Area Abbonati
LoginPassword
doi   10.1700/1377.15313
Tumori 2013;99(5):623-633



Treatment of depression in patients with breast cancer:
a critical review

Antonio Callari1, Mauro Mauri1, Mario Miniati1, Maricia Mancino2,
Giulia Bracci
1,3, Liliana Dell’Osso1, and Carlo Greco2
1Department of Clinical and Experimental Medicine, Section of Psychiatry, and 2Department of
Radiotherapy, University of Pisa, Pisa, Italy;
3Department of Psychiatry, Columbia University Division of Molecular Imaging and Neuropathology, New York State Psychiatric Institute, New York, NY, USA

Key words: antidepressants, breast cancer, depression treatment, psychotherapy.

Acknowledgments: The authors gratefully acknowledge the assistance of Dr Giulia Gray of the University of Pisa, Italy, for the English revision.

Conflict of interest: The authors have no conflict of interest.

Correspondence to: Maricia Mancino, MD, Department of Radiotherapy, University of Pisa School of Medicine, 57 Roma Street, 56100 Pisa, Italy.
Tel +39-050-992829;
fax +39-050-992960;
email ma.mancino@ao-pisa.toscana.it

Received October 6, 2012;
accepted May 3, 2013.

abstract

Aims and background. To summarize current knowledge on psychopharmacological and psychotherapeutic options for patients with breast cancer and comorbid depression, starting from the psychiatric viewpoint. Issues on diagnostic boundaries of depression and outcome measures are raised.
Methods. We completed a literature review from the last 30 years (until March 2012) using PubMed by pairing the key words: ‘breast cancer and depression treatment’ (about 1431 works, including 207 reviews), ‘breast cancer and antidepressants’ (about 305 works, including 66 reviews), and in particular ‘selective serotonin reuptake inhibitors and breast cancer’ (38 works, including 10 reviews) and ‘breast cancer and psychotherapy’ (603 works, including 84 reviews). Papers in the English language were selected, including recent reviews.
Results. There is little evidence for the superiority of any one specific intervention with pharmacological options or psychotherapy. The heterogeneity of assessment criteria, the small number of subjects collected in systematic studies, the difficulty in adopting standardized outcome measures, and the limited numbers of available drugs with a favorable side effect profile are the main limitations that emerge from the literature. No conclusive findings are available on mid-term/long-term treatment strategies, or when depression is part of a bipolar disorder.
Conclusions. Further research is necessary to define the most appropriate approach to depression when it occurs in comorbidity with breast cancer. A more accurate definition of the clinical phenotypes of depression in the special population of patients with breast cancer is suggested as a key issue.
Introduction
Breast cancer is the most common malignant disease among women. The incidence of breast cancer in the USA in 2011 was 226,870 new cases1. Diagnosis and treatment of breast cancer are still associated with a negative stigma. Signs and symptoms of depression, such as a high level of distress, demoralization, fatigue, sadness and hopelessness, are present in more than 40% of subjects with breast cancer2. Moreover, the prevalence of a major depressive episode (MDE) in patients with breast cancer ranges from 10 to 25%3. Several research lines have addressed topics related to the occurrence of depression in breast cancer: depression might be a complication of cancer, a direct consequence of physical suffering, or a comorbid condition between two disorders commonly reported in the general population4-8. Chemotherapy, including long-term prophylaxis with tamoxifen, might be associated with a higher risk of developing depressive symptoms and cognitive dysfunctions9-15. Moreover, depressive symptomatology might interfere with patients’ compliance with cancer treatment8,16,17.
Given that, the importance of accurate detection and treatment of depression in patients with breast cancer is widely accepted. Previous reviews have addressed this clinical area appropriately3. However, even if new knowledge has accumulated in recent years, several questions on treatment strategies remain unanswered.
The aim of the present review is to summarize current knowledge on psychopharmacological and psychotherapeutic options for patients with breast cancer and comorbid depression, starting from the psychiatric viewpoint. Methodological issues regarding experimental study designs, diagnostic boundaries of depression and outcome measures are raised.
Methods
We searched the literature using the database of the US National Center for Biotechnology Information (NCBI)-MedLine/Pubmed system. We considered published research reports related to treatment of depression in patients with breast cancer appearing through March 2012, based on applying various combinations of the following search terms: [breast cancer] and [depression] and [treatment] (1431 records, including 207 reviews of the literature), [breast cancer] and [antidepressants] (305 records, including 66 reviews of the literature), [selective serotonin reuptake inhibitors, SSRI] and [breast cancer] (38 records, including 10 reviews of the literature) and [psychotherapy] and [breast cancer] (603 works, including 84 reviews of the literature). We selected the following: 1) English language studies; 2) papers on psychopharmacological treatment of depression in breast cancer patients, from the psychiatrist’s point of view; 3) papers focused on potential interactions between tamoxifen and SSRI; 4) papers on the most widely used psychotherapies for depression in the special population of patients with breast cancer, with special interest to the most recent ones, namely interpersonal psychotherapy.
Results
Antidepressants for the treatment of depressive spectrum disorders among patients with breast cancer
Several studies have evaluated the efficacy of antidepressants in patients with breast cancer, considering also that the impact of depressive symptomatology on adherence to anti-cancer therapies is a crucial issue18 (Table 1). Early observations involved patients with different types of cancer. Only the most recent reports were specifically dedicated to patients with breast cancer.
One of the first studies was conducted on a sample of 73 women with a different subtype of cancer. Forty-seven patients were included with the diagnosis of breast cancer19. A significant improvement of the Hamilton Rating Scale for Depression (HAM-D) scores was demonstrated with mianserin (a tetra-cyclic noradrenergic and serotonergic antidepressant) compared to placebo. Nonetheless, several limitations were intrinsically linked to the original study design and, more in general, were typical of the early observations in this field. Depression was considered as a ‘major complication of cancer’, according to the basic idea of the distinction between the ‘primary’ depressions of ‘psychiatric patients’, and the ‘situational’ depressions, secondary to a physical and life-threatening disease. Research diagnostic criteria were utilized for the diagnosis of major depressive episodes, with a sub-classification in ‘dominantly depressivevsdepressive-anxious’. Mianserin was superior to placebo mainly in reducing sleep disturbances and anxiety somatic symptoms. The finding raised questions on the usefulness of outcome measures that mixed together the assessment of somatic, neurovegetative and anxious symptoms with depressed mood and anhedonia.
