INT’L. J. PSYCHIATRY IN MEDICINE, Vol. 46(4) 375-386, 2013
MENTAL ADJUSTMENT TO CANCER: THE ROLE OF ANXIOUS AND DEPRESSIVE SYMPTOMS UNDER TREATMENT*
PASQUALE DE FAZIO, MD ANGELA BARBERI, MD FRANCESCA CAGLIOTI, MD TASSONE PIERFRANCESCO, MD TAGLIAFERRI PIERSANDRO, MD CRISTINA SEGURA-GARCÍA, MD, PHD University Magna Græcia of Catanzaro, Italy
ABSTRACT
Objective: Depression is a risk factor for poor quality of life and mental adjustment to cancer. This research aims to evaluate the course of mental adjustment to illness of cancer patients with anxious-depressive symptoms who receive antidepressant therapy (ADT). Method: Eighty oncological patients with and without depressive symptoms were divided into three groups. Group 1: 30 depressed cancer patients who underwent ADT with SSRI; Group 2: 30 depressed cancer patients who refused ADT; Group 3: 20 non-depressed cancer patients. Patients were evaluated at t0 and 4 (t1) and
*The present research was supported by an Italian grant from the Ministry of University and Scientific Research (Progetto di Ricerca di Interesse Nazionale: Caratterizzazione fenogenotipica dell’adattamento mentale al cancro e della risposta al trattamento con farmaci antidepressivi in oncologia 20074XMRSE_003). 375 Ó 2013, Baywood Publishing Co., Inc. doi: http://dx.doi.org/10.2190/PM.46.4.d http://baywood.com
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12 (t2) weeks later through: Hamilton Depression Rating Scale (HDRS), Hamilton Anxiety Rating Scale (HARS), Hospital Anxiety Depression Scale (HADS), and MINI-MAC. Results: HDRS and HARS mean scores were stable and under threshold across the study only in Group 3; at t2 they improved in Group 1 and worsened in Group 2. The improvements in anxiety and depression scores were associated with ADT and related to the changes in Mini-MAC helpless-hopeless, anxious preoccupations, cognitive avoidance and fighting spirit dimensions. Conclusion: The improvement of mental adjustment to illness is directly related to the decrease of anxious-depressive symptoms among depressed cancer patients under antidepressant therapy. (Int’l. J. Psychiatry in Medicine 2013;46:375-386)
Key Words: cancer, psychological adjustment, depression, anxiety, antidepressive agents
INTRODUCTION Depression represents the most frequent psychopathological complication of patients with cancer; the comorbidity has been reported to reach 50% of patients but it is only adequately recognized and cured in a small number of cases [1-4]. Several reasons can explain this fact. First, depression is considered a normal adaptive reaction to cancer diagnosis, so this problem is often neglected and an accurate clinical diagnosis tends not to be done [5] and accordingly not treated [6, 7]. Second, depressive symptoms that do not fulfill the DSM-IV criteria for Depressive Disorders [8] are more frequent [9]. Third, oncologists are able to identify depressed mood and crying without difficulty, but anhedonia, weight loss, ideas of guilt, suicidal thoughts, and hopelessness can remain hindered to less trained doctors regarding the psychic examination [10]. Fourth, somatic symptoms may have greater weight than the psychological symptoms to diagnose depression in some patients with cancer [11]. Consequently, mild to moderate depression, secondary to other disorders, is less clearly recognized by oncologists compared to more serious forms. The clinical and social meaning of depression in cancer patients is given by the important individual and familiar consequences of the symptoms. Depressive disorders are demonstrated to be a risk factor for longer hospitalization and functional recovery, non-adaptive coping and abnormal illness behavior, poorer quality of life, greater perception of physical symptoms as pain, less compliance to the medical therapy, less efficient chemotherapy treatment, higher suicidal risk, higher recurrence and mortality risk, and higher rate of psychiatric disorders in relatives [12, 13]. The present study aims to evaluate the course of mental adjustment to cancer of oncological patients with anxious-depressive symptoms who receive antidepressant therapy (ADT).
