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An open label pilot study of citalopram for depression and boredom in ambulatory cancer patients

Published online by Cambridge University Press:  29 April 2003

DALE E. THEOBALD ,
KENNETH L. KIRSH ,
ELIZABETH HOLTSCLAW ,
KATHLEEN DONAGHY  and
STEVEN D. PASSIK
DALE E. THEOBALD
Affiliation:
Oncology Symptom Control & Research, Community Cancer Care, Indianapolis, Indiana
KENNETH L. KIRSH
Affiliation:
Markey Cancer Center, University of Kentucky Cancer Center, Lexington, Kentucky
ELIZABETH HOLTSCLAW
Affiliation:
Oncology Symptom Control & Research, Community Cancer Care, Indianapolis, Indiana
KATHLEEN DONAGHY
Affiliation:
Oncology Symptom Control & Research, Community Cancer Care, Indianapolis, Indiana
STEVEN D. PASSIK
Affiliation:
Markey Cancer Center, University of Kentucky Cancer Center, Lexington, Kentucky
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Abstract

Objective: Significant levels of depressive symptoms are an impediment to adjustment and affect greater than one-third of people with cancer. The clinical diagnosis of major depression is estimated to occur in 25%. Depression is dramatically underrecognized by oncologists and oncology nurses, and as a result, often undertreated. Clinical experience suggests that antidepressants of virtually all types are well tolerated and potentially efficacious. There is, however, a lack of an evidence base for the use of antidepressants in cancer patients.

Methods: We undertook an open-label pilot study using citalopram in 30 cancer patients who reported a high level of depressive symptoms on the Zung Self-Rating Depression Scale (ZSDS). In addition to the ZSDS, eligible patients completed a series of visual analog scales for pain, depression, and sleep disturbance; the Functional Assessment of Cancer Therapy-General Module; and the Purposelessness, Understimulation, and Boredom Scale developed by the research team. Patients began a 2-month course of therapy with citalopram 20 mg, increasing to 40 mg at the end of the fourth week if the patient was in the same range of depressive symptoms as measured by the ZSDS.

Results: Twenty-one of 30 patients completed the protocol. The average age of the sample was 57.32 years (SD = 12.6) and was comprised of 11 women (52.4%) and 10 men (47.6%). Depressive symptoms decreased and quality of life improved during the 8-week treatment period. Of special interest was the rate of improvement in boredom, and using the total boredom score of the PUB, significant improvement compared to baseline was seen in weeks 6 (F = 5.266, p < .05) and 8 (F = 9.248, p < .01).

Significance of results: Overall, the positive findings suggest the need for a randomized, double-blind, placebo-controlled trial of citalopram in cancer patients. Regarding the interplay of boredom and depression, the relationship between improvements in depressive symptoms and boredom is complex. This is illustrated by the way in which the different elements respond to antidepressant treatment. Depression began to improve almost immediately upon initiation of treatment whereas improvement in boredom does not become evident until week 6.

Keywords

CitalopramDepressionBoredomCancer
Type
Research Article
Information
Palliative & Supportive Care , Volume 1 , Issue 1 , March 2003 , pp. 71 - 77
Copyright
© 2003 Cambridge University Press

INTRODUCTION

Many forms of cancer have been transformed from acute life-threatening illnesses into chronic life-threatening ones (Passik et al., 1998b). While 50% of patients diagnosed today will go on to be long-term survivors, even among those who will eventually die of their disease, 50% will live at least 1 year and 33% will live 2 years or more (Brescia, 1993). With this transformation to a chronic disease, the facilitation of adjustment throughout a prolonged course is a major goal of care with a focus on helping the patient function as normally as possible in the psychological, social, and vocational domains (Portenoy & Bruera, 1998). There are considerable barriers to this normal functioning however. Studies have suggested that the average ambulatory cancer patient has 10 distressing physical and psychological symptoms with which to contend on a daily basis, with 5 of the 10 being psychosocial in nature (Portenoy et al., 1994).

Significant levels of depressive symptoms are both an impediment to and a sign of difficulty in adjustment and affect greater than one-third of people with cancer (Dugan et al., 1998). The clinical diagnosis of major depression is estimated to occur in 25%. Depression is dramatically under-diagnosed by oncologists and oncology nurses (McDonald et al., 1999; Passik et al., 1998a). As a result of this underrecognition, depression in cancer patients is undertreated. Estimates are that only 2–7% of cancer patients ever receive treatment with antidepressant medication, despite the multiple benefits that might be derived from these medications and their ease of use. Clinical experience suggests that antidepressants of virtually all types are well tolerated and potentially efficacious (Breitbart & Passik, 1993).

