as number/total number (percentage). The table contains the results summarized for each group for the primary and secondary end points. It contains the number out of the total and percentage for the citalopram and placebo groups, along with the difference in percentages and the asymptotic 95% CIfor the difference. The P value is computed using Fisher exact test. If a subject was depressed at any of the 4 visits they were said to be depressed at any visit, forthe primary end point for HDRS. The other primary end points were computed similarly.
b One subject in the citalopram group did not have week 12 data.
d According to the Mini-International Neuropsychiatric Interview I.
Table 3. Confidence Intervals (CIs) for the Citalopram Hydrobromide and Placebo Groupsa
Patients Who Were Depressed
Patients With Diagnosis of MDD
Patients With a CGI-S Score
(HDRS Ն15) at Any Visit
(MINI) at Any Visit
of Mildly Ill or Greater at Any Visit
Abbreviations: CGI-S, Clinical Global Impression–Severity; HDRS, Hamilton Rating Scale for Depression; MDD, major depressive disorder; MINI, Mini-International Neuropsychiatric Interview I; NNT, number needed to treat.
a The CIs for these 3 outcomes expand on the data shown in Table 2 and demonstrate the potential effect size that might be shown with adequate numbers.
of cancer with a subsequent change in lifestyle) can sub-stantially elevate an individual’s risk for MDD, particu-larly when magnified by a lack of interpersonal support KEY FINDINGS
and deficient social skills. Finally, the symbolic mean- This study suggests that the use of a prophylactic anti- ing of loss (eg, the loss of voice) can be profound.
depressant (citalopram) may prevent some cases of MDD Untreated MDD in patients with other types of can- during the first 16 weeks following initiation of cancer cer has been shown to adversely affect length of hospital therapy in patients with HNC. It further suggests that some stay, self-care abilities, compliance with medical treat- mitigation in the expected decline in QOL typically seen ment, QOL, and survival.27-29 The full effect of un- during HNC therapy may be achieved. Finally, overall treated MDD in patients with HNC has not been stud- psychological health as measured by the CGI may be bet- ied; however, it is likely to play an important role in prognosis for these reasons. It is known that timelycompletion of radiation therapy is also an important pre- MDD DIAGNOSIS
dictor of successful disease control.30-32 Major depres-sive disorder may be 1 factor that adversely affects ad- Diagnosis and treatment of MDD is critical to the over- all treatment of patients with HNC. It is likely that MDD One of the most important reasons that prevention, is the end result of a complicated interplay between ge- recognition, and treatment of MDD is so vital in pa- netic predisposition and environmental influences. Con- tients with HNC is the known increased risk of sui- current life events (such as the diagnosis and treatment cide.33-35 One study36 demonstrated that cancers of the (REPRINTED) ARCH OTOLARYNGOL HEAD NECK SURG/ VOL 134 (NO. 5), MAY 2008 2008 American Medical Association. All rights reserved.
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larynx and tongue accounted for 2 of the 3 highest sui-cide rates among patients with cancer. Cancers of the lar- ynx and tongue accounted for 19% of the cases in this series of in-hospital suicides.36 Suicide rates also seemhighest in the first 3 months following diagnosis, sug- gesting a critical window of opportunity for treatment Investigations into the psychological aspects of HNC have primarily focused on establishing the prevalence of, and predictive factors for, psychiatric morbidity. There are very few studies applying interventions aimed at im-proving psychiatric and psychological outcomes to pre- vent or reduce suffering and improve health-related QOL.37,38 Remarkably, to our knowledge there are no pub- lished studies evaluating the effects of antidepressants on clinical MDD and their impact on health-related QOL inpatients with HNC.
Figure 5. Results of the University of Washington Disease-Specific Quality of
Life (QOL) Questionnaire expressed as a median change from baseline
Interesting work in the field of laboratory research in demonstrate the continued decline in QOL in the placebo arm compared with MDD suggests a potential model for depression sur- a decline in improvement in the treatment arm. The asterisk indicates the rounding HNC and perhaps other cancer treatments.
Wilcoxon P value, P = .14.