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METHODS Subjects and Recruitment From September to December 2009, 80 consecutive oncological patients from a Day Hospital Oncological Unit were recruited for this study. Patients were evaluated following a request of psychiatric consultation by an oncologist. All patients gave their written informed consent both to the psychiatric visit and to enter the study. This research protocol was approved by the Ethics Committee of the Azienda Ospedaliera Universitaria Mater Domini of Catanzaro according to local and international standards. Criteria for inclusion in the study were considered: cancer patients at their first oncological diagnosis and the request of psychiatric consultation by an oncologist for suspected anxious-depressive symptoms. Furthermore, age under 18, tumors originated in or metastasized to the central nervous system, neoplastic recurrences, previous psychiatric history of affective disorders and actual psychiatric comorbidity according to DSM-IV TR were considered exclusion criteria. In the same period, 20 control non-depressed oncological patients were recruited from the same unit. The same exclusion criteria were used for the control group. Eighty oncological patients were initially enrolled and subdivided into three groups depending on the presence of anxious-depressive symptoms and the adherence to the ADT proposed by the psychiatrist (Figure 1). Patients that fulfilled the criteria for Mayor Depressive Disorder, Adjustment Disorder with Depressed Mood, Adjustment Disorder with Mixed Anxiety and Depressed Mood, or Depressive Disorders due to Medical Conditions according to DSM-IV TR criteria were included. An antidepressant therapy with escitalopram (5-15 mg daily) was proposed to patients with clinically relevant symptoms of depression. Escitalopram was chosen on the basis of data on efficacy, tolerability, and lack of interactions with other possible therapies currently used by oncological patients [14-16]. Measures Patients were evaluated in three moments: at the time of the first psychiatric visit (t0) and four (t1) and twelve weeks (t2) after the first psychiatric visit. Both objective and subjective evaluation of depressive and anxious symptoms were respectively done through the following self-report and investigatorbased tests: • Hamilton Depression Rating Scale (HDRS) [17, 18]: This 21-item heteroadministered scale was used to evaluate depressive symptoms and their modification after treatment. Total HDRS score £ 7 is considered subclinical depression, 8-17 mild depression, 18-24 moderate depression, and ³ 25 serious depression. In the present research, Cronbach’s alpha coefficients were respectively .819, .882, and .898 at t0, t1, and t2.
Figure 1. Groups description.
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• Hamilton Anxiety Rating Scale (HARS) [19, 20]: This scale aims to measure the modification of anxiety under therapy through 14 items rated by an investigator. HARS total score ³ 18 is considered pathological. Cronbach’s alpha coefficients were respectively .890, .930, and .938 at each evaluation. • Hospital Anxiety Depression scale (HADS) [21]: This well-validated selfrated questionnaire was created to assess general anxiety and depression in non-psychiatric medical patients through two separate scores, respectively HADS-A and HADS-D. Its utility in evaluating anxiety and depression in cancer patients has been previously demonstrated [22]. For both the anxiety and depression scales, a score < 8 is considered within the normal range, 8-10 indicates a possible, and > 10 a probable mood disorder. In our study, Cronbach’s alpha coefficients were .881, .897, and .931. • The Mini-MAC [23] is a revised version of the well known Mental Adjustment to Cancer scale (MAC) [24], that measures mental adjustment to cancer in a general cancer population. The Mini-MAC consists of 29 Likert-type items rated on a 4-point scale that assesses current patients’ experiences and gives information on five dimensions: Helpless-Hopeless, Cognitive Avoidance, Fighting Spirit, Anxious Preoccupation, and Fatalism. Higher scores represent higher endorsement of the adjustment responses. The domains can be scored separately through simple addition and the final score of each domain can be calculated by dividing the sum by number of items. The test was administered at t0, t1, and t3 and Cronbach’s alpha coefficients were respectively .750, .804, and .764. Assessments took place individually by one of two well-trained psychiatrists under the supervision of an investigator. Participants were informed that the participation in the study was voluntary and anonymous, were reassured that there were no right or wrong answers to the tests, and were guaranteed the confidentiality of the responses.