Taken as a whole, early studies showed methodological limitations. First, the adoption of heterogeneous criteria for patient selection: some studies included women who met criteria for major depressive disorder20-22, others included patients with adjustment disorders23, and yet others patients with depressive symptoms not fulfilling the diagnostic criteria for a major depressive episode24-26. The second limitation was on breast cancer stage selection: several studies did not differentiate between women with advanced metastatic cancer and women with early stage cancer22,23,27,28,. Third, improvements in depressive symptomatology or in quality of life were the main goal of treatments, whereas recent studies have focused attention on the percentage of women achieving full remission29.
The adoption of nonhomogeneous outcome measures across the different experimental study designs is also complicated by the intriguing relationship between improvement of depressive symptoms on short-term observations and the hypothesized impact of a successful treatment of depression on compliance with chemotherapy on the mid-term/long-term follow-up.
Efficacy of short-term treatment of antidepressants for depression among patients with breast cancer has been demonstrated by a number of observations. Less is known about long-term treatment of depression, compliance with chemotherapy or prophylactic treatments and survival percentages. Fann et al.3 summarized available studies with antidepressants among patients with breast cancer. As far as we know, two more studies have been carried out during the last four years25,30. Available data derived from studies with a time frame no longer than 12 weeks, except for the study by Navari et al.25, which was carried out with a 6-month follow-up.






As already described, Costa et al.19 treated 47 patients with breast cancer with mianserin compared to placebo, in a 4-week trial. Van Heeringen and Zivkov21 enrolled 57 patients with breast cancer and major depression in a 6-week trial. Both studies showed a significant improvement of HAM-D scores, with a reduction in severity and duration of depressive episodes.
Trazodone (an atypical antidepressant) and clorazepate (a long-acting benzodiazepine) were compared in a small 4-week open label study conducted on 18 patients with breast cancer at any stage and an adjustment disorder with depressed mood. Trazodone was superior to clorazepate in improving mood, anxiety and quality of life perception. Nonetheless, no significant differences were found23.
Fluoxetine, the first SSRI approved for the treatment of depression, was compared to placebo in a 5-week trial31. The sample included 69 patients with different types of cancer: 42 patients were diagnosed with breast or gynecological cancer, in comorbidity with major depression or adjustment disorder. Fluoxetine was not superior to placebo in terms of response. Moreover, dropouts were more frequent among patients randomized to fluoxetine than among patients randomized to placebo, even though the incidence of side effects was similar.
In a double-blind placebo-controlled trial32, women with advanced cancer, including 30 patients with breast cancer, were randomized to desipramine, fluoxetine or placebo. Fluoxetine was equal to desipramine in treating depression or adjustment disorders; both were superior to placebo.
More recently, Fisch et al.24 demonstrated that fluoxetine was superior to placebo for the treatment of depressive symptoms and for improvement of quality of life, in a sample of 163 patients with advanced solid cancer, including 27 patients with breast cancer.
A multicenter double-blind study on 179 patients with breast cancer and major depression compared the efficacy of paroxetine and amitriptilyne5. Both drugs were equally effective in improving depressive symptomatology (assessed with the Clinical Global Impression Scale) and quality of life. Paroxetine had a more favorable side effect profile.
Paroxetine (20 mg/day) was compared to placebo in an 8-week double-blind study on 549 patients (259 patients with breast cancer) undergoing chemotherapy7. The main goal of the study was to investigate the efficacy of paroxetine on depressed mood and fatigue. Patients were not required to meet criteria for major or minor depression. Response rates among patients with these diagnoses were not separately considered. Paroxetine was superior to placebo for the treatment of depressive mood (evaluated with the Center for Epidemiologic Studies Depression Scale, CESDS), but was equal to placebo for the treatment of fatigue.
A 6-week double-blind placebo-controlled study compared paroxetine and desipramine28. The study sample included 35 women with breast cancer (at any stage) and major depression. No significant differences between the two treatment groups and the placebo group were found on HAM-D and Clinical Global Impression scores, probably because of the small sample size and the short-term design of the study.
Sertraline (50-100 mg/day) was administered to 35 patients with cancer, including 19 patients with breast cancer, comorbid with adjustment disorders or mood spectrum depressive disorders (namely, major depression, dysthymia and sub-threshold depression defined with a score >5 on the Structured Clinical Interview for DSM-IV scale - depression subscale, but not enough to meet DSM-IV criteria for major depressive disorder)33. Sertraline was effective, with a significant improvement in depression and anxiety subscales of the Hospital Anxiety and Depression Scale (HADS) and of the Montgomery-Asberg Depression Rating Scale (MADRS).
In a small open-label study, 20 women with breast cancer at any stage meeting DSM-IV criteria for major depression were treated with reboxetine (a norepinephrine reuptake inhibitor). Depressive symptoms, hopelessness and ‘anxious worry for malignancy’ significantly decreased during treatment22.
More recently, in an open-label 12-week prospective trial, escitalopram was found to improve depressive mood and quality of life in a sample of 79 outpatients with breast cancer, evaluated with the HAM-D, the Distress Thermometer (DT) and the Clinical Global Impression-Severity of Illness scale (CGISI-S). Surprisingly, improvement was noted starting from the first week of treatment30.
Interaction between SSRI antidepressant treatment and adjuvant therapy with tamoxifen
Tamoxifen (an estrogen-receptor modulator for the treatment of hormone receptor-positive breast cancer) is a pro-drug, and its efficacy is mediated by two active metabolites: 4 hydroxytamoxifen and 4-hydroxy-N-desmethyltamoxifen (endoxifen), with a 100-fold higher potency than the parent drug. Cytochrome P450 2D6 is responsible for tamoxifen conversion to active metabolites34,35. It has been hypothesized that patients with breast cancer who are CYP2D6 poor metabolizers’ might be at high risk of relapse and at low incidence of hot flushes induced by tamoxifen, mainly because of low endoxifen levels35. Nonetheless, results from clinical studies addressing the issue of a direct relationship between the decrease in plasma concentrations of endoxifen, the concomitant use of CYP2D6 inhibitors, and breast cancer relapse risk are inconsistent.