Exposure to severe, inescapable stress results in subse-quent behavioral depression, termed “learned helpless- Antidepressants are considered to be safe for the treat- ness.” Learned helplessness has been extensively stud- ment of MDD in patients with cancer.16,28,29,40-42 The use ied in the rat but also can be demonstrated in a range of of antidepressants as prophylactic agents in medically ill other species, including humans. Learned helplessness patients is an emerging field. Musselman et al43 re- is considered to be an animal model for MDD. In the rat, ported that the risk of depression in patients with ma- learned helplessness can be prevented by treatment with lignant melanoma treated with interferon could be re- antidepressant drugs, including SSRIs, if these agents are duced by prophylactic use of the SSRI paroxetine administered in repeated doses prior to inescapable stress hydrochloride. Treatment also significantly reduced the exposure. Antidepressants given prior to stress main- likelihood that therapy for the melanoma would be dis- tain levels of cortical serotonin and prevent stress- continued. Thus, early intervention in a high-risk popu- induced depletion of serotonin in proportion to preven- lation resulted in marked diminution of depressive symp- tion of stress-induced depressive behavior.39 If learned toms plus improved delivery of treatment.
helplessness models are relevant to clinical MDD in- Roscoe et al44 studied fatigue in women undergoing che- duced by the stress of the diagnosis and treatment of can- motherapy for breast cancer and, as a secondary focus, also cer, prior treatment with antidepressants should pre- measured depression. Patients who reported fatigue by day vent subsequent depression in humans. This hypothesis 7 following the second of at least 4 cycles of chemo- may best explain the findings in this study. It may be hy- therapy were randomly assigned to receive either parox- pothesized that repeated stress from cancer therapy low- etine, 20 mg, or a placebo. Patients then completed ques- ers cortical serotonin, and an antidepressant given pro- tionnaires at home to measure fatigue and depression. A phylactically may serve to lesson this decrement.
total of 244 patients treated with paroxetine and 235 pa- Additional study is clearly needed to support or refute tients treated with placebo had assessable data. Although the authors did not see any improvement in fatigue in the To consider prophylactic therapy for a disorder, sev- treatment group, paroxetine significantly reduced depres- eral conditions must first be met. The agent must be safe sion as measured by the CES-D during chemotherapy.44 and effective in preventing the disease. The disease must Taken together, these studies support the role of preven- exist with a high enough frequency and result in suffi- tion of depression in high-risk patients. None of these stud- cient morbidity to warrant the risk of the intervention ies address the specific and unique nature of HNC. The pres- to the entire group. The agent must be cost-effective.
ent data reinforce these studies’ findings in other malignant First, consider the types of therapies for MDD. Treat- neoplasms and support the concept of MDD prevention in ment options for clinical MDD include psychotherapy, pharmacological therapy, and electroconvulsive therapy.
The data from this pilot trial suggest that prevention Medication and/or psychotherapy are effective in most of MDD in patients undergoing treatment for HNC may medically ill patients experiencing mild to moderate de- be an attainable goal. The data show trends toward MDD pression.40 However, patients with HNC frequently have prevention in this small sample. All measures of psychi- marked impairment in communication, making psycho- atric well-being favored the group taking citalopram. The therapy difficult and possibly limiting its effectiveness, HRSD, the most widely used measure of depression se- particularly in the first 3 months following diagnosis of verity in clinical trials evaluating antidepressants, showed cancer. Antidepressant medications may be particularly a clear trend toward a reduction in depressive symp- advantageous for these patients because they require less toms in the citalopram group compared with placebo.
interaction on the part of the patient and, furthermore, Similarly, the number of patients who met criteria for a are readily available to nonpsychiatric physicians.
diagnosis of MDD showed the same trend. Although cau- (REPRINTED) ARCH OTOLARYNGOL HEAD NECK SURG/ VOL 134 (NO. 5), MAY 2008 2008 American Medical Association. All rights reserved.
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tion is indicated in evaluating these outcomes, addi- which to our knowledge is the first in HNC, begins to tional investigation is warranted, as suggested by the con- lay the groundwork for a more proactive approach to the fidence intervals reported in Table 3. Given the range of global health of the patient with HNC.
the confidence intervals, a substantial effect may possi- This study has a number of limitations. Clearly, the sample size is small, and the study was stopped prior toachieving the predicted power necessary for statistical sig- QUALITY OF LIFE
nificance owing to personnel changes. The initial inclu-sion and randomization of subjects with MDD to in- Clinical MDD is one of the few factors consistently found clude more subjects was likely not ideal, but because these to be an independent predictor of health-related QOL both individuals were not included in the analyses, it did not during treatment for HNC and for years thereafter.11 Pa- affect the results. Because this was a pilot study, mul- tients who are clinically depressed at diagnosis are more tiple assessments were used. This possibly created a bur- likely to have a poor health-related QOL during and af- den that reduced the ability to recruit subjects to this study ter treatment,11,29,45-50 Diminished health-related QOL is and ultimately may have led to slow accrual.