Statistics Data were analyzed using the Statistical Package for the Social Science, version 18.0 (SPSS Inc., Chicago Illinois) and are presented as means, standard deviations, and frequency of occurrence (%). Univariate analysis was applied to group comparisons by means of t-test for continuous variables and chi-square test for categorical ones. The level of statistical significance was set at p < .05. Multivariate analysis, including General Linear Model with Repeated Measures (GLM Repeated Measures), were done to compare the modification of depression and anxiety levels and coping strategies during the time (t0, t1, and t2) between the three groups.
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Effect sizes (ES) were calculated for all significant findings, with values (negative or positive) of 0.2, 0.6, 1.2, and > 1.2 indicating trivial, small, moderate, and large effect sizes, respectively. RESULTS During the course of the research, 37 patients dropped-out due to death, transfer to other hospitals, lack of compliance to the compilation of the tests, or refusal of informed consent to the subsequent psychiatric visits. No drop-out was observed due to escitalopram therapy side-effects. Forty-three patients completed the research and were divided into the three following groups (Figure 1): • Group I: Fifteen oncological patients (mean age 53.9 ± 8.8) with clinically relevant affective symptoms at the first psychiatric consultation that accepted to undergo ADT with escitalopram (12.2 ± 2.7 mg/day; range = 5-15 mg/day). • Group II: Fourteen oncological patients (mean age 56.9 ± 14.4) with clinically relevant affective symptoms at the first psychiatric consultation that refused to undergo ADT. • Group III: Fourteen oncological patients (mean age 51.1 ± 8.4) without relevant affective symptoms at t0 to whom ADT was not proposed. So, the final sample was made of 31 female and 12 male oncological patients, average age 53.95 (SD = 9.32; range = 18-65), predominantly married patients with medium cultural level (Table 1). The groups were homogeneous regarding gender, age, marital status, and education. Group II showed the most advanced stage of illness at t0 (c2 = 24.393; p < .001). The most common diagnoses were digestive tract and breast cancer; diagnoses were similar with regard to group (c2 = 54.18; p = .10) and the stage of the cancer (c2 = 42.14; p = .16). Sixty-two percent of patients had a metastasis at t0; metastasis were significantly associated to cancer stage (c2 = 25.20; p < .001) and the length of the illness (c2 = 11.90; p < .01); nonetheless there was no association between the length of illness and the cancer stage (c2 = 11.65; p = .23). The length of illness in more than one-third of the sample exceeded 36 months. About half of patients had a positive oncological family history, especially Group 2 (c2 = 7.19; p < .05). A high percentage of patients showed depressive and anxious symptoms at t0, and GLM Repeated Measures showed significant differences in anxiety and depression scores between groups through time (Table 2). The same pattern of improvement of depression and anxiety levels in Group 1 and a worsening in Group 2 was evident for HDRS, HARS, and HADS; Group 3 remained stationary at every evaluation. Every patient in Group 1 and Group 2 showed depressive symptoms at t0 when measured through HDRS. There was a decrement of patients positive to HDRS in Group 1 at t2 while in Group 2 symptoms were not only
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Table 1. Sample Descriptiona Group 1 N = 15
Group 2 N = 14
Group 3 N = 14
Gender Female
10 (67)
10 (71)
11 (79)
Marital status Married Divorced Widow
13 (87) 0 2 (13)
13 (93) 0 1 (7)
11 (79) 2 (14) 1 (7)
0.515
2 (13) 7 (47) 3 (20) 3 (20)
5 (36) 1 (7) 6 (43) 2 (14)
1 (7) 6 (43) 4 (29) 3 (21)
9.053
Active worker (yes)
12 (80)
11 (79)
10 (71)
0.337
Stage of cancer (t0) I II III IV
1 (7) 5 (33) 9 (60) 0
0 2 (14) 7 (50) 5 (36)
5 (36) 7 (50) 2 (14) 0
***24.393
Metastasis (yes)
8 (53)
12 (86)
7 (50)
4.703
Cortisone therapy (yes)
9 (60)
12 (86)
13 (93)
5.278
Cancer familiarity (yes)
8 (53)
10 (71)
3 (21)
*7.190
Psychiatric familiarity (yes)
5 (33)
3 (21)
3 (21)
0.727
Education Elementary Middle school High school College
c2
aValues are presented as Frequencies (Percentages).