The treatment of a concomitant depressive episode complicates tamoxifen therapy, also because antidepressants might inhibit CYP2D6 to varying degrees. Paroxetine and fluoxetine are the strongest inhibitors, with paroxetine irreversibly inhibiting CYP2D6 activity. Compounds such as fluvoxamine and citalopram are instead weaker inhibitors36. Reduced plasma concentrations of endoxifen have been described for patients using paroxetine concomitantly with tamoxifen, not for those who were taking tamoxifen with venlafaxine (weak CYP2D6 inhibitor)34,37. Two studies carried out in the USA showed no association between antidepressants and rates of breast cancer recurrence or mortality, among users of the most potent CYP2D6 inhibitors fluoxetine and paroxetine, although these studies had the limitation of a low statistical power38,39.
A Danish population-based case-control study showed that the concurrent use of citalopram/escitalopram (the most frequently used SSRI among patients with breast cancer) and tamoxifen was not associated with a higher risk of breast cancer recurrence, regardless of the duration of concurrent use of the two compounds. Moreover, in a small subset of women taking more potent CYP2D6 inhibitors, namely fluoxetine, paroxetine and sertraline, concomitantly with tamoxifen, no association was demonstrated with breast cancer recurrences 40-42.
Conversely, Kelly et al.43 described higher breast cancer mortality among women who were taking paroxetine concurrently with tamoxifen. The highest mortality occurred in women with the longest concurrent use of the two drugs.
In a recent Dutch study, no association was found between CYP2D6 inhibitor use (most frequently paroxetine and fluoxetine) tamoxifen prophylaxis, and breast cancer recurrences, although the finding was based on the occurrence of 18 breast cancers among SSRI users44.
As far as we know, no studies have examined the impact of concurrent use of the weaker CYP2D6 inhibitor, fluvoxamine on breast cancer outcome.
On the whole, results from the observational studies currently available seem to support the hypothesis of a negative impact of CYP2D6 inhibitors on breast cancer recurrence risk, when tamoxifen is utilized as prophylactic treatment. Therefore, it is possible that the reduction in plasma concentrations of active metabolites of tamoxifen from concurrent SSRI treatment does not correlate with efficacy of the same45,46.
Nonetheless, it is still recommended that weak inhibitors of CYP2D6, such as venlafaxine, citalopram or escitalopram, should be considered as first choice pharmacological treatment of depression (as well as of vasomotor symptoms) in patients who are currently treated with tamoxifen47.
Psychotherapy for depression in breast cancer
A limited number of studies has investigated psychotherapy for depression in patients with breast cancer; most of the studies enrolled patients with several forms of cancer. A meta-analysis summarized available data derived from randomized trials with different models of psychosocial treatments on patients with cancer, not exclusively breast cancer48. Interventions were classified in five categories, namely ‘cognitive-behavioral psychotherapies’, ‘informational and educational treatments’, ‘non-behavioral interventions’, ‘social support by non-professionals’, and ‘unusual treatments’. No differences were found, in terms of response, between patients with ‘early stage cancer’ and patients with ‘advanced metastatic illness’. Moreover, psychotherapies were found to be equally effective, when studies on patients with well-defined psychiatric syndromes were compared with studies on patients with distress secondary to the life-threatening diagnosis of cancer.
Two meta-analyses summarized results from trials with different psychotherapeutic approaches, among patients with cancer and anxiety or mood disorders49. Preventative psychosocial interventions in patients with cancer might have a moderate clinical effect upon anxiety and a negligible effect on distress. Group therapy was found to be at least as effective as individual therapy. Nonetheless, most observations in this field did not focus on ‘depressed mood’ but on the reduction of pain, fatigue and distress, or on the improvement of quality of life. More refined information derives from studies on the Supportive-Expressive Group Psychotherapy (SEGT). SEGT has a specific target on existential concerns, with strategies focused on the expression and management of disease-related emotions, the optimization of social support, and the enhancement of relationships with family and physicians.
The first prospective study on the efficacy of SEGT, in patients with breast cancer, was carried out by Spiegel et al.50 A sample of women treated with weekly SEGT and self-hypnosis for pain had a mean survival time (37.6 months) significantly higher than the control group followed-up with a routine treatment (18.9 months). However, the finding was not confirmed by a subsequent study of the same research group51.
In a clinical intervention trial, Classen et al.52 found that patients treated with SEGT showed a significantly greater decline in traumatic stress symptoms on the Impact of Event Scale than controls. The overall reduction in traumatic stress symptoms was linked to the decrease in avoidance symptoms. It has been hypothesized that the usefulness of SEGT might be due to the exposure to feared stimuli and to the focus on coping with a life-threatening condition. Survival time was not assessed as an outcome measure in the study.
A large multicenter study on 235 women with metastatic breast cancer showed that patients randomized to SEGT improved in several aspects of depressive spectrum symptomatology, such as sadness, anxiety, anger, confusion and worsening of pain. The most significant improvement was for patients who scored higher on distress at baseline. However, psychotherapy did not prolong survival time53. The same result was confirmed in a more recent randomized trial with SEGT54. Patients treated with psychotherapy showed lower levels of hopelessness and helplessness, had a smaller number of new depressive episodes, and improved in social functioning compared to the patients without psychotherapy. Again, survival time was not influenced by psychotherapy. Conversely, in a recent secondary analysis of a randomized trial with SEGT, patients with breast cancer showed a decrease of depressive symptoms over the first year, and this result was associated with a longer subsequent survival time 55.
Cognitive behavioral therapy (CBT) is also considered an effective treatment for depression among patients with breast cancer. A randomized study was conducted on patients with any form of cancer who were treated with a brief, problems-focused CBT, specifically adapted for the needs of patients with cancer56. Patients on CBT, after 8 weeks of treatment, showed significantly higher scores than controls on ‘fighting spirit’, and significantly lower scores on helplessness, anxious preoccupation, fatalism, anxiety and orientation towards health care. After a 4-month follow-up, patients receiving CBT showed significantly lower scores than controls on anxiety, depression and distress56. In a more recent clinical trial specifically dedicated to patients with metastatic breast cancer, patients randomized to individual cognitive therapy showed a significant improvement in depressed mood, anxiety, fatigue, and insomnia compared to untreated patients57. Cognitive-existential group therapy (combining education, cognitive reappraisal and promotion of enhanced coping with existentially oriented and supportive-expressive strategies) was found to be able to decrease anxiety and to improve family interactions in a sample of patients with early breast cancer58.