Equally problematic is the lack of an evidence base for the use of antidepressants until relatively recently. Recent randomized trials have suggested efficacy for Prozac and Paxil over placebo for depression and quality of life (Fisch et al., 2001; Roscoe et al., 2002). Our group has completed an open-label examination of fluoxetine (Passik et al., 2002) and an open-label evaluation of mirtazapine (Theobald et al., 2001) in advanced cancer patients, suggesting multiple benefits for symptom relief and quality of life. The dramatic, life-changing impact of cancer can lead to great anxiety, feelings of discouragement, and demoralization (Sivesind & Baile, 2001).

We chose the antidepressant citalopram, a selective serotonin reuptake inhibitor (SSRI) which has been effective in treating depression in medically ill patients (Keller, 2000), to use in an open-label trial in a series of cancer patients who reported high levels of depressive symptoms on the Zung Self-Report Depression Scale (Zung, 1965). While the SSRIs are seen as recommended antidepressants for cancer patients (Lovejoy et al., 2000), there are no published open-label or randomized trials of citalopram with cancer patients despite the fact that its side effect profile and tolerability in other populations suggest it would be well suited. We also measured other symptom distress and quality of life. In addition, patients were asked to complete the boredom scale developed by our group to assess the relationship between patient's report of depressive symptoms and boredom and track them over the course of antidepressant treatment. Given the other stressors that cancer patients sometimes face, boredom may sound like a trivial problem; however, it can become a major problem for patients when they can no longer work and function socially as they could before. Especially during quiescent times during the disease course, caregivers go on about their daily routines, but the patient may be left alone or with little to occupy his thoughts and his time. Extended periods of inactivity and isolation can lead to emotional reactions that, on the surface, may resemble depression (with an unclear relationship to depression and its treatment). Our group has recently become interested in sorting out the differences between the phenomenological experience of depression and boredom as the interventions required to improve the quality of life for the patient would be very different (Passik et al., 2002). Boredom was found to be correlated with depression, decreased activities of daily living, and advanced disease.

METHODS

Procedures

The study was reviewed and approved by the Western Institutional Review Board. Thirty cancer patients who reported moderate to severe symptoms of depression during our routine clinical screening process were recruited for this study. To be eligible patients had to have a diagnosis of solid tumor or hematological malignancy and a Zung Self-Rating Depression Scale (ZSDS) raw score > 48. The patients also had to be at least 18 years old and able to give informed consent. Patients were ineligible if they had been on antidepressant medications within the previous 4 weeks, were on any medications that would preclude the use of citalopram, BUN > 40 mg/dl, creatinine > 2.8 mg/dl, manifested encephalopathy or psychiatric disease that would compromise informed consent or data collection, or their expected survival was less than 3 months.

The study design was an open-label, nonrandomized trial. Following screening and after informed consent was obtained, eligible patients were asked to complete a series of visual analog scales (VAS) for pain, depression, and sleep disturbance, the Functional Assessment of Cancer Therapy–General Module (FACT-G; Cella et al., 1993), the ZSDS (Zung, 1965), and the Purposelessness, Understimulation, and Boredom Scale (PUB) developed by the research team (Passik et al., 2003). Patients were then instructed to initiate therapy with citalopram 20 mg by mouth in the morning. The dose was increased to 40 mg at the end of the fourth week of therapy if the patient was in the same range of depressive symptoms as measured by ZSDS scores at study entry (moderate or severe). Dose escalations were held at the discretion of the clinician. The patients were treated with citalopram for 2 months. During the 2-month treatment period, all patients completed the same battery of instruments (the ZSDS, VASs for pain, depression, and sleep disturbance, the FACT-G, and the PUB) at 2-week intervals. During the first weeks of therapy, the research staff contacted the patients by telephone to ensure compliance with the prescribed regimen.

Study Instruments

Medical and Demographic Information

All pertinent demographics (age, gender, weight, SES) and medical data (site and stage of disease, laboratory values, medications, and present therapies including present oncologic therapy and medications for palliative care) were recorded.

Zung Self-Rating Depression Scale (ZSDS)

The ZSDS (Zung, 1965) is a 20-item self-report measure of the symptoms of depression. Subjects rate each item regarding how they felt during the preceding week using a 4-point Likert scale, with 4 representing the most unfavorable response. After correcting for the 10 items that are reverse-scored, the items are summed to create a total depression score. Scores are not meant to offer strict diagnostic guidelines but rather denote levels of depressive symptomatology that may be of clinical significance. Overall, the ZSDS has been shown to be relatively valid and to have high internal consistency, exhibiting an alpha coefficient of 0.84.