*p < .05; ***p < .001.
constant in all patients but the severity of depression worsened. Two-thirds of patients were positive to HARS at t0 (HARS ³ 18). Group 3 never scored higher than the threshold. Each of the 43 patients scored both HADS-D and HADS-A ³ 8 at each evaluation indicating that, even among these cancer patients for whom the clinician had not detected clinically relevant depressive symptoms (Group 3), at least a minimum perception of anxiety and depression was detected by selfreport scales (HADS-A and HADS-D). Nonetheless, multivariate analysis showed significant differences between groups where Group 2 showed a clear worsening at t2 when compared to the others. Depression levels (HADS-D) were always higher than anxiety levels (HADS-A) except for Group 3 at t1 and t2.
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Table 2. GLM Repeated Measures of HDRS, HARS, HADS, and Mini-MACa Tests of betweensubjects effects
Time
Group 1 N = 15
Group 2 N = 14
Group 3 N = 14
HDRS
t0 t1 t2
18.1 (3.5) 11.9 (4.4) 10.8 (6.0)
19.9 (3.5) 22.9 (3.5) 24.2 (3.6)
6.5 (1.7) 6.0 (1.6) 6.7 (1.9)
***113.3005
HARS
t0 t1 t2
22.0 (6.7) 14.4 (7.7) 14.3 (7.9)
22.4 (5.2) 25.6 (6.5) 29.1 (5.1)
10.9 (3.8) 9.3 (3.5) 10.1 (3.5)
***36.417
HADS-D
t0 t1 t2
18.1 (3.4) 16.1 (3.3) 14.4 (3.5)
19.2 (3.3) 21.2 (3.3) 20.9 (2.9)
10.9 (1.7) 11.0 (2.1) 10.0 (2.1)
***16.443
HADS-A
t0 t1 t2
19.4 (4.0) 15.1 (3.8) 14.3 (4.1)
18.4 (2.7) 19.8 (3.1) 20.4 (3.0)
12.3 (2.3) 12.5 (2.0) 11.7 (2.4)
***15.698
Mini-MAC HelplessHopeless
t0 t1 t2
19.9 (4.7) 17.1 (7.2) 17.6 (8.1)
19.6 (7.8) 19.6 (7.5) 21.6 (7.0)
10.6 (2.3) 11.2 (3.0) 11.4 (2.9)
***13.148
Mini-MAC Anxious preoccupations
t0 t1 t2
24.3 (6.5) 23.0 (5.3) 22.1 (5.5)
26.5 (4.4) 26.1 (4.5) 26.6 (4.3)
19.4 (6.2) 20.0 (8.0) 20.3 (6.8)
**6.250
Mini-MAC Fighting spirit
t0 t1 t2
11.5 (2.2) 12.1 (3.4) 12.5 (3.0)
11.4 (2.8) 11.6 (2.8) 11.9 (3.0)
14.0 (2.1) 14.1 (1.9) 13.8 (2.3)
*3.842
Mini-MAC Cognitive avoidance
t0 t1 t2
14.4 (7.4) 12.1 (2.6) 15.0 (7.3)
12.9 (2.3) 12.9 (2.5) 12.6 (1.7)
11.5 (4.0) 11.9 (4.0) 12.9 (3.5)
0.761
Mini-MAC Fatalism
t0 t1 t2
15.5 (2.6) 15.9 (3.9) 16.7 (2.7)
16.6 (2.4) 17.8 (2.1) 17.2 (2.2)
16.9 (3.3) 15.4 (3.7) 15.9 (4.0)
1.109
aValues are presented as Means (SD). *p < .05; **p < .01; ***p < .001.
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Regarding Mini-MAC scores, the highest difference between groups was found in the Helpless-Hopeless dimension: Group 3 showed the lowest and most stable scores, Group 1 a decrease and Group 2 an increase at the end of the study. A similar pattern was observed for Anxious Preoccupations while the Fighting Spirit improved only in Group 1. No differences in Cognitive Avoidance and Fatalism were found between groups across the evaluation.