Reports on other forms of psychotherapy are anecdotal and inconclusive. Peer-delivered telephone interventions were not able to reduce depression or distress59. A combination of psycho-educational support and nutritional interventions was proposed, with the aim to reduce depressive symptomatology and to improve physical functioning, among patients with several forms of cancer. A diminished interference of intrusive thoughts regarding cancer recurrence and mortality risk and an improvement in self-concept perceptions, or self-efficacy expectation, were described with these techniques60. Surprisingly, patients with low psychosocial resources seemed to benefit from nutrition interventions more than patients with a greater amount of psychosocial resources61. A recent randomized trial on patients with breast cancer showed that both psycho-education and group psychotherapy were unable to reduce distress, to increase quality of life, to promote mental adjustment or to improve marital relationships62.
An ongoing randomized clinical trial carried out by Blanco et al.63 is currently comparing the efficacy of iterpersonal psychotherapy (IPT) with problem-solving therapy and brief supportive psychotherapy on depressive symptoms, psychosocial functioning and quality of life among patients with breast cancer and major depressive disorder. IPT is an evidence-based time-limited psychotherapy with a soundly based evidence of efficacy for the treatment of major depression64-66, including depression in human immunodeficiency virus67 and in other chronic physical diseases68,69.
Taken as a whole, studies with psychotherapy for patients with breast cancer are promising, even if, as observed for clinical trials with antidepressants, studies on psychotherapy for depression in patients with breast cancer are mainly limited by the selection of nonhomogeneous populations and the adoption of different study designs or outcome measures.
Discussion
The management of comorbid depression is important in order to improve quality of life of patients with breast cancer and to minimize the risk of non-compliance to cancer treatments. Nonetheless, studies systematically addressing the issue of a multidisciplinary management of comorbidity between depression and breast cancer show several important methodological limitations.
SSRI have been extensively tested for patients with breast cancer, but no conclusive findings have emerged as yet from studies on the superiority of one SSRI over another. The combined and the sequential approaches (namely, pharmacotherapy and psychotherapy or pharmacotherapy followed by psychotherapy) are suggested strategies for the treatment of depression70. However, no systematic studies have addressed the question of whether to utilize the combined or the sequential treatment for depression in patients with breast cancer. Moreover, studies on brief psychotherapies with a soundly based knowledge of efficacy for depression, such as IPT, are still limited.
The selection of breast cancer patients for controlled studies is largely inadequate, both from an oncologic and a psychiatric point of views. Several observations have been carried out without any differentiation between the breast cancer stages. Studies on the efficacy of antidepressants, psychotherapy or their combination often included patients with adjustment disorders or demoralization, concurring to high placebo response rates71.
We strongly believe that the occurrence of depressive symptoms concomitantly with a stressful life event, such as a diagnosis of breast cancer, has to be considered as clinically relevant as the so-called ‘endogenous’ forms of depression. The importance of treating a clinically relevant depressive symptomatology is now universally accepted even when symptoms are apparently ‘justified’ by the occurrence of a stressful event. The debate is on the most appropriate strategy to treat depressive symptoms. Thus, when a full-blown depressive episode is present, the pharmacological approach still appears as the first line option, especially when suicidal thoughts or ideation are present. The occurrence of sub-threshold forms of depression, including transient demoralization, raises the question of whether to adopt a sequential approach with psychotherapy or psycho-educational support as the first-line option and pharmacotherapy as second-line treatment if symptoms become more severe 65,72. Moreover, several observations have pointed out the importance of incomplete or attenuated forms of depression as precursors or prodromal of a subsequent full-blown depressive episode73,74.
A more refined description of the different phenotypes of depression, from the sub-threshold forms to the full-blown manifestations that might occur in comorbidity with breast cancer, is still lacking. For example, several studies have assessed the efficacy of psychotherapy in reducing distress, pain and fatigue48,49,56,58,75-79. Less is known about treatment response to full-blown forms of unipolar major depression, and virtually no distinction is present in the literature between the unipolar and the bipolar forms of depression.
Although more recent studies have been conducted with a much better understanding of the various presentations of depression, only a few research groups have attempted to underpin the new appreciation of the complexity of depressive disorders. The re-conceptualization of the clinical phenotypes of depression in breast cancer underlying the specific pharmacotherapy and psychotherapy treatment choices constitutes a real need for further investigation in a manner that more closely approximates clinical reality. Given that, the problem of an accurate definition of specific diagnostic criteria able to define depression in cancer patients is crucial. Thus, many symptoms overlap the side effects of cancer treatment and often improve after the end of such treatments 80. Nonetheless, in clinically depressed patients, depressive concerns are extended beyond the implications of the somatic illness. These include a pervasive sense of hopelessness and helplessness, excessive guilt or self-deprecatory thinking, feelings of worthlessness, and a feeling that one is being punished or that life is without value, raising the risk of suicidal ideation or suicide attempts81,82. Obviously, even in this special population of patients, the strongest predictors of a full-blown comorbid depressive episode still remain the family and the personal history of depression and a personal history of previous suicide attempts.
The problem of measurement of depression in cancer patients leads to the question of whether specific tools are needed. There are a number of self-reported depression measures available for use in cancer care and oncology research. Several studies have been conducted comparing the psychometric performance of depression measures in cancer. The Hospital Anxiety and Depression Scale and the Center for Epidemiological Studies Depression Scale resulted as the most commonly studied measure3,83, with the limitation of a cross-sectional observation in a number of cases83,84. It is still unclear whether or not to use instruments that include physical symptoms when assessing depression in patients with cancer. The finding of an increased prevalence of false-positive depression when somatic items are included in the evaluation of patients with cancer is questionable85.
Recent studies found that the inclusion of somatic symptoms when depression is screened among patients with severe somatic illnesses did not lead to the overdiagnosis of depression86-88. Considering that not all ‘depressed’ patients respond in a similar manner to current pharmacologic or psychotherapeutic interventions (even in the absence of an important comorbidity for a life-threatening condition), such a phenotypic re-conceptualization may offer a new opportunity for progress in treatment and their biological underpinnings.
Moreover, we strongly believe that psychotherapies other than cognitive therapy, cognitive behavioral therapy or SEGT should be systematically tested for patients with breast cancer. For example, IPT is one of the best-studied and empirically validated psychotherapies for depression89. IPT is a time-limited psychotherapy based on the premise of a bidirectional relationship between depression and interpersonal difficulties or stressful life events90,91. During treatment, an interpersonal re-conceptualization of a patient’s difficulties is developed, and one or more of four problematic areas are considered as the ‘focus of treatment’. Problematic areas include interpersonal dispute, grief and loss, interpersonal deficit and role transitions, frequently occurring when a life-threatening disease is diagnosed.
