Depression in Cancer Patients Danielle Snyderman, MD a, *, Daisy Wynn, MD b Anger, shock, denial, disbelief, and sadness frequently affect patients after they are given a diagnosis of cancer. As the impact of the news of a life-threatening illness settles in on patients and their family members, it is natural for patients to experience intense emotional distress. Although this normal grief response is expected to resolve in the first 2 weeks after diagnosis, many cancer patients eventually suffer from clin- ically diagnosable depression. Heightened depression is not limited to the active treat- ment period and may persist for months or even years after successful cancer treatment. 1 Depression adversely affects cancer patients’ quality of life, compliance with treatment, and relationship with their caretakers and may have an effect on mortality. 2 As primary care clinicians are increasingly playing a vital role in the complex care of cancer patients, greater emphasis will be placed on their ability to recognize depression and guide treatment options. EPIDEMIOLOGY The rate of depression in cancer patients is estimated to be four times that of the general population. 3 Studies indicate the prevalence of depression in cancer patients is 3% to 38% depending on criteria used and it has been reported that as high as 58% of patients have depressive symptoms. 4 Several factors account for the variable rates, including the multiple instruments used to diagnosis depression, various types and stages of cancer studied, and heterogeneous populations (inpatients and outpatients) included in study samples. A general consensus based on current prevalence studies, however, is that one in four to five cancer patients suffers from a major depressive episode after the time of diagnosis. 3,5 The rates of depression in cancer patients are similar to those seen in other serious medical conditions, such as myocardial infarction and stroke. 6–9 The highest percentage of depression occurs with more a Division of Geriatric Medicine, Department of Family and Community Medicine, Thomas Jefferson University, 1015 Walnut Street, Suite 401, Philadelphia, PA 19107, USA b Division of Geriatric Medicine, Department of Family and Community Medicine, Thomas Jefferson University, 1500 Locust Street, Apt 3819, Philadelphia, PA 19102, USA * Corresponding author. E-mail address: [email protected](D. Snyderman). KEYWORDS Depression Cancer Treatment Suicide Caregiver depression Prim Care Clin Office Pract 36 (2009) 703–719 doi:10.1016/j.pop.2009.07.008 primarycare.theclinics.com 0095-4543/09/$ – see front matter ª 2009 Elsevier Inc. All rights reserved.
Transcript
Depressionin Cancer Patients
Danielle Snyderman, MDa,*, Daisy Wynn, MDb
KEYWORDS
� Depression � Cancer � Treatment � Suicide� Caregiver depression
Anger, shock, denial, disbelief, and sadness frequently affect patients after they aregiven a diagnosis of cancer. As the impact of the news of a life-threatening illnesssettles in on patients and their family members, it is natural for patients to experienceintense emotional distress. Although this normal grief response is expected to resolvein the first 2 weeks after diagnosis, many cancer patients eventually suffer from clin-ically diagnosable depression. Heightened depression is not limited to the active treat-ment period and may persist for months or even years after successful cancertreatment.1 Depression adversely affects cancer patients’ quality of life, compliancewith treatment, and relationship with their caretakers and may have an effect onmortality.2 As primary care clinicians are increasingly playing a vital role in the complexcare of cancer patients, greater emphasis will be placed on their ability to recognizedepression and guide treatment options.
EPIDEMIOLOGY
The rate of depression in cancer patients is estimated to be four times that of thegeneral population.3 Studies indicate the prevalence of depression in cancer patientsis 3% to 38% depending on criteria used and it has been reported that as high as 58%of patients have depressive symptoms.4 Several factors account for the variable rates,including the multiple instruments used to diagnosis depression, various types andstages of cancer studied, and heterogeneous populations (inpatients and outpatients)included in study samples. A general consensus based on current prevalence studies,however, is that one in four to five cancer patients suffers from a major depressiveepisode after the time of diagnosis.3,5 The rates of depression in cancer patientsare similar to those seen in other serious medical conditions, such as myocardialinfarction and stroke.6–9 The highest percentage of depression occurs with more
a Division of Geriatric Medicine, Department of Family and Community Medicine, ThomasJefferson University, 1015 Walnut Street, Suite 401, Philadelphia, PA 19107, USAb Division of Geriatric Medicine, Department of Family and Community Medicine, ThomasJefferson University, 1500 Locust Street, Apt 3819, Philadelphia, PA 19102, USA* Corresponding author.E-mail address: [email protected] (D. Snyderman).
Prim Care Clin Office Pract 36 (2009) 703–719doi:10.1016/j.pop.2009.07.008 primarycare.theclinics.com0095-4543/09/$ – see front matter ª 2009 Elsevier Inc. All rights reserved.
advanced cancer, disability, and unrelieved pain. Studies have explored potentialdifferences in the prevalence of depression in cancer patients with regard to type ofcancer, gender, and age.
Cancer types most highly associated with depression include oopharyngeal,pancreatic, breast, and lung. Cancers associated with a lower prevalence of depres-sion include colon, gynecologic, and lymphoma.3 Since the 1930s, a sensation of im-pending doom has been attributed to the prodrome of symptoms leading to oraccompanying a diagnosis of pancreatic cancer.10 In patients with pancreatic cancer,affective symptoms may present even several months before the presence of cancer-related physical symptoms, suggesting that tumor-related changes in the neuroendo-crine system may lead to depression.11
In the general population, depression is more prevalent in women12 but depressionrates are similar in men and women diagnosed with cancer. In a review exploringgender differences, of five prevalence studies, two showed a greater prevalence ofdepression in female cancer patients and the other three did not show any evidenceof a gender difference.3,13,14 Due to limited evidence, it is still unclear whether ornot there are gender differences in prevalence or severity of depression in cancerpatients. If future research confirms a difference in depression prevalence associatedwith gender, exploration of the mechanisms contributing to this difference and ofgender-specific treatment options will be necessary.