DISCUSSION The requests for psychiatric consultation by the oncologists were appropriate in the group of cancer patients included in the present study as all patients in Groups 1 and 2 had at least moderate symptoms of anxiety and depression. Data have also demonstrated a minimum perception of anxiety and depression in Group 3. This fact stands out once again of the different perception and evaluation of the symptoms by the clinician and the patient [10, 25], even if the symptoms remained stable at a subclinical level for the duration of the study in the control group. As previously demonstrated [26, 27], anxiety, depression, and mental maladjustment to cancer were present but modifiable by antidepressant treatment: ADT significantly reduced the levels of anxiety and depression among the depressed oncological patients that accepted the treatment and, contrarily, anxiety and depression worsened without pharmacological therapy in the group of depressed patients that rejected the antidepressant treatment. Data related to depressed oncological patients who refused antidepressant therapy (Group 2) were particularly interesting. They had a greater family history of cancer and were in a more advanced stage of cancer even if they were the same age as the other groups [28]. Although patients in more advanced stages of cancer are less likely to receive antidepressant therapy compared to patients in earlier stages, or the antidepressants are often prescribed too late in the final two weeks of life [26], it should be investigated if the previous oncological family experience of cancer patients can undermine the expectation of improvement and result in the rejection of ADT. It could explain that more advanced stage of illness together with the untreated depression results in worse adjustment to cancer, i.e., higher helpless-hopeless and fatalism and lower fighting spirit. Hope and optimism have been negatively correlated to cancer patients’ level of anxiety and depression [29, 30]. In our study there was a parallel change in the levels of anxious and depressive symptoms and in the adaptation to cancer disease, with major reduction in the Helpless-Hopeless and Anxious Preoccupations dimensions and a significant increase of the Fighting Spirit component that we consider related to a better adherence to cancer treatment as described by others [31].
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Clinical Implications These results let us not consider depression as a normal reaction to cancer but to recommend a specialized evaluation with further therapy if necessary in depressed oncological patients. The mental adaptation to cancer should not be considered dependent on the illness itself but on the patient’s affective state, so the improvement of patients’ anxiety and depression through ADT could enhance their coping skills with cancer. Limits The most important limit of this study was the small sample size. This was due, in part, to the restrictive inclusion criteria; that is, a specific population of oncological patients with anxious-depressive symptoms referred by the oncologists for psychiatric consultation and secondly to the large number of drop-outs. Therefore, a more complex statistical analysis of the data could not be carried out. REFERENCES 1. Pasquini M, Biondi M. Depression in cancer patients: A critical review. Clinical Practice and Epidemiology in Mental Health 2007;3:2. doi: 10.1186/1745-0179-3-2 2. Caplette-Gingras A, Savard J. Depression in women with metastatic breast cancer: A review of the literature. Palliative & Supportive Care 2008;6:377-387. doi: 10.1017/ S1478951508000606 3. Wein S, Sulkes A, Stemmer S. The oncologist’s role in managing depression, anxiety, and demoralization with advanced cancer. The Cancer Journal 2010;16:493-499. doi: 10.1097/PPO.0b013e3181f28b64 4. Salvo N, Zeng L, Zhang L, Leung M, Khan L, Presutti R, Nguyen J, Holden L, Culleton S, Chow E. Frequency of reporting and predictive factors for anxiety and depression in patients with advanced cancer. Clinical Oncology 2012;24:139-148. doi: 10.1016/j.clon.2011.05.003 5. Fulcher CD, Badger T, Gunter AK, Marrs JA, Reese JM. Putting evidence into practice: Interventions for depression. Clinical Journal of Oncology Nursing 2008; 12:131-140. doi: 10.1188/08.CJON.131-140 6. 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. General Hospital Psychiatry 2008;30:112-126. doi: 10.1016/j.genhosp psych.2007.10.008 7. Theobald DE, Kirsh KL, Holtsclaw EBA, Donaghy K, Passik SD. An open label pilot study of citalopram for depression and boredom in ambulatory cancer patients. Palliative & Supportive Care 2003;1:71-77. doi: 10.1017/S1478951503030037 8. American Psychiatric Association. Diagnostical and statistical manual of mental disorders (4th ed.; text revision). Washington, DC: American Psychiatric Press, 2000. 9. Spoletini I, Gianni W, Repetto L, Bria P, Caltagirone C, Bossù P, Spalletta G. Depression and cancer: An unexplored and unresolved emergent issue in elderly