Empirical support for the efficacy of IPT has been well established in a variety of clinical contexts, including patients recruited in medical settings92-94, patients with chronic illnesses and pain68, coronary diseases95, HIV+67, and medically frail older adults96. However, studies on IPT for depressed patients with breast cancer are lacking, despite the epidemiological and clinical relevance of the two diseases.
Given the addressed limitations of current knowledge on comorbidity between breast cancer and depression, we suggest the following recommendations for future research:
• Treatment studies should benefit from a more refined approach to clinical phenotypes of depression among patients with breast cancer.
• Clinical trials of pharmacotherapy for patients with breast cancer should be conducted not only for unipolar depression but also for bipolar depression.
• Randomized, controlled trials should be carried out to investigate whether the sequential or the combined approach (pharmacotherapy plus psychotherapy) is preferable, when depression is comorbid to breast cancer.
• Evidence-based psychotherapies other than cognitive therapy, cognitive behavioral therapy or SEGT should be tested as valid treatment options. IPT is suggested for future research.
References
1. National Cancer Institute at the National Institute of Health. www.cancer.gov/cancertopics/types/breast
2. Hegel MT, Moore CP, Collins ED, Kearing S, Gillock KL, Riggs RL, Clay KF, Ahles TA: Distress, psychiatric syndromes, and impairment of function in women with newly diagnosed breast cancer. Cancer, 107: 2924-2931, 2006.
3. Fann JR, Thomas-Rich AM, Katon WJ, Cowley D, Pepping M, McGregor BA, Gralow J: Major depression after breast cancer: a review of epidemiology and treatment. Gen Hosp Psychiatry, 30: 112-126, 2008.
4. Pirl WF, Roth AJ: Diagnosis and treatment of depression in cancer patients. Oncology, 13: 1293-1301, discussion 1301-1302, 1305-1306, 1999.
5. Pezzella G, Moslinger-Gehmayr R, Contu A: Treatment of depression in patients with breast cancer: a comparison between paroxetine and amitriptyline. Breast Cancer Res Treat, 70: 1-10, 2001.
6. Somerset W, Stout SC, Miller AH, Musselman D. Breast cancer and depression. Oncology, 18: 1021-1034; discussion 1035-1036, 1047-1048, 2004.
7. Morrow GR, Hickok JT, Roscoe JA, Raubertas RF, Andrews PL, Flynn PJ, Hynes HE, Banerjee TK, Kirshner JJ, King DK: University of Rochester Cancer Center Community Clinical Oncology Program. Differential effects of paroxetine on fatigue and depression: a randomized, double-blind trial from the University of Rochester Cancer Center Community Clinical Oncology Program. J Clin Oncol, 21: 4635-4641, 2003.
8. Colleoni M, Mandala M, Peruzzotti G, Robertson C, Bredart A, Goldhirsch A: Depression and degree of acceptance of adjuvant cytotoxic drugs. Lancet, 356: 1326-1327, 2000.
9. Cathcart CK, Jones SE, Pumroy CS, Peters GN, Knox SM, Cheek JH: Clinical recognition and management of depression in node negative breast cancer patients treated with tamoxifen. Breast Cancer Res Treat, 27: 277-281, 1993.
10. van Dam FS, Schagen SB, Muller MJ, Boogerd W, vd Wall E, Droogleever Fortuyn ME, Rodenhuis S: Impairment of cognitive function in women receiving adjuvant treatment for high-risk breast cancer: high-dose versus standard-dose chemotherapy. J Natl Cancer Inst, 90: 210-218, 1998.
11. Thompson DS, Spanier CA, Vogel VG: The relationship between tamoxifen, estrogen, and depressive symptoms. Breast J, 5: 375-382, 1999.
12. Schagen SB, van Dam FS, Muller MJ, Boogerd W, Lindeboom J, Bruning PF: Cognitive deficits after postoperative adjuvant chemotherapy for breast carcinoma. Cancer, 85: 640-650, 1999.
13. Leedham B, Ganz PA: Psychosocial concerns and quality of life in breast cancer survivors. Cancer Invest, 17: 342-348, 1999.
14. Thompson DS: Mirtazapine for the treatment of depression and nausea in breast and gynecological oncology. Psychosomatics, 41: 356-359, 2000.
15. Lee KC, Ray GT, Hunkeler EM, Finley PR: Tamoxifen treatment and new-onset depression in breast cancer patients. Psychosomatics, 48: 205-210, 2007.
16. Ayres A, Hoon PW, Franzoni JB, Matheny KB, Cotanch PH, Takayanagi S: Influence of mood and adjustment to cancer on compliance with chemotherapy among breast cancer patients. J Psychosom Res, 38: 393-402, 1994.
17. Bui QU, Ostir GV, Kuo YF, Freeman J, Goodwin JS: Relationship of depression to patient satisfaction: findings from the barriers to breast cancer study. Breast Cancer Res Treat, 89: 23-28, 2005.
18. DiMatteo MR, Lepper HS, Croghan TW: Depression is a risk factor for noncompliance with medical treatment: meta-analysis of the effects of anxiety and depression on patient adherence. Arch Intern Med, 160: 2101-2107, 2000.
19. Costa D, Mogos I, Toma T: Efficacy and safety of mianserin in the treatment of depression of women with cancer. Acta Psychiatr Scand Suppl, 320: 85-92, 1985.
20. Möslinger-Gehmayr R, Zaninelli R, Contu A, Oberhoff C, Gutschow K, Schindler AE, Staab HJ: A double-blind comparative study of the effectiveness and tolerance of paroxetine and amitriptyline in treatment of breast cancer patients with clinically assessed depression. Zentralbl Gynakol, 122: 195-202, 2000.
21. van Heeringen K, Zivkov M: Pharmacological treatment of depression in cancer patients. A placebo-controlled study of mianserin. Br J Psychiatry, 169: 440-443, 1996.
22. Grassi L, Biancosino B, Marmai L, Righi R: Effect of reboxetine on major depressive disorder in breast cancer patients: an open-label study. J Clin Psychiatry, 65: 515-520, 2004.
23. Razavi D, Kormoss N, Collard A, Farvacques C, Delvaux N: Comparative study of the efficacy and safety of trazodone versus clorazepate in the treatment of adjustment disorders in cancer patients: a pilot study. J Int Med Res, 27: 264-272, 1999.