DEPRESSION, BIOLOGY, AND PROGNOSIS
For many years, debate has centered on whether or not having depression is a riskfactor for developing cancer. The relationship between depression and the develop-ment of serious illnesses is well documented and seems to be reciprocal: chronicillness raises the risk of depression and depression and increases the risk of devel-oping diseases, such as diabetes and coronary artery disease.15–17
Many studies have explored the potential biologic alterations predisposing cancerpatients to depression. The association between dysfunction of the hypothalamic-pituitary-adrenal axis and depression has led to examination of high interleukin 6and low cortisol levels as potential measurable biomarkers for depression in cancerpatients.18 For example, researchers have demonstrated that circadian trends ofcortisol secretion vary in cancer patients with advanced disease. Additionally, stageIV breast cancer patients with greater quality of social support have lower cortisollevels, suggesting a neuroendocrine link. This inverse relationship may be related toa stress-buffering effect of social support, although methodologic limitations precludecausal conclusions.19 Researchers hypothesize that depression may have an adverseimpact on cancer mortality by altering cellular immune response and decreasingnatural killer cell activity.
The inverse relationship between depression and survival has also been observed inindividuals with other serious diseases. The presence of depression correlates withincreased mortality in patients who have had a recent stroke and patients who havesuffered a myocardial infarction or hip fracture.7,20,21
These data raise questions about depression’s impact on cancer mortality. A largeretrospective cohort study conducted in Denmark designed to explore the role ofdepression as a prognostic factor for breast cancer mortality concluded that breastcancer patients with depression necessitating psychiatric hospital admission hada modestly but significantly higher mortality rate than those who were not depressed.This effect varied with cancer staging and the timing of depression.22 A retrospectiveanalysis using Surveillance, Epidemiology and End Results (SEER) data and Medicare
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claims aimed to determine whether or not depression in elderly breast cancer patientsaffects diagnosis, treatment, and survival.23 Although depressed patients did not havea delay in cancer diagnosis, they were found to have higher risk for less definitive treat-ment and poorer survival. Drawing definitive conclusions from these data is hamperedby small sample size and the inevitable confounding of depression with other potentialpredictors of mortality, such as functional status. A study of patients with hepatobiliarycarcinoma found a relationship between depression and decreased survival rates.24
Depression has a negative impact on survival in patients 1 and 3 years after stemcell transplantation.25 Such studies underscore the importance of prompt diagnosisand treatment of major depression in cancer patients.
Although uncertainty persists, depression is negatively associated with cancersurvival. Changes in neuroendocrine function and in immune modulation may helpaccount for this observation.
ASSESSMENTAND DIAGNOSIS
Depression in patients with cancer, despite its high prevalence, is under-recognizedand therefore undertreated. As illustrated in Box 1, many factors contribute to physi-cians’ under-recognition and underdiagnosis of depression. A commonly cited reasonis the lack of a single screening tool that serves as a gold standard for accurate andprompt diagnosis of depression. In 2002, the United States Preventive ServicesTask Force and the National Institutes of Health recommended depression screeningfor all medical, cancer, and palliative care patients.26 These groups did not endorsea specific screening tool for physicians to use to make the diagnosis, however. TheAmerican College of Physicians recommends that clinicians assess depression (inaddition to pain and dyspnea) in patients with serious illness at the end of life.27 TheNational Comprehensive Cancer Network (NCCN) has developed guidelines to screenfor ‘‘distress,’’ including assessment of symptoms ranging from normal sadness todepression.28
The distinction between symptoms of normal sadness and grief and symptoms sug-gesting a diagnosis of depression has important clinical implications. Feelings ofsadness, shock, anger, and fear that may accompany a cancer diagnosis are normalreactive symptoms and typically resolve within 2 weeks. Such emotions may return atdifferent times during the progression of the disease course, including after learning oftreatment failure, relapse, or presence of metastases. Despite the presence of thesesymptoms, however, patients usually adapt to their situation, display resilience, andmove forward with their cancer care. These patients are often reassured by a clini-cian’s validation of their feelings. Mistakenly diagnosing depression and prescribingantidepressants puts patients at risk for unnecessary side effects and potential
Box1Barriers to diagnosing depression in cancer patients
Myth that all cancer patients are depressed
Difficulty distinguishing between depression and normal sadness
Misconception that depression is a normal part of the disease process
Symptoms of depression closely mirror physiologic symptoms of cancer
Clinicians’ fear of fully exploring psychologic symptoms at a vulnerable time for patients
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adverse drug reactions with antineoplastics and other medications used for symptommanagement.
According to the DSM-IV criteria, the diagnosis of major depressive disorder (MDD)is made if a patient has five or more symptoms for at least 2 weeks.29 The familiaracronym, SIGECAPS, prompts clinicians to inquire about increased or decreasedsleep, loss of interest, guilt, energy levels, concentration, appetite, psychomotor retar-dation, and suicidal ideation. The use of DSM-IV criteria alone may be less predictivein cancer patients because somatic symptoms so closely mirror physiologic manifes-tations of cancer.30
The reality of diagnosing depression in cancer patients is that more often than not,the symptoms are due to a combination of the cancer or its treatment and a majordepression. The type and stage of the cancer, treatment, existence of pain, func-tional status, and social support are only some of the additional issues that cancomplicate a physician’s recognition and diagnosis of depression.31 The presenceof pain illustrates another challenge that often confronts a clinician. Specifically,how does a clinician assess if the depressive symptoms are caused by the primarycancer, isolated depression, or a combination of both? Clinicians have to avoid theautomatic attribution of depressive symptoms to cancer. Conversely, the overlap ofsymptoms seen in medically ill patients can potentially lead to an overdiagnosis ofdepression.
Despite many available screening methods (Table 1), many clinicians do notroutinely screen for depression in cancer patients. One survey revealed that onlyhalf of palliative care medical staff used a screening study. Lack of time and an appro-priate focus on cancer-specific treatment contribute to oncologists’ under-recognitionof depression.32 Primary care physicians have an opportunity to contribute to cancerpatients’ care by recognizing and treating depression.