Functional Assessment of Cancer Therapy–General (FACT-G)

The FACT-G (Cella et al., 1993) is a 27-item self-administered questionnaire covering the quality of life domains of physical, social and family, emotional, and functional well-being. Items are rated on a 5-point likert scale, from 0 (not at all) to 4 (very much) for how true each statement has been for the patient in the past 7 days. After accounting for reverse-scored items, questions are summed across the four subscales as well as added for a total score, with higher scores indicative of greater overall quality of life. The instrument is easy to use, brief, reliable, and valid. The measure has been shown to yield adequate to high internal consistency, exhibiting coefficient alphas ranging from 0.63 to 0.86 on the subscales and 0.90 to 0.95 for the total scale. The scale has also shown high test-retest reliability (r = 0.87).

Purposelessness, Understimulation, and Boredom (PUB) Scale

The PUB Scale (Passik et al., 2003) is a 14-item scale designed to assess boredom in cancer patients. The scale consists of two factors that yield a total scale score. Factor I (8 items) relates to overt boredom and Factor II (6 items) relates to diminished meaning and purpose in life. Participants rate each item according to how true it is for them. Response choices range from 1 (none of the time) to 4 (all of the time). Total scale internal consistency, when all 14 items were included in the analysis, yielded a coefficient alpha of 0.84. A significant Spearman–Brown coefficient (r = .80, p < .001) was found indicating good test–retest reliability at 2 weeks. The 14-item PUB Scale was significantly correlated to other measures of boredom; the Boredom Proneness Scale (r = −.588, p < .001) and the Leisure Boredom Scale (r = .576, p < .001). The scale was found to be a potentially useful tool with the ability to detect boredom and differentiate it from depression. The PUB was used to assess boredom in the participants.

Visual Analog Scales (VAS)

The VAS consisted of six questions covering pain, anxiety, nausea, insomnia, hot flashes, and appetite. Patients were asked to indicate the area of the line that best described the symptom at its worst during a 1-week period. The items utilize a 0–10 scale, with 0 meaning no presence of the symptom and 10 meaning that the symptom was as bad as could be imagined.

RESULTS

Of 30 patients screened for participation in the study, 21 patients completed the protocol. Three of the patients withdrew from the study after they signed the consent form but before taking any citalopram. The other six patients had mild side effects, but they were not significant enough that the patients did not wish to continue medication. The side effects reported for these patients were head-ache (n = 2), rash (n = 1), nausea (n = 1), insomnia (n = 1), and unexplained pain (n = 1).

The demographic characteristics of the sample of 21 completers are described in Table 1. The average age of the sample was 57.32 years (SD = 12.6) and was comprised of 11 women (52.4%) and 10 men (47.6%). The majority were Caucasian (n = 20, 95.2%) and married (n = 17, 81%). In addition, the patients had a variety of cancer diagnoses. Most had either colon (n = 7, 33.3%), lung (n = 4, 19.0%), or hematologic (n = 4, 19.0%) cancer.

Demographics of the study sample (n = 21)

Responses to the Study Measures

The responses to the study instruments over the course of the study are listed in Table 2. As can be seen, the general trend was for depression and boredom ratings to go down (indicating improved functioning) while overall quality of life ratings increased. Scores on the VAS scales, however, indicated more variation for items such as pain and nausea. The results with individual measures are described in further detail below.

Mean responses for the study assessment tools at baseline, week 2, week 4, week 6, and week 8

Zung Self-Rating Depression Scale Scores

A series of repeated measures ANOVAs were conducted using simple contrasts to compare the patients' report of depressive symptoms at 2 weeks, 4 weeks, 6 weeks, and 8 weeks to baseline. ZSDS scores were significantly reduced at all points (week 2, F = 13.770, p < .05; week 4, F = 20.284, p < .001; week 6, F = 16.657, p < .001, week 8, F = 26.898, p < .001), indicating significant decreases in reported depressive symptoms.

FACT-G Scores (Quality of Life)

Similar repeated measures ANOVAs performed on the FACT-G scores revealed significant changes at weeks 4, 6, and 8 when compared to baseline (week 4, F = 5.437, p < .05; week 6, F = 7.102, p < .05; week 8, F = 11.502, p < .01). Patients were reporting a perceived difference in their quality of life.

VAS Measurements of Other Symptoms

Pain, nausea, anxiety, insomnia, appetite, and hot flashes were assessed at each assessment point using VASs. Of these symptoms, only anxiety and hot flashes improved significantly when compared to baseline. Both symptoms improved at weeks 4, 6, and 8 (anxiety: week 4, F = 5.326, p < .05; week 6, F = 5.673, p < .05; week 8, F = 4.639, p < .05; hot flashes: week 4, F = 12.308, p < .05; week 6, F = 6.760, p < .05; week 8, F = 21.739, p < .01).