24. Fisch MJ, Loehrer PJ, Kristeller J, Passik S, Jung SH, Shen J, Arquette MA, Brames MJ, Einhorn LH; Hoosier Oncology Group: Fluoxetine versus placebo in advanced cancer outpatients: a double-blinded trial of the Hoosier Oncology Group. J Clin Oncol, 21: 1937-1943, 2003.
25. Navari RM, Brenner MC, Wilson MN: Treatment of depressive symptoms in patients with early stage breast cancer undergoing adjuvant therapy. Breast Cancer Res Treat, 112: 197-201. 2008.
26. Ballin A, Gershon V, Tanay A, Brener J, Weizman A, Meytes D: The antidepressant fluvoxamine increases natural killer cell counts in cancer patients. Isr J Med Sci, 33: 720-723, 1997.
27. Roscoe JA, Morrow GR, Hickok JT, Mustian KM, Griggs JJ, Matteson SE, Bushunow P, Qazi R, Smith B: Effect of paroxetine hydrochloride (Paxil) on fatigue and depression in breast cancer patients receiving chemotherapy. Breast Cancer Res Treat, 89: 243-249, 2005.
28. Musselman DL, Somerset WI, Guo Y, Manatunga AK, Porter M, Penna S, Lewison B, Goodkin R, Lawson K, Lawson D, Evans DL, Nemeroff CB: A double-blind, multicenter, parallel-group study of paroxetine, desipramine, or placebo in breast cancer patients (stages I, II, III, and IV) with major depression. J Clin Psychiatry, 67: 288-296, 2006.
29. Keller MB: Past, present, and future directions for defining optimal treatment outcome in depression: remission and beyond. JAMA, 289: 3152-3160, 2003.
30. Park HY, Lee BJ, Kim JH, Bae JN, Hahm BJ: Rapid improvement of depression and quality of life with escitalopram treatment in outpatients with breast cancer: A 12-week, open-label prospective trial. Prog Neuropsychopharmacol Biol Psychiatry, 36: 318-323, 2012.
31. Razavi D, Allilaire JF, Smith M, Salimpour A, Verra M, Desclaux B, Saltel P, Piollet I, Gauvain-Piquard A, Trichard C, Cordier B, Fresco R, Guillibert E, Sechter D, Orth JP, Bouhassira M, Mesters P, Blin P: The effect of fluoxetine on anxiety and depression symptoms in cancer patients. Acta Psychiatr Scand, 94: 205-210, 1996.
32. Holland JC, Romano SJ, Heiligenstein JH, Tepner RG, Wilson MG: A controlled trial of fluoxetine and desipramine in depressed women with advanced cancer. Psychooncology, 7: 291-300, 1998.
33. Torta R, Siri I, Caldera P: Sertraline effectiveness and safety in depressed oncological patients. Support Care Cancer, 16: 83-91, 2008.
34. Jin Y, Desta Z, Stearns V, Ward B, Ho H, Lee KH, Skaar T, Storniolo AM, Li L, Araba A, Blanchard R, Nguyen A, Ullmer L, Hayden J, Lemler S, Weinshilboum RM, Rae JM, Hayes DF, Flockhart DA: CYP2D6 genotype, antidepressant use, and tamoxifen metabolism during adjuvant breast cancer treatment. J Natl Cancer Inst, 97: 30-39, 2005.
35. Jordan VC: New insights into the metabolism of tamoxifen and its role in the treatment and prevention of breast cancer. Steroids, 72: 829-842, 2007.
36. Jeppesen U, Gram LF, Vistisen K, Loft S, Poulsen HE, Brøsen K: Dose-dependent inhibition of CYP1A2, CYP2C19 and CYP2D6 by citalopram, fluoxetine, fluvoxamine and paroxetine. Eur J Clin Pharmacol, 51: 73-78, 1996.
37. Stearns V, Johnson MD, Rae JM, Morocho A, Novielli A, Bhargava P, Hayes DF, Desta Z, Flockhart DA: Active tamoxifen metabolite plasma concentrations after coadministration of tamoxifen and the selective serotonin reuptake inhibitor paroxetine. J Natl Cancer Inst, 95: 1758-1764, 2003.
38. Chubak J, Buist DS, Boudreau DM, Rossing MA, Lumley T, Weiss NS: Breast cancer recurrence risk in relation to antidepressant use after diagnosis. Breast Cancer Res Treat, 112: 123-132, 2008.
39. Lehmann D, Nelsen J, Ramanath V, Newman N, Duggan D, Smith A: Lack of attenuation in the antitumor effect of tamoxifen by chronic CYP isoform inhibition. J Clin Pharmacol, 44: 861-865, 2004.
40. Lash TL, Cronin-Fenton D, Ahern TP, Rosenberg CL, Lunetta KL, Silliman RA, Hamilton-Dutoit S, Garne JP, Ewertz M, Sørensen HT, Pedersen L: Breast cancer recurrence risk related to concurrent use of SSRI antidepressants and tamoxifen. Acta Oncol, 49: 305-312, 2010.
41. Ahern TP, Pedersen L, Cronin-Fenton DP, Sørensen HT, Lash TL: No increase in breast cancer recurrence with concurrent use of tamoxifen and some CYP2D6-inhibiting medications. Cancer Epidemiol Biomarkers Prev, 18: 2562-2564, 2009.
42. Lash TL, Pedersen L, Cronin-Fenton D, Ahern TP, Rosenberg CL, Lunetta KL, Silliman RA, Hamilton-Dutoit S, Garne JP, Ewertz M, Sørensen HT: Tamoxifen’s protection against breast cancer recurrence is not reduced by concurrent use of the SSRI citalopram. Br J Cancer, 99: 616-621, 2008.
43. Kelly CM, Juurlink DN, Gomes T, Duong-Hua M, Pritchard KI, Austin PC, Paszat LF: Selective serotonin reuptake inhibitors and breast cancer mortality in women receiving tamoxifen: a population based cohort study. BMJ, 340: c693, 2010.
44. Dezentjé VO, van Blijderveen NJ, Gelderblom H, Putter H, van Herk-Sukel MP, Casparie MK, Egberts AC, Nortier JW, Guchelaar HJ: Effect of concomitant CYP2D6 inhibitor use and tamoxifen adherence on breast cancer recurrence in early-stage breast cancer. J Clin Oncol, 28: 2423-2429, 2010.