In an attempt to delineate which symptoms are attributable to medical conditions,such as cancer, and which symptoms are attributable to a major depression,researchers have characterized inclusive and exclusive approaches to diagnosis.33
The inclusive approach counts every depressive symptom whereas the exclusiveapproach excludes symptoms, such as fatigue, diminished appetite, and decreasedconcentration. These somatic symptoms can be attributed to a neoplasm or its treat-ment. In the exclusive approach, a clinician assigns only nonsomatic symptoms, suchas hopelessness, guilt, and suicidal ideation, to a possible diagnosis ofdepression.31,33
Another approach to assessing depression is to apply a risk factor profile to cancerpatients to identify those individuals who are at increased risk of having depression.Young age, low socioeconomic status, social isolation, substance abuse, pastdepression or suicide attempt, advanced stage of disease, complex or toxic chemo-therapy or radiation regimens, presence of significant symptoms, and high level ofdisability or functional impairment are all factors known to increase risk of depres-sion.31 Table 2 highlights risk factors for depression in cancer patients. If patientsexhibit depressive symptoms and possess any of these factors, a clinician shouldmore thoroughly investigate for depression.
Brief depression screening tools are preferable in cancer patients, especially forthose who have poor performance status. To improve the efficiency of diagnosis, ultra-short methods of depression screening have been studied in the clinical setting. Thedistress thermometer is the main distress management measure recommended bythe NCCN.34 This is a visual-analog scale, much like Wong-Baker FACES pain ratingscale, in which patients circle a number that corresponds to their distress experiencedin the past week, with 0 reflecting no distress and 10 extreme distress. A systemic
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literature review of 38 ultrashort screening analyses conducted in cancer settingsconcluded that tools, such as the distress thermometer, have a high accuracy for rulingout mood disorders but are not as effective as ruling in a diagnosis of depression,anxiety, or distress in cancer patients.34
Hoffman and Weiner offer a useful two-question screening method to aid busy clini-cians35: ‘‘Have you been feeling down, depressed, or hopeless in the last month’’ and‘‘Have you been bothered by little interest or pleasure in doing things?’’ If patientsanswer yes to both or yes to the first question and their daily function is affected,then further investigation by DSM-IV assessment or referral to a mental healthspecialist is recommended.
Some studies have found that a single-question interview was just as likely touncover depression as a longer-item questionnaire. The single question, ‘‘Do youoften feel sad or depressed?’’ has been demonstrated to be as accurate in identifyingdepression as the 30-item geriatric depression scale.36 Similarly, Chochinov andcolleagues37 reported that the single question, ‘‘Are you depressed?’’ can be a reliablescreen. Ohno and colleagues38 found that patients who answered ‘‘neither’’ to thesingle-question interview, ‘‘Are you depressed or not?’’ are depressed. A significantnumber of patients who answered ‘‘neither’’ scored 11 or more on the Hospital Anxietyand Depression Scale, indicating depression.38
Clinicians can be overwhelmed by the vast number of available screening tools fordepression. Inquiring about depression frequently and implementing a screening toolthat is suitable for the practice and can be completed by a clinician or patient in a timelymanner can provide a great service to cancer patients.
TREATMENTPharmacologic: General Principles
As emerging data negate the notion that depression is inevitable in cancer patients,more attention has focused on its treatment. Unfortunately, there is a paucity ofrandomized clinical trials of treatment for depression in cancer patients. Currently,whether or not pharmacologic or psychotherapeutic treatments are more effectiveremains unclear and no guidelines recommend one approach over another.
Pain and other reversible physical symptoms should be treated before initiationof antidepressant therapy. Additionally, clinicians should investigate possiblereversible organic causes of depression. Once a diagnosis of depression is estab-lished in a cancer patient, therapy should be tailored specifically for the individual.The principles of treatment with antidepressant medication should be the same asin other patients. Selective serotonin reuptake inhibitors (SSRIs) are preferredfirst-line agents due to their general tolerability and wide margin of safety.39 Atten-tion to possible side effects of antidepressants is essential for cancer patients.Specifically, clinicians must be mindful of the proemetic effects of SSRIs andthe anticholinergic side effects of tricyclic antidepressants. Table 3 highlights thecommonly used antidepressant classes for use in cancer patients and dosagesand efficacy data.
Awareness of potential interactions between common cancer treatments and anti-depressants can aid in treatment of depression. Antidepressants from the SSRI andserotonin-norepinephrine reuptake inhibitors (SNRI) classes are known CYP2D6(a gene in the cytochrome P450 system) enzyme inhibitors commonly prescribed totreat hot flashes in women who take tamoxifen. The interaction of these medicationsmay result in altered tamoxifen metabolism and decreased formation of the metabo-lite, endoxifen, thereby adversely affecting cancer treatment outcomes. Currently, for
Table 1Common screening instruments for diagnosis of depression in cancer patients
Year DevelopedScreeningMethod(Number of Items) Components Comments Literature
1960 (reviewed,reevaluated in1966, 1967,1969, and 1980)
HAM-D (21) Clinician-administeredmultiple choice
Often effectivein monitoringtreatment
Modified HAM-D scale, usingitems insomnia, agitation,anxiety, diurnal variation,depressed mood, and genitalsymptoms; more sensitive andspecific for MDD in cancerpatients than HADS.33 Not yetvalidated.