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25. Pasquini M, Berardelli I, Cabra A, Maraone A, Matteucci G, Biondi M. Core depressive symptoms in depressed cancer outpatients. Clinical Practice and Epidemiology in Mental Health 2011;7:178-181. doi: 10.2174/1745017901107010178 26. Potash M, Breitbart W. Affective disorders in advanced cancer. Hematology/Oncology Clinics of North America 2002;16:671-700. doi: 10.1016/s0889-8588(02)00013-8 27. Torta R, Leombruni P, Borio R, Castelli L. Duloxetine for the treatment of mood disorder in cancer patients: A 12-week case-control clinical trial. Human Psychopharmacology 2011;4-5:291-299. doi: 10.1002/hup.1202 28. Weinberger MI, Bruce ML, Roth AJ, Breitbart W, Nelson CJ. Depression and barriers to mental health care in older cancer patients. International Journal of Geriatric Psychiatry 2011;26:21-26. doi: 10.1002/gps.2497 29. Shapiro JP, McCue K, Heyman EN, Dey T, Haller HS. Coping-related variables associated with individual differences in adjustment to cancer. Journal of Psychosocial Oncology 2010;28:1-22. doi: 10.1080/07347330903438883 30. Rajandram RK, Ho SM, Samman N, Chan N, McGrath C, Zwahlen RA. Interaction of hope and optimism with anxiety and depression in a specific group of cancer survivors: A preliminary study. BMC Research Notes 2001;4:519. doi: 10.1186/ 1756-0500-4-519 31. Schillani G, Capozzo MA, Era D, De Vanna M, Grassi L, Conte MA, Giraldi T. Pharmacogenetics of escitalopram and mental adaptation to cancer in palliative care: Report of 18 cases. Tumori 2012;97:358-361. doi: 10.1700/912.10034
Direct reprint requests to: Cristina Segura-García Chair of Psychiatry Department of Health Sciences University “Magna Græcia” of Catanzaro Campus Universitario “Salvatore Venuta” Viale Europa 88100-Catanzaro, Italy e-mail: [email protected]
MENTAL ADJUSTMENT TO CANCER: THE ROLE OF ANXIOUS AND DEPRESSIVE SYMPTOMS UNDER TREATMENT*
PASQUALE DE FAZIO, MD ANGELA BARBERI, MD FRANCESCA CAGLIOTI, MD TASSONE PIERFRANCESCO, MD TAGLIAFERRI PIERSANDRO, MD CRISTINA SEGURA-GARCÍA, MD, PHD University Magna Græcia of Catanzaro, Italy
ABSTRACT
Objective: Depression is a risk factor for poor quality of life and mental adjustment to cancer. This research aims to evaluate the course of mental adjustment to illness of cancer patients with anxious-depressive symptoms who receive antidepressant therapy (ADT). Method: Eighty oncological patients with and without depressive symptoms were divided into three groups. Group 1: 30 depressed cancer patients who underwent ADT with SSRI; Group 2: 30 depressed cancer patients who refused ADT; Group 3: 20 non-depressed cancer patients. Patients were evaluated at t0 and 4 (t1) and
*The present research was supported by an Italian grant from the Ministry of University and Scientific Research (Progetto di Ricerca di Interesse Nazionale: Caratterizzazione fenogenotipica dell’adattamento mentale al cancro e della risposta al trattamento con farmaci antidepressivi in oncologia 20074XMRSE_003). 375 Ó 2013, Baywood Publishing Co., Inc. doi: http://dx.doi.org/10.2190/PM.46.4.d http://baywood.com
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12 (t2) weeks later through: Hamilton Depression Rating Scale (HDRS), Hamilton Anxiety Rating Scale (HARS), Hospital Anxiety Depression Scale (HADS), and MINI-MAC. Results: HDRS and HARS mean scores were stable and under threshold across the study only in Group 3; at t2 they improved in Group 1 and worsened in Group 2. The improvements in anxiety and depression scores were associated with ADT and related to the changes in Mini-MAC helpless-hopeless, anxious preoccupations, cognitive avoidance and fighting spirit dimensions. Conclusion: The improvement of mental adjustment to illness is directly related to the decrease of anxious-depressive symptoms among depressed cancer patients under antidepressant therapy. (Int’l. J. Psychiatry in Medicine 2013;46:375-386)
Key Words: cancer, psychological adjustment, depression, anxiety, antidepressive agents