45. Ratliff B, Dietze EC, Bean GR, Moore C, Wanko S, Seewaldt VL: Re: Active tamoxifen metabolite plasma concentrations after coadministration of tamoxifen and the selective serotonin reuptake inhibitor paroxetine, 96: 883; author reply 884-885, 2004.
46. Lash TL, Lien EA, Sørensen HT, Hamilton-Dutoit S: Genotype-guided tamoxifen therapy: time to pause for reflection? Lancet Oncol, 10: 825-833, 2009.
47. National Comprehensive Cancer Network. www.nccn.org
48. Meyer TJ, Mark MM: Effects of psychosocial interventions with adult cancer patients: a meta-analysis of randomized experiments. Health Psychol, 14: 101-108, 1995.
49. Sheard T, Maguire P: The effect of psychological interventions on anxiety and depression in cancer patients: results of two meta-analyses. Br J Cancer, 80: 1770-1780, 1999.
50. Spiegel D, Bloom JR, Kraemer HC, Gottheil E: Effect of psychosocial treatment on survival of patients with metastatic breast cancer. Lancet, 2: 888-891: 1989.
51. Spiegel D, Butler LD, Giese-Davis J, Koopman C, Miller E, DiMiceli S, Classen CC, Fobair P, Carlson RW, Kraemer HC: Effects of supportive-expressive group therapy on survival of patients with metastatic breast cancer: a randomized prospective trial. Cancer, 110: 1130-1138, 2007.
52. Classen C, Butler LD, Koopman C, Miller E, DiMiceli S, Giese-Davis J, Fobair P, Carlson RW, Kraemer HC, Spiegel D: Supportive-expressive group therapy and distress in patients with metastatic breast cancer: a randomized clinical intervention trial. Arch Gen Psychiatry, 58: 494-501, 2001.
53. Goodwin PJ, Leszcz M, Ennis M, Koopmans J, Vincent L, Guther H, Drysdale E, Hundleby M, Chochinov HM, Navarro M, Speca M, Hunter J: The effect of group psychosocial support on survival in metastatic breast cancer. N Engl J Med, 345: 1719-1726, 2001.
54. Kissane DW, Grabsch B, Clarke DM, Smith GC, Love AW, Bloch S, Snyder RD, Li Y: Supportive-expressive group therapy for women with metastatic breast cancer: survival and psychosocial outcome from a randomized controlled trial. Psychooncology, 16: 277-286, 2007.
55. Giese-Davis J, Collie K, Rancourt KM, Neri E, Kraemer HC, Spiegel D: Decrease in depression symptoms is associated with longer survival in patients with metastatic breast cancer: a secondary analysis. J Clin Oncol, 29: 413-420, 2011.
56. Greer S, Moorey S, Baruch JD, Watson M, Robertson BM, Mason A, Rowden L, Law MG, Bliss JM: Adjuvant psychological therapy for patients with cancer: a prospective randomised trial. BMJ, 304: 675-680, 1992.
57. Savard J, Simard S, Giguère I, Ivers H, Morin CM, Maunsell E, Gagnon P, Robert J, Marceau D: Randomized clinical trial on cognitive therapy for depression in women with metastatic breast cancer: psychological and immunological effects. Palliat Support Care, 4: 219-237, 2006.
58. Kissane DW, Bloch S, Smith GC, Miach P, Clarke DM, Ikin J, Love A, Ranieri N, McKenzie D: Cognitive-existential group psychotherapy for women with primary breast cancer: a randomised controlled trial. Psychooncology, 12: 532-546, 2003.
59. Gotay CC, Moinpour CM, Unger JM, Jiang CS, Coleman D, Martino S, Parker BJ, Bearden JD, Dakhil S, Gross HM, Lippman S, Albain KS: Impact of a peer-delivered telephone intervention for women experiencing a breast cancer recurrence. J Clin Oncol, 25: 2093-2099, 2007.
60. Scheier MF, Helgeson VS, Schulz R, Colvin S, Berga S, Bridges MW, Knapp J, Gerszten K, Pappert WS: Interventions to enhance physical and psychological functioning among younger women who are ending nonhormonal adjuvant treatment for early-stage breast cancer. J Clin Oncol, 23: 4298-4311, 2005.
61. Scheier MF, Helgeson VS, Schulz R, Colvin S, Berga SL, Knapp J, Gerszten K: Moderators of interventions designed to enhance physical and psychological functioning among younger women with early-stage breast cancer. J Clin Oncol, 25: 5710-5714, 2007.
62. Boesen EH, Karlsen R, Christensen J, Paaschburg B, Nielsen D, Bloch IS, Christiansen B, Jacobsen K, Johansen C: Psychosocial group intervention for patients with primary breast cancer: a randomised trial. Eur J Cancer, 47: 1363-1372, 2011.
63. Blanco C: Interpersonal therapy for depression in breast cancer. Clinical Trials.gov Identifier: NCT01191580. Available at http://clinicaltrials.gov/ct2/show/NCT01191580
64. Brown C, Schulberg HC, Sacco D, Perel JM, Houck PR: Effectiveness of treatments for major depression in primary medical care practice: a post hoc analysis of outcomes for African American and white patients. J Affect Disord, 53: 185-192, 1999.
65. Rucci P, Frank E, Calugi S, Miniati M, Benvenuti A, Wallace M, Fagiolini A, Maggi L, Kupfer DJ, Cassano GB: Incidence and predictors of relapse during continuation treatment of major depression with SSRI, interpersonal psychotherapy, or their combination. Depress Anxiety, 28: 955-962, 2011.
66. Markowitz JC, Weissman MM: Interpersonal psychotherapy: past, present and future. Clin Psychol Psychother, 19: 99-105, 2012.
67. Markowitz JC, Kocsis JH, Fishman B, Spielman LA, Jacobsberg LB, Frances AJ, Klerman GL, Perry SW: Treatment of depressive symptoms in human immunodeficiency virus-positive patients. Arch Gen Psychiatry, 55: 452-457, 1998.
68. Karp JF, Scott J, Houck P, Reynolds CF, Kupfer DJ, Frank E: Pain predicts longer time to remission during treatment of recurrent depression. J Clin Psychiatry, 66: 591-597, 2005.
69. Poleshuck EL, Gamble SA, Cort N, Hoffman-King D, Cerrito B, Rosario-McCabe LA, Giles DE: Interpersonal psychotherapy for co-occurring depression and chronic pain. Prof Psychol Res Pr, 41: 312-318, 2010.