1979 Montgomery-AsbergDepression RatingScale (10)
Clinician administered Scored from 0–6 Found to be more effective thanHADS in identifying depressionin lung cancer patients.67
1983 HADS (14 total: 7depression, 7 anxiety)
Self-administered, Likert, 4-pointscale rating symptoms ofdepression or anxiety
Score of 11 or greaterindicates depressionor anxiety
Created for inpatient but reliablein other settings.68
1987 Edinburgh DepressionScale (10)
Excludes somatic symptomsQuestions on worthlessness,
sadness, and suicidal ideation
Originally developedas screening test forpostnatal depression69
Modified six-item brief versionmore effectively identifiesdepression in cancer patients.70
1991 Edmonton SymptomAssessment Scale (9)
Self-administered, 9-item, visualanalog used for symptomassessment in palliative carepopulation; 10th symptom maybe added as ‘‘other’’ by patient
Include symptom assessmentof depression in additionto physical symptoms
Emotional symptoms are poorlycaptured by items specific todepression and anxiety.71
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1994 BCD (4) ‘‘Over the past coupleof weeks, have you:
A. Been having restlessor disturbed nights?
B. Been feeling unhappyor depressed?
C. Felt unable to overcomeyour difficulties?
D. Been dissatisfied withthe way you’ve beendoing things?’’
Probable depression if answeris yes at least one of A andB and ne of C and D
Recognized depression moreoften than the HADS, BDI, andPrimary Care Evaluation ofMental Disorders in oncologypatients.72
1996 BDI II (21) Self-administered; questions focuson psychologic and physicalsymptoms
Identified 15% of radiation-oncology patients who haddepressive symptoms using thistool. Somatic symptoms of lossof energy/fatigue were mostcommon.73
Abbreviations: BCD, Brief Case-Find for Depression; BDI, Beck Depression Inventory; HADS, Hospi l Anxiety and Depression Scale; HAM-D, Hamilton DepressionScale.
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Table 2Risk factors for depression in cancer patients
Genetic factors First-degree relative with depressionPrior personal history of depression
Environmental factors Loss of friends who have died of cancerSocial isolationSocioeconomic factors, such as job loss and
Cancer related Advance stagingBrain metastasesUncontrolled pain
Data from Jackson CW, Jackson KH. Comorbid depression in adult oncology. J Pharm Pract2007;20:360–7.
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depressed breast cancer patients on tamoxifen, choosing venlaxafine or citalopram isrecommended, as they are unlikely to interact with tamoxifen.40
PSYCHOSTIMULANTS
In addition to the challenges (discussed previously) of treating depression in cancerpatients, individuals with short survival time may not benefit from antidepressanttherapy.41 SSRIs and tricyclics may not be beneficial because of the lag time beforedepressive symptoms improve with these medications. An alternative option inpatients with depression and a short life expectancy of less than 1 month is the useof psychostimulants, specifically methylphenidate. Psychostimulants act centrally,have a rapid onset of action (between 1–7 days) and are generally well tolerated.The potential benefits of psychostimulants in patients with terminal illness are multi-faceted. These drugs can elevate mood, potentiate analgesic effect of opioids,counter sedation secondary to opioid therapy, stimulate appetite, and improve cogni-tion.42 Methlyphenidate has been studied in several nonrandomized trials and demon-strated to have a role in improving depression symptoms in cancer patients. The mostfavorable response was reported from a retrospective study evaluating 59 hospital-ized cancer patients with depression who were treated with methylphenidate or dex-amphetamine, 73% of whom showed moderate or marked improvement, mostlyoccurring within 2 days of starting therapy.43
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The starting dose for the short-acting preparations of methylphenidate is 5 to 10 mgdaily. This can be titrated to a maintenance dose of 20 mg daily divided into 2 to 3 dailydoses due to its short half-life. For elderly or fragile patients, clinicians may opt to startwith a 2.5 mg daily dose. Lack of response after a dose of 20 mg is reached may beconsidered a treatment failure. The most common side effects are insomnia and rest-lessness, which can be reduced by administering the last dose before 4 pm.44
ROLE OFANTIDEPRESSANTS IN CANCER PATIENTS LACKINGMAJOR DEPRESSION
Although MDD is considered treatable even in patients with a life-limiting cancer, it isuncertain whether or not treatment of depressive symptoms that do not fulfill criteria ofMDD yields clinical benefit. The Zoloft’s Effects on Symptoms and Survival Time Trial,a randomized controlled trial conducted over approximately 5 years, aimed to identifythe effects of antidepressant therapy on patients with advanced cancer and withdepressive symptoms not meeting the criteria for MDD.45 Because the use of sertra-line in this study did not improve symptoms, well-being, or survival in patients withadvanced cancer who did not have major depression, treatment with a SSRI shouldbe reserved for proved indications. Previous proved indications for SSRIs in patientswith cancer include treatment of major depression in cancer patients, prevention ofmajor depression during treatment with high-dose interferon, and treatment of hotflashes.46,47
PSYCHOTHERAPY
Nonpharmacologic treatment is postulated to help cancer patients and their familiesdevelop stronger coping skills. Studies of the use of psychotherapy for depressionin cancer patients have yielded mixed results. Findings from several systematicreviews investigating the effectiveness of psychologic treatment are conflicting.Jacobsen and Jim1 recently reviewed 14 systematic reviews and meta-analyses ofpsychosocial interventions for anxiety or depression in adult cancer patients. Ninepublications reported positive results regarding the efficacy of psychosocial interven-tions for depression in cancer patients. A recent Cochrane review found cancerpatients with depressive symptoms had a better response to psychotherapy thanpatients with clinically diagnosed depression.48 A systematic review of treatment forcancer patients with depression found limited evidence to support the efficacy ofpsychotherapy. Seven small trials, however, found cognitive behavioral therapy effec-tive in reducing depressive symptoms with persistent improvement up to a year aftertherapy, highlighting a need for future research and adequately powered studies.49