INTRODUCTION Depression represents the most frequent psychopathological complication of patients with cancer; the comorbidity has been reported to reach 50% of patients but it is only adequately recognized and cured in a small number of cases [1-4]. Several reasons can explain this fact. First, depression is considered a normal adaptive reaction to cancer diagnosis, so this problem is often neglected and an accurate clinical diagnosis tends not to be done [5] and accordingly not treated [6, 7]. Second, depressive symptoms that do not fulfill the DSM-IV criteria for Depressive Disorders [8] are more frequent [9]. Third, oncologists are able to identify depressed mood and crying without difficulty, but anhedonia, weight loss, ideas of guilt, suicidal thoughts, and hopelessness can remain hindered to less trained doctors regarding the psychic examination [10]. Fourth, somatic symptoms may have greater weight than the psychological symptoms to diagnose depression in some patients with cancer [11]. Consequently, mild to moderate depression, secondary to other disorders, is less clearly recognized by oncologists compared to more serious forms. The clinical and social meaning of depression in cancer patients is given by the important individual and familiar consequences of the symptoms. Depressive disorders are demonstrated to be a risk factor for longer hospitalization and functional recovery, non-adaptive coping and abnormal illness behavior, poorer quality of life, greater perception of physical symptoms as pain, less compliance to the medical therapy, less efficient chemotherapy treatment, higher suicidal risk, higher recurrence and mortality risk, and higher rate of psychiatric disorders in relatives [12, 13]. The present study aims to evaluate the course of mental adjustment to cancer of oncological patients with anxious-depressive symptoms who receive antidepressant therapy (ADT).
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METHODS Subjects and Recruitment From September to December 2009, 80 consecutive oncological patients from a Day Hospital Oncological Unit were recruited for this study. Patients were evaluated following a request of psychiatric consultation by an oncologist. All patients gave their written informed consent both to the psychiatric visit and to enter the study. This research protocol was approved by the Ethics Committee of the Azienda Ospedaliera Universitaria Mater Domini of Catanzaro according to local and international standards. Criteria for inclusion in the study were considered: cancer patients at their first oncological diagnosis and the request of psychiatric consultation by an oncologist for suspected anxious-depressive symptoms. Furthermore, age under 18, tumors originated in or metastasized to the central nervous system, neoplastic recurrences, previous psychiatric history of affective disorders and actual psychiatric comorbidity according to DSM-IV TR were considered exclusion criteria. In the same period, 20 control non-depressed oncological patients were recruited from the same unit. The same exclusion criteria were used for the control group. Eighty oncological patients were initially enrolled and subdivided into three groups depending on the presence of anxious-depressive symptoms and the adherence to the ADT proposed by the psychiatrist (Figure 1). Patients that fulfilled the criteria for Mayor Depressive Disorder, Adjustment Disorder with Depressed Mood, Adjustment Disorder with Mixed Anxiety and Depressed Mood, or Depressive Disorders due to Medical Conditions according to DSM-IV TR criteria were included. An antidepressant therapy with escitalopram (5-15 mg daily) was proposed to patients with clinically relevant symptoms of depression. Escitalopram was chosen on the basis of data on efficacy, tolerability, and lack of interactions with other possible therapies currently used by oncological patients [14-16]. Measures Patients were evaluated in three moments: at the time of the first psychiatric visit (t0) and four (t1) and twelve weeks (t2) after the first psychiatric visit. Both objective and subjective evaluation of depressive and anxious symptoms were respectively done through the following self-report and investigatorbased tests: • Hamilton Depression Rating Scale (HDRS) [17, 18]: This 21-item heteroadministered scale was used to evaluate depressive symptoms and their modification after treatment. Total HDRS score £ 7 is considered subclinical depression, 8-17 mild depression, 18-24 moderate depression, and ³ 25 serious depression. In the present research, Cronbach’s alpha coefficients were respectively .819, .882, and .898 at t0, t1, and t2.
Figure 1. Groups description.