Purposelessness, Understimulation, and Boredom Scale Scores

Finally, a series of repeated measure ANOVAs were calculated to determine rates of improvement for boredom. Using the total boredom score derived from the PUB, significant improvement compared to baseline was seen in weeks 6 (F = 5.266, p < .05) and 8 (F = 9.248, p < .01). Upon examining the overt boredom factor, no significant changes were noted across any of the time periods compared to baseline. Finally, when examining the boredom related to meaning and spirituality factor, significant improvements were noted at weeks 6 (F = 8.046, p < .05) and 8 (F = 6.648, p < .05) compared to baseline.

In addition, it was also of interest to explore the relationship between boredom and depression (see Fig. 1). Pearson correlation analyses were used to examine this relationship, including the two factors of overt boredom and boredom related to meaning and spirituality. The results were complex. At baseline, there was no significant relationship between ZSDS and PUB scores (overall r = .015, p = .933). At week 8 the overall PUB scores were correlated with the ZSDS scores (r = .529, p < .05), a result that is consistent with our earlier work (Passik et al., 2003). The factor scores were also consistent with earlier data. The overt boredom factor score was correlated with ZSDS scores (r = .608, p < .01) and boredom related to meaning and spirituality was not correlated (r = .102, p = .661). These values suggest that overt boredom may be related to fatigue and other somatic sensations that are measured by the ZSDS, while issues of meaning and spirituality are not.

Comparison of ZSDS and PUB scores over the course of the study.

DISCUSSION

The results of this open-label trial of citalopram with cancer patients suggest that treating patients who have cancer can be beneficial in terms of decreasing depressive symptoms and improving quality of life. Citalopram was well tolerated by the patients. The other two symptoms that improved were reports of anxiety and severity of hot flashes. Improvement in ratings of hot flash severity is consistent with other data from trials of SSRIs in cancer populations (Quella et al., 1999; Loprinzi et al., 2000). These results suggest the need for a randomized, double-blind, placebo-controlled trial to establish efficacy.

Boredom and Depression

The relationship between depression and boredom is complex, as illustrated by the way in which the different elements respond to antidepressant treatment. Depression began to improve almost immediately upon initiation of treatment—by week 2 there is a significant change from baseline. The improvement in boredom does not become evident until week 6. This is an interesting observation. One explanation is that, especially in this open-label pilot, the placebo response differentially affected depression as patients knew they were taking an antidepressant medication (as opposed to an antiboredom one). On the other hand, perhaps there is a true difference, and a unique element of depression is affected by antidepressant therapy, some improvement in which must be realized before boredom can be expected to improve. Perhaps patients with depression have multiple symptoms interfering with their ability to be involved in activities, and when they respond, what is left are elements of depression/boredom that are shared; hence the scales' interrelationships are complicated as noted below.

Zung Self-Report Depression Scale scores were correlated with the overall boredom scale (r = .529, p < .05). In related work by our group a factor analysis of the boredom scale yielded two factors: Factor I Overt Boredom, Factor II Spirituality. Posttreatment Factor I scores were highly correlated with ZSDS scores (r = .608, p < .01). Factor II showed little correlation (r = .102, p < .661). These results suggest further research to delineate the differences between physical symptoms, cognitive symptoms of depression, and the role of spirituality in experiencing and reporting of those symptoms.

Interestingly, in the present study, the time 1 (baseline) data for the ZSDS and PUB Scale were not correlated. At week 8, data results are consistent with prior research on the development of the PUB Scale (Passik et al., 2003). The ZSDS and PUB Scale Total are correlated, but this is solely due to overlap between Factor I (overt boredom) and depression as measured by the ZSDS.

Caveats and Limitations

This study is a small, open-label pilot, and results must be understood in that light. Larger, randomized trials are needed along with comparisons between SSRIs to examine differences in efficacy and tolerability. The results related to boredom suggest a complicated relationship between depression, boredom, and antidepressant treatment that necessitates further study.

ACKNOWLEDGMENTS

This study was supported by Forest Laboratories. Dr. Theobald holds the Methodist Health Foundation Chair in Clinical Research in oncology symptom management.

References

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Figure 0

Demographics of the study sample (n = 21)

Figure 1

Mean responses for the study assessment tools at baseline, week 2, week 4, week 6, and week 8

Figure 2

Comparison of ZSDS and PUB scores over the course of the study.