In addition to the value of conventional treatment for depression, recent studieshave explored the utility of a collaborative care model. The randomized SymptomManagement Research Trial in Oncology (SMaRT) included 200 patients at a regionalcancer center in Scotland.50 Inclusion criteria included a cancer prognosis of greaterthan 6 months and a diagnosis of MDD using the Hospital Anxiety and DepressionScale questionnaire and a telephone interview using the Diagnostic and StatisticalManual of Mental Disorders, Fourth Edition (DSM-IV) criteria. Exclusion criteriaincluded patients who were receiving or were thought to require specialist psychiatristcare. Patients were randomized to receive usual care or usual care plus the interven-tion. The intervention was delivered by a cancer-trained nurse who had no previouspsychiatric training. During the course of seven (average number) sessions, patientslearned problem-solving skills to overcome helplessness and discussed their depres-sion and its treatment. Ongoing communication was maintained between a nurse,oncologist, and primary care physician. Reduction of depressive symptoms was
Table 3Summary of common antidepressants used in cancer patients
Drug Class and Agents Dosages Drug-Drug Interactions Comments Efficacy DataSSRIs: fluoxetine,
Extra caution in elderly andin advanced cancerpatients with fluoextine,paroxetine, andfluvoxamine
Fluoxetine may take up to 6weeks to reach steady state
Many SSRIs (fluoxetine,citalopram, paroxetine,and sertraline) come inliquid forms
Fluoxetine: shown in tworandomized controlledtrials to improve quality oflife and reduce depressivesymptoms in cancerpatients.74,75
Paroxetine: significantreduction of depressionprevalence and severity ofsymptoms in randomizedcontrolled trial of patientswith melanoma receivinginterferon.47
Citalopram: smallrandomized controlledtrial concludedprophylactic use (afterdiagnosis of head and neckcancer) may reduceincidence of depressionduring treatment of headand neck cancer.76
SNRIs: venlaxafineand duloxetine
Venlaxafine: initial 18.75–37.5 mg before noon, twicea day; maximum 225 mgdaily
Duloxetine: initial 10–20 mgdaily or twice a day;maximum 60 mg daily
Not likelyNot likely
Dose-dependent risk ofhypertension (>150 mg)
Reduction of hot flashes inbreast cancer patients.46
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Noradrenergic and specificserotonergicantidepressant:mirtazapine
Mirtazapine: initial7.5–15 mg every night;maximum 45 mg everynight
Not likely Adverse effects of increasedsleep and appetite may bebeneficial in select patients
Available in dissolving form
Antagonistic effect on 5-HT3receptors beneficial insymptoms of nausea andfatigue in cancer patientswith depression.77
Atypical antidepressant Trazodone: initial 25–50 mgdaily; maximum up to 400–600 mg
Very likely Sedating; may be desirableeffect in depressed patientswith insomnia
Caution in male patients:may cause priapism
Not a statistically significantresponse in loweringsymptoms on ClinicalGlobal Impression Scalealthough dose in trial wasless than typical dose totreat depression.78
Amitriptyline andimipramine: initial 25 mgdaily; maximum 300 mgdaily
Very likely Adverse effects may includeanticholinergic symptoms,postural hypotension,sedation, and cardiacarrhythmias
Trial of imipramine showed80% improvement ofsymptoms versusplacebo.79
Superior effect ofdesipramine overfluoxetine in women withadvanced cancer.75
Study concludingamitriptyline improvesneuropathic pain alsoevaluated efficacy fordepression and showed noimprovement.80
a Specific risk of interaction with drugs frequently administered to cancer patients: phenytoin, carbamazepine, nonsteroidal anti-inflammatory drugs, antivitaminK, or 5-HT3 antagonists.
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observed after 3 months. Additionally, the treatment effect was sustained at 6 and 12months. The intervention group reported improved anxiety and fatigue but not painand physical functioning compared with the cohort in the usual care arm of the study.The findings suggest that this cost-effective program may be potentially feasible.50
CANCER AND SUICIDE
In addition to depression, the desire of hastened death is also prevalent in patientsdiagnosed with terminal cancer. In a study designed to determine factors predictingpatient preference for hastening death, depression and hopelessness were foundthe two biggest factors.51 Another study identified associations between depression,hopelessness, and suicidal ideation.52
Recently, three studies reviewing suicide trends in the cancer population shed lighton the depth of suffering many cancer patients endure. One studied demonstratedthat the incidence of suicide (31.4 per 100,000 person-years) in patients with canceris approximately double that in the general population. Patients with increased riskof suicide are white, male, and older at the time of diagnosis. The highest suicide ratesare among patients diagnosed with lung, stomach, oral/pharyngeal, and laryngealcancers.53 The risk of suicide was greatest within the first 5 years after cancer diag-nosis but remained elevated for up to 15 years. Another study conducted in cancerpatients over age 65 concluded suicide risk was 2.3 times higher in cancer patientsthan those without cancer. This increased risk persisted even after researchersadjusted for age, gender, race, medical and psychiatric illnesses, and use of prescrip-tion medications. The study patients who committed suicide were more likely to havemetastatic disease and most of them had seen a physician in the month before theirdeath; 25% of them had seen a physician with a week before their suicide. Two thirdsof the patients used a firearm to commit suicide.54 A third study found that cancerpatients receiving outpatient care were nearly four times more likely to have hadsuicidal thoughts in the 2 weeks before being surveyed than patients without a cancerdiagnosis. Additionally, the study demonstrated an association between suicide riskand emotional distress and pain but not necessarily with cancer severity.55
Increased risk of suicide in cancer patients is associated with general risk factors orwith cancer-specific risk factors. General risk factors include a personal history ofdepression or other psychiatric illness of psychiatric disorders, family history ofsuicide, history of prior suicide attempts, few social supports, recent loss of a friendor spouse, and a history of substance abuse. Cancer-specific risk factors includethe type of cancer, advanced stage of cancer at the time of diagnosis, treatmentcontraindications and surgeries that are unable to be performed, poorly controlledpain, delirium, and loss of functionality. A gender-comparative study, using a popula-tion-based analysis from the SEER program, concluded that men with cancer are athigher risk of committing suicide than women. Race and ethnicity are shown tohave an influence on suicide risk in cancer patients, with a decreased risk in AfricanAmericans, a statistic that mirrors the risk in the general population.56,57 Their averageage of completed suicide, however, is approximately a decade younger than that ofwhites.