70. Keller MB, McCullough JP, Klein DN, Arnow B, Dunner DL, Gelenberg AJ, Markowitz JC, Nemeroff CB, Russell JM, Thase ME, Trivedi MH, Zajecka J: A comparison of nefazodone, the cognitive behavioral-analysis system of psychotherapy, and their combination for the treatment of chronic depression. N Engl J Med, 342: 1462-1470, 2000.
71. Williams JW Jr, Barrett J, Oxman T, Frank E, Katon W, Sullivan M, Cornell J, Sengupta A: Treatment of dysthymia and minor depression in primary care: A randomized controlled trial in older adults. JAMA, 284: 1519-1526, 2000.
72. Frank E, Cassano GB, Rucci P, Thompson WK, Kraemer HC, Fagiolini A, Maggi L, Kupfer DJ, Shear MK, Houck PR, Calugi S, Grochocinski VJ, Scocco P, Buttenfield J, Forgione RN: Predictors and moderators of time to remission of major depression with interpersonal psychotherapy and SSRI pharmacotherapy. Psychol Med, 41: 151-162, 2011.
73. Cassano GB, Dell’Osso L, Frank E, Miniati M, Fagiolini A, Shear K, Pini S, Maser J: The bipolar spectrum: a clinical reality in search of diagnostic criteria and an assessment methodology. J Affect Disord, 54: 319-328, 1999.
74. Fava GA, Tossani E: Prodromal stage of major depression. Early Interv Psychiatry, 1: 9-18, 2007.
75. Fawzy FI: Psychosocial interventions for patients with cancer: what works and what doesn’t. Eur J Cancer, 35: 1559-1564, 1999.
76. Edwards AG, Hailey S, Maxwell M: Psychological interventions for women with metastatic breast cancer. Cochrane Database Syst Rev, (2): CD004253, 2004.
77. Devine EC, Westlake SK: The effects of psychoeducational care provided to adults with cancer: meta-analysis of 116 studies. Oncol Nurs Forum, 22: 1369-1381, 1995.
78. Newell SA, Sanson-Fisher RW, Savolainen NJ: Systematic review of psychological therapies for cancer patients: overview and recommendations for future research. J Natl Cancer Inst, 94: 558-584, 2002.
79. Antoni MH, Lehman JM, Kilbourn KM, Boyers AE, Culver JL, Alferi SM, Yount SE, McGregor BA, Arena PL, Harris SD, Price AA, Carver CS: Cognitive-behavioral stress management intervention decreases the prevalence of depression and enhances benefit finding among women under treatment for early-stage breast cancer. Health Psychol, 20: 20-32, 2001.
80. Chochinov HM: Depression in cancer patients. Lancet Oncol, 2: 499-505, 2001.
81. Lander M, Wilson K, Chochinov HM: Depression in the elderly terminally ill. Clin Geriatr Med, 16: 335-356, 2000.
82. Breitbart W, Chochinov HM, Passik S: Psychiatric aspects of palliative care. In: Doyle D, Hanks G, MacDonald N (Eds). Oxford textbook of palliative medicine. 2nd edn, pp 933-954, Oxford University Press, New York, 1997.
83. Luckett T, Butow PN, King MT, Oguchi M, Heading G, Hackl NA, Rankin N, Price MA: A review and recommendations for optimal outcome measures of anxiety, depression and general distress in studies evaluating psychosocial interventions for English-speaking adults with heterogeneous cancer diagnoses. Support Care Cancer, 18: 1241-1262, 2010.
84. Pirl WF: Evidence report on the occurrence, assessment, and treatment of depression in cancer patients. J Natl Cancer Inst Monogr, 32: 32-39, 2004.
85. Dugan W, McDonald MV, Passik SD, Rosenfeld BD, Theobald D, Edgerton S: Use of the Zung Self-Rating Depression Scale in cancer patients: feasibility as a screening tool. Psychooncology, 7: 483-493, 1998.
86. Johns SA, Kroenke K, Krebs EE, Theobald DE, Wu J, Tu W: Longitudinal comparison of three depression measures in adult cancer patients. J Pain Symptom Manage, 45: 71-82, 2013.
87. Williams JW Jr, Noel PH, Cordes JA, Ramirez G; Pignone M: Is this patient clinically depressed? JAMA, 287: 1160-1170, 2002.
88. Simon GE, Von Korff M: Medical co-morbidity and validity of DSM-IV depression criteria. Psychol Med, 36: 27-36, 2006.
89. Cuijpers P, Geraedts AS, van Oppen P, Andersson G, Markowitz JC, van Straten A: Interpersonal psychotherapy for depression: a meta-analysis. Am J Psychiatry, 168: 581-592, 2011.
90. Stuart S, Robertson M: Interpersonal Psychotherapy: A Clinician’s Guide. Oxford University Press London: Arnold, New York, 2003.
91. Weissman MM, Markowitz JC, Klerman GL: Comprehensive Guide to Interpersonal Psychotherapy. Basic Books, New York, 2000.
92. Grote NK, Bledsoe SE, Swartz HA, Frank E: Feasibility of providing culturally relevant, brief interpersonal psychotherapy for antenatal depression in an obstetrics clinic: A pilot study. Res Social Work Pract, 14: 397-407, 2004.
93. Schulberg HC, Block MR, Madonia MJ, Scott CP, Rodriguez E, Imber SD, Perel J, Lave J, Houck PR, Coulehan JL: Treating major depression in primary car practice. Eight-month clinical outcomes. Arch Gen Psychiatry, 53: 913-919, 1996.
94. Zlotnick C, Johnson SL, Miller IW, Pearlstein T, Howard M: Postpartum depression in women receiving public assistance: Pilot study of an interpersonal-therapy-oriented group intervention. Am J Psychiatry, 158: 638-640, 2001.
95. Koszycki D, Lafontaine S, Frasure-Smith N, Swenson R, Lespérance F: An open-label trial of interpersonal psychotherapy in depressed patients with coronary disease. Psychosomatics, 45: 319-324, 2004.
96. Miller MD, Paradis C, Houck P, Rifai AH, Mazumdar S, Pollock BG, Perel J, Frank E, Reynolds CF: Chronic medical illness in patients with recurrent major depression: Effects on acute treatment outcome. Am J Geriatr Psychiatry, 4: 281-290, 1996.