reflected in increased severity of symptoms and poorer Many questions still exist. The study needs to be re- physical, psychological, and social functioning. The na- peated in a larger, appropriately powered study. There is ture of the relationship between MDD and health- the possibility that preventing MDD might have addi- related QOL in terms of cause and effect is complex and tional benefits not detected in short-term clinical trials like incompletely understood. The data from this study sug- the one reported herein. Given that many patients with gest 2 important findings. First, although both groups HNC have been shown to experience MDD for years after demonstrated the expected worsening of QOL as mea- diagnosis of their cancer, long-term studies and fol- sured by the UW-QOL, the placebo group evidenced a low-up studies of patients treated prophylactically also need steeper slope. Second, at the 16-week visit, the placebo to be performed. In addition, 14% of the patients had MDD group continued to show a decline in QOL, whereas the at baseline in the current study and were excluded from citalopram group demonstrated a slight improvement.
analysis. There is a clear need to establish whether treat-ment with an antidepressant might help patients who al- GLOBAL ASSESSMENT
ready have MDD at the time treatment is instituted as well.
In conclusion, this study reports data from the first MDD prevention trial in HNC and suggests that prophy- The global assessment of psychological health, the CGI, lactic treatment may decrease the incidence of MDD dur- did demonstrate a statistically significant improvement ing HNC therapy. The clinical significance of the reduc- in the treatment arm compared with placebo at 16 weeks tion in MDD was best demonstrated by the CGI-S scale, (see Table 2 for P values). At that time, only 15% of the which showed a notable difference in global psychiatric patients treated with citalopram were considered to be and physical well-being between the treatment arm and mildly ill or worse compared with 60% of the placebo the placebo arm. Finally, no subjects in the treatment arm group. As a global measure, the CGI may be the most clini- expressed suicidal ideation. This study suggests a tan- cally relevant measure of mood. A patient who is feeling gible means to improve outcome in patients with HNC stronger psychologically may be more likely to com- and supports additional research toward this aim.
plete therapy and have an improved QOL.
Submitted for Publication: July 5, 2006; final revision
received July 4, 2007; accepted September 4, 2007.
Correspondence: William M. Lydiatt, MD, Department
Suicide is likely an underreported problem in patients of Otolaryngology–Head and Neck Surgery, University with HNC. Suicide prevention is difficult for the head and of Nebraska Medical Center, Omaha, NE 68198-1225 neck oncologist to manage owing to lack of training and expertise. It is important to emphasize that this discus- Author Contributions: Drs Lydiatt, Denman, McNeilly,
sion is not dealing with the question of suicide at the end and Burke and Ms Puumula had full access to all the data of life but rather the premature termination of life ow- in the study and take responsibility for the integrity of ing to active MDD. The data from this study are very sparse the data and the accuracy of the data analysis. Study con- on this issue, but 2 subjects in the placebo group expe- cept and design: Lydiatt, Denman, and Burke. Acquisition rienced suicidal ideation compared with none in the of data: Lydiatt, Denman, and McNeilly. Analysis and in- treated group. This suggests that prophylaxis with cita- terpretation of data: Lydiatt, Denman, Puumula, and Burke.
lopram may be an avenue warranting further study, par- Drafting of the manuscript: Lydiatt, Denman, Puumula, ticularly in the first 3 months following diagnosis. This and Burke. Critical revision of the manuscript for impor- is known to be a high-risk period for suicidal ideation tant intellectual content: Lydiatt, Denman, McNeilly, among patients with cancer, particularly male patients.
Puumula, and Burke. Statistical analysis: Puumula. Ob- In summary, this study provides preliminary evi- tained funding: Lydiatt, Denman, and Burke. Administra- dence suggesting that prophylactic use of the SSRI cita- tive, technical, and material support: McNeilly. Study lopram may lessen the risk of MDD occurring in the first 3 months following diagnosis and initiation of treat- Financial Disclosure: Dr Burke has served as a consul-
ment for HNC. Furthermore, this strategy may also pre- tant and received honoraria and research support from serve QOL compared with a placebo condition. This study, (REPRINTED) ARCH OTOLARYNGOL HEAD NECK SURG/ VOL 134 (NO. 5), MAY 2008 2008 American Medical Association. All rights reserved.
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Funding/Support: This study was supported by the Uni-
21. Folstein MF, Folstein SE, McHugh PR. Mini-Mental State: a practical method for versity of Nebraska Clinical Research Center and an un- grading the state of patients for the clinician. J Psychiatr Res. 1975;12(3):189-198.
restricted grant from Ted Kooser. Forest Laboratories Inc 22. Sheehan DV, Lecrubier Y, Sheehan KH, et al. The Mini-International Neuropsy- chiatric Interview (M.I.N.I.): the development and validation of a structured di- Previous Presentations: This study was presented as an
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