A greater understanding of the risk of suicide in cancer patients can empower clini-cians to explore patients’ risk for suicide at key transition points, such as diagnosis,recurrence, or changes in therapeutic goals. Quill and Cassel,58 in a discussion ofthe concept and obligation of ‘‘physician nonabandonment,’’ encourage physiciansto explicitly discuss patient fears, including inquiring about any suicidal thoughts.Patients often may be reassured by clinicians who engage in such discussions.
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DEPRESSION IN CAREGIVERS
An indirect result of the trend toward improved cancer survival is the impact it has onthe caregivers of cancer patients. More family members are assuming the role of theprimary caregiver and the corresponding burden of this has increasingly becomea topic of interest. Frequently, a spouse becomes the primary caregiver and withthis role comes a risk of emotional distress that may be as high, if not higher, thanthat experienced by a cancer patient.59 Caregivers who are more likely to sufferfrom depression have the following attributes: female gender, spousal relationship,older age, poorer health, and caring for a patient with advanced disease.60 In a studyof patients with advanced cancer of the gastrointestinal tract or lung and their spousecaregivers (two thirds were women), researchers found that approximately 39% ofcaregivers had significant symptoms of depression compared with 23% of their illspouses. Spouse caregivers who had the greatest risk of depression were thosewho were very attached to their spouse and were anxious about losing him or her.61
Comprehensive care for cancer patients’ caregivers is important not only for care-givers’ wellbeing but also because the presence of a supportive caregiver, in particulara spouse, is associated with positive effects for the patients themselves.62
PEDIATRIC CANCER
There are few data on the impact, prevalence, and diagnosis of depression in pediatriccancer patients. Therefore, guidelines to aid clinicians in treatment are lacking. A studyaimed at identifying the prevalence of antidepressant use in children with cancer indi-rectly estimated prevalence of depression in this population. A 10.2% prevalence issignificantly higher than that found in the general pediatric population (4%–8%).63
Concern about depression’s impact on treatment compliance and medical outcomesalso apply to the pediatric population. As in adult depression, it is important to distin-guish normal sadness that is transitory from irritability, insomnia, lack of self-esteem,anorexia, and poor social/school adjustment, which may signify depression. WhereasSSRIs are often first-line antidepressants in the adult general and cancer population,the benefit/risk profile is not as favorable in children and adolescents due a lack oftrials studying SSRIs in the pediatric cancer population and controversies surroundingsuicidal ideation in children taking antidepressants.64 Trials of antidepressants in pedi-atric cancer patients have shown favorable results with tricyclic antidepressants andshort-term use of benzodiazepines.65,66
Components of psychotherapy may include individual and group therapy, playtherapy, and special consideration of developmental stages. Care should be multidis-ciplinary and also often include family members Given the complexity of treatment ofdepression in the pediatric cancer population, it is advisable to consult a mental healthspecialist to help direct treatment options.
SUMMARY
Primary care clinicians who care for cancer patients are integral to the recognition,diagnosis, and management of depression in this population. A review of risk factorsthat may make patients more likely to develop depression can be a useful first step inscreening for depression. Several screening instruments may guide clinicians infurther work-up of patients suspected of being depressed. Depression is treatablein this patient population and prompt management may have a positive impact onoverall outcomes. Pharmacologic and psychotherapeutic treatment options arenumerous, and consideration of specific cancer treatments, including side-effect
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profiles, patient comorbidity, patient preference, and clinician resources, should directmanagement.
REFERENCES
1. Jacobsen P, Jim H. Psychosocial interventions for anxiety and depression in adultcancer patients: achievements and challenges. CA Cancer J Clin 2008;58:214–30.
2. Pirl W, Roth A. Diagnosis and treatment of depression in cancer patients.Oncology 1999;13(9):1293–301.
3. Pirl W. Evidence report on the occurrence, assessment and treatment of depres-sion in cancer patients. J Natl Cancer Inst Monogr 2004;32:32–9.
4. Massie MJ. Prevalence of depression in patients with cancer. J Natl Cancer InstMonogr 2004;32:57–71.
5. Jackson CW, Jackson KH. Comorbid depression in adult oncology. J Pharm Pract2007;20:360–7.
6. House A, Dennis M, Magridge L, et al. Mood disorders in the first year afterstroke. Br J Psychiatry 1991;158:83–92.
7. Morris PL, Robinson RG, Andrzejewski P, et al. Association of depression with 10-year poststroke mortality. Am J Psychiatry 1993;150(1):124–9.
8. Mallik S, Krumholz HM, Lin ZQ, et al. Patients with depressive symptoms havelower health status benefits after coronary artery bypass surgery. Circulation2005;111:271–7.
9. Schleifer SJ, Macari-Hinson MM, Coyle DA, et al. The nature and course ofdepression following myocardial infarction. Arch Intern Med 1989;149:1785–9.
10. Makrilia N, Indeck B, Syrigos K, et al. Depression and pancreatic cancer andcancer: a poorly understood link. JOP J Pancreas (Online) 2009;10(1):69–76.
11. Boyd AD, Riba M. Depression and pancreatic cancer. J Natl Compr Canc Netw2007;5(1):113–6.
12. Kornstein SG. The evaluation and management of depression in women acrossthe life span. J Clin Psychiatry 2001;62(Suppl 24):11–7.
13. Miaskowski C. Gender differences in pain, fatigue, and depression in patientswith cancer. J Natl Cancer Inst Monographs 2004;32:139–43.
14. DeFlorio ML, Massie MJ. Review of depression in cancer: gender differences.Depression 1995;3:66–80.
15. Kravitz RL, Ford DE. Introduction: chronic medical conditions and depression-theview from primary care. Am J Med 2008;121(11 Suppl 2):S1–7.
16. Wagner J, Allen N, Melkus D, et al. Depression treatment and insulin sensitivity inadults at risk for type 2 diabetes [abstract]. American Diabetes Association: 69thscientific sessions. June, 2009.
17. Frasure-Smith N, Lesperance F, Irwin MR, et al. Depression, C-reactive proteinand two year major adverse cardiac events in men after acute coronarysyndromes. Biol Psychiatry 2007;62(4):302–8.
18. Jehn CF, Kuehnhardt D, Bartholomae A, et al. Biomarkers of depression in cancerpatients. Cancer 2006;107(11):2723–9.
19. Turner-Cobb JM, Sephton SE, Koopman C, et al. Social support and salivarycortisol in women with metastatic breast cancer. Psychosom Med 2000;62:337–45.
20. Ariyo AA, Haan M, Tangen CM, et al. Depressive symptoms and risks of coronaryheart disease and mortality in elderly Americans. Cardiovascular Health StudyCollaborative Research Group. Circulation 2000;102(15):1773–9.
Depression in Cancer Patients 717
21. Holmes J, House A. Psychiatric illness predicts poor outcome after surgery forhip fracture: a prospective cohort study. Psychol Med 2000;30:921–9.
22. Hjerl K, Andersen E, Kieding N, et al. Depression as a prognostic factor for breastcancer mortality. Psychosomatics 2003;44:24–30.
23. Goodwin J, Zhang D, Ostir G. Effect of depression on diagnosis, treatment, andsurvival of older women with breast cancer. J Am Geriatr Soc 2004;52(1):106–11.
24. Steel J, Geller D, Gamblin C, et al. Depression, immunity, and survival in patientswith hepatobiliary carcinoma. J Clin Oncol 2007;25:2397–405.
25. Prieto JM, Atala J, Blanch J, et al. Role of depression as a predictor of mortalityamong cancer patients after stem-cell transplantation. J Clin Oncol 2005;23(25):5878–80.
26. Robinson J, Crawford G. Identifying palliative care patients with symptoms ofdepression: an algorithm. Palliat Med 2005;19:278–87.
27. Qaseem A, Snow V, Shekelle P, et al. Evidence-based interventions to improvethe palliative care of pain, dyspnea, and depression at the end of life: a clinicalpractice guideline from the American College of Physicians. Ann Intern Med2008;148(2):141–6.
28. National Comprehensive Cancer Network Clinical Practice Guidelines inOncology. Guildelines for supportive care. Available at: http://www.nccn.org/professionals/physician_gls/f_guidelines.asp. Accessed June 29, 2009.
29. American Psychiatric Association. Diagnostic and statistical manual of mentaldisorders. 4th edition. Washington, DC: American Psychiatric Association; 1994.
30. Simon GE, Von KM. Medical co-morbidity and validity of DSM 1V depressioncriteria. Psychol Med 2006;36:27–36.
31. Schwenk T. Cancer and depression. Primary Care: Clinics in Office Practice1998;25(2):505–13.
32. Smith G, Toonen T. Primary care of the patient with cancer. Am Fam Physician2007;75(8):1207–14.
33. Guo Y, Musselman D, Mantunga A, et al. The diagnosis of major depression inpatients with cancer: a comparative approach. Psychosomatics 2006;47(5):376–84.
34. Mitchell A. Pooled results from 38 analyses of the accuracy of distress thermom-eter and other ultra-short methods of detecting cancer-related mood disorders.J Clin Oncol 2007;25(29):4670–81.
35. Hoffman M, Weiner J. Is Mrs. S depressed? Diagnosing depression in the cancerpatient. J Clin Oncol 2007;25(19):2853–6.
36. Mahoney J, Drinka TJK, Abler R, et al. Screening for depression: single questionversus GDS. J Am Geriatr Soc 1994;9:1006–8.
37. Chochinov HM, Wilson KG, Enns M, et al. ‘‘Are you depressed?’’ Screening fordepression in the terminally ill. Am J Psychiatry 1997;154:674–5.
38. Ohno T, Noguchi W, Nakayama Y, et al. How do we interpret the answer ‘‘neither’’when physicians ask patients with cancer ‘‘are you depressed or not?’’ J PalliatMed 2006;9(4):861–5.
39. Mulrow CD, Williams JW Jr, Chiquette E, et al. Efficacy of newer medications fortreating depression in primary care patients. Am J Med 2000;108(1):54–64.
40. Henry NL, Stearns V, Flockhart DA, et al. Drug interactions and pharmacogenom-ics in the treatment of breast cancer and depression. Am J Psychiatry 2008;165:1251–5.
41. Shimizu K, Akechi T, Shimamoto M, et al. Can psychiatric intervention improvemajor depression in very near end-of-life cancer patients? Palliat Support Care2007;5:3–9.
42. Jackson V, Block S. Psychostimulants in palliative care. Facts Facts and Concept#61: 2002. End-of-Life/Palliative Education Resource Center. Available at: www.eperc.mcw.edu.
43. Olin J, Masand P. Psychostimulants for depression in hospitalized cancerpatients. Psychosomatics 1996;37(1):57–62.
44. Sood A, Barton DL, Loprinzi CL. Use of methylphenidate in patients with cancer.Am J Hosp Palliat Care 2006;23:35–40.
45. Stockler M, O’Connell R, Nowak A, et al. Effect of sertraline on symptoms and survivalin patients with advanced cancer, but without major depression: a placebo-controlled double-blind randomised trial. Lancet Oncol 2007;8(7):603–12.
46. Loprinzi CL, Kugler JW, Sloan JA, et al. Venlafaxine in management of hot flashesin survivors of breast cancer:a randomized controlled trial. Lancet 2000;356:2059–63.
47. Musselman DL, Lawson DH, Gummick JF, et al. Paroxetine for the prevention ofdepression induced by high-dose interferon alfa. N Engl J Med 2001;344:961–6.
48. Akechi T, Okuyama T, Onishi J, et al. Psychotherapy for depression among incur-able cancer patients. Cochrane Database Syst Rev 2008;(2). Art. No.:CD005537.
49. Williams S, Dale J. The effectiveness of treatment for depression/depressivesymptoms in adults with cancer: a systematic review. Br J Cancer 2006;94:372–90.
50. Strong V, Waters R, Hibberd C, et al. Management of depression for people withcancer (SMaRT oncology 1): a randomized trial. Lancet 2008;372:40–8.
51. Breitbart W, Rosenfeld B, Pessin H, et al. Depression, hopelessness, and desirefor hastened death in terminally ill patients with cancer. JAMA 2000;284:2907–11.
52. Chochinov HM, Wilson KG, Enns M, et al. Depression, hopelessness, andsuicidal ideation. Psychosomatics 1998;39:366–70.
53. Misono S, Weiss NS, Fann JR, et al. Incidence of suicide in persons with cancer.J Clin Oncol 2008;26(29):4731–8.
54. Miller M, Mogun H, Azrael D, et al. Cancer and the risk of suicide in older Amer-icans. J Clin Oncol 2008;26(29):4720–4.
55. Walker J, Waters RA, Murray G, et al. Better off dead: suicidal thoughts in cancerpatients. J Clin Oncol 2008;26(29):4725–30.
56. Kendal WS. Suicide and cancer. Ann Oncol 2007;18:381–7.57. Garlow SJ, Purselle D, Heninger M. Ethnic differences in patterns of suicide
across the life cycle. Am J Psychiatry 2005;162:319–23.58. Quill TE, Cassel CK. Nonabandonment: a central obligation for physicians. Ann
Intern Med 1995;122:368–74.59. Vanderwerker LC, Laff RE, Kaden-Lottick NS, et al. Psychiatric disorders and
mental health service use among caregivers of advanced cancer patients.J Clin Oncol 2005;23:6899–907.
60. Rhee YS, Yun YH, Park S, et al. Depression in family caregivers of cancerpatients: the feeling of burden as a predictor of depression. J Clin Oncol 2008;26:5890–5.
61. Braun M, Mikulincer M, Rydall A, et al. Hidden morbidity in cancer: spouse care-givers. J Clin Oncol 2007;25:4829–34.
62. Northouse LL, Templin T, Mood D. Couples adjustment to breast disease duringthe first year following diagnosis. J Behav Med 2001;24:115–36.
63. Portteus A, Ahmad N, Tobey D, et al. The prevalence and use of antidepressantmedication in pediatric cancer patients. J Child Adolesc Psychopharmacol 2006;16(4):467–73.
64. U.S. Food and Drug Administration. Antidepressant use in children, adolescents,and adults. Rockville (MD): Food and Drug Administration, Center for Drug Eval-uation and Research; 2007.
65. Pfefferbaum-Levine B, Kumor K, Cangir A, et al. Tricyclic antidepressants for chil-dren with cancer. Am J Psychiatry 1983;140(8):1074–6.
66. Coffey BJ. Review and update: benzodiazepines in childhood and adolescence.Psychiatr Ann 1993;23(6):332–9.
67. Neron S, Correa JA, Dajczman E, et al. Screening for depressive symptoms inpatients with unresectable lung cancer. Support Care Cancer 2007;15:1207–12.
68. Block SD. Assessing and managing depression in the terminall ill patient. ACP-ASIM End-Of-Life Care Consensus Panel. American college of Physicians-Amer-ican Society of Internal Medicine. Ann Intern Med 2000;132:209–18.
69. Cox JL, Holden JM, Sagovsky R. Detection of postnatal depression. Develop-ment of the 10-item Edinburgh Postnatal Depression Scale. Br J Psychiatry1987;150:782–6.
70. Lloyd-Williams M, Shiels C, Dowrich C, et al. The development of the Brief Edin-burgh Depression Scale (BEDS) to screen for depression in patients withadvanced cancer. J Affect Disord 2007;99:259–64.
71. Richardson LA, Jones GW. A review of the reliability and validity of the edmontonsymptom assessment system. Curr Oncol 2009;16(1):53–64.
72. Jefford M, Mileshkin L, Richards K, et al. Rapid screening for depression—valida-tion of the brief case-find for depression (BCD) in medical oncology and palliativecare patients. Br J Cancer 2004;91:900–6.
73. Hahn C, Dunn R, Halperin EC, et al. Routine screening for depression in radiationoncology patients. Am J Clin Oncol 2004;27(5):497–9.
74. Fisch MJ, Loehrer PJ, Kristeller J, et al. Fluoxetine versus placebo in advancedcancer outpatients: a double-blinded trial of the Hoosier Oncology Group.J Clin Oncol 2003;21(10):1937–43.
75. Holland JC, Romano SJ, Heiligenstein JH, et al. A controlled trial of fluoxetine anddesipramine in depressed women with advanced cancer. Psychooncology 1998;7:291–300.
76. Lydiatt W, Denman D, McNeilly D, et al. A randomized, placebo-controlled trial ofcitalopram for the prevention of major depression during treatment for head andneck cancer. Arch Otolaryngol Head Neck Surg 2008;134(5):528–35.
77. Kim SW, Shin IS, Kim JM, et al. Effectiveness of mirtazapine for nausea andinsomnia in cancer patients with depression. Psychiatry Clin Neurosci 2008;62:75–83.
78. Razavi D, Kormoss N, Collard A, et al. Comparative study of the efficacy andsafety of trazodone versus clorazepate in the treatment of adjustment disordersin cancer patients: a pilot study. J Int Med Res 1999;27:264–72.
79. Purohit DR, Naviakha PL, Modi RS, et al. The role of antidepressants in hospital-ized cancer patients. J Assoc Physicians India 1978;26:245–8.
80. Eija K, Tiina T, Pertti NJ. Amitriptyline effectively relieves neuropathic painfollowing treatment of breast cancer patients. Pain 1996;64:293–302.