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• Hamilton Anxiety Rating Scale (HARS) [19, 20]: This scale aims to measure the modification of anxiety under therapy through 14 items rated by an investigator. HARS total score ³ 18 is considered pathological. Cronbach’s alpha coefficients were respectively .890, .930, and .938 at each evaluation. • Hospital Anxiety Depression scale (HADS) [21]: This well-validated selfrated questionnaire was created to assess general anxiety and depression in non-psychiatric medical patients through two separate scores, respectively HADS-A and HADS-D. Its utility in evaluating anxiety and depression in cancer patients has been previously demonstrated [22]. For both the anxiety and depression scales, a score < 8 is considered within the normal range, 8-10 indicates a possible, and > 10 a probable mood disorder. In our study, Cronbach’s alpha coefficients were .881, .897, and .931. • The Mini-MAC [23] is a revised version of the well known Mental Adjustment to Cancer scale (MAC) [24], that measures mental adjustment to cancer in a general cancer population. The Mini-MAC consists of 29 Likert-type items rated on a 4-point scale that assesses current patients’ experiences and gives information on five dimensions: Helpless-Hopeless, Cognitive Avoidance, Fighting Spirit, Anxious Preoccupation, and Fatalism. Higher scores represent higher endorsement of the adjustment responses. The domains can be scored separately through simple addition and the final score of each domain can be calculated by dividing the sum by number of items. The test was administered at t0, t1, and t3 and Cronbach’s alpha coefficients were respectively .750, .804, and .764. Assessments took place individually by one of two well-trained psychiatrists under the supervision of an investigator. Participants were informed that the participation in the study was voluntary and anonymous, were reassured that there were no right or wrong answers to the tests, and were guaranteed the confidentiality of the responses.
Statistics Data were analyzed using the Statistical Package for the Social Science, version 18.0 (SPSS Inc., Chicago Illinois) and are presented as means, standard deviations, and frequency of occurrence (%). Univariate analysis was applied to group comparisons by means of t-test for continuous variables and chi-square test for categorical ones. The level of statistical significance was set at p < .05. Multivariate analysis, including General Linear Model with Repeated Measures (GLM Repeated Measures), were done to compare the modification of depression and anxiety levels and coping strategies during the time (t0, t1, and t2) between the three groups.
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Effect sizes (ES) were calculated for all significant findings, with values (negative or positive) of 0.2, 0.6, 1.2, and > 1.2 indicating trivial, small, moderate, and large effect sizes, respectively. RESULTS During the course of the research, 37 patients dropped-out due to death, transfer to other hospitals, lack of compliance to the compilation of the tests, or refusal of informed consent to the subsequent psychiatric visits. No drop-out was observed due to escitalopram therapy side-effects. Forty-three patients completed the research and were divided into the three following groups (Figure 1): • Group I: Fifteen oncological patients (mean age 53.9 ± 8.8) with clinically relevant affective symptoms at the first psychiatric consultation that accepted to undergo ADT with escitalopram (12.2 ± 2.7 mg/day; range = 5-15 mg/day). • Group II: Fourteen oncological patients (mean age 56.9 ± 14.4) with clinically relevant affective symptoms at the first psychiatric consultation that refused to undergo ADT. • Group III: Fourteen oncological patients (mean age 51.1 ± 8.4) without relevant affective symptoms at t0 to whom ADT was not proposed. So, the final sample was made of 31 female and 12 male oncological patients, average age 53.95 (SD = 9.32; range = 18-65), predominantly married patients with medium cultural level (Table 1). The groups were homogeneous regarding gender, age, marital status, and education. Group II showed the most advanced stage of illness at t0 (c2 = 24.393; p < .001). The most common diagnoses were digestive tract and breast cancer; diagnoses were similar with regard to group (c2 = 54.18; p = .10) and the stage of the cancer (c2 = 42.14; p = .16). Sixty-two percent of patients had a metastasis at t0; metastasis were significantly associated to cancer stage (c2 = 25.20; p < .001) and the length of the illness (c2 = 11.90; p < .01); nonetheless there was no association between the length of illness and the cancer stage (c2 = 11.65; p = .23). The length of illness in more than one-third of the sample exceeded 36 months. About half of patients had a positive oncological family history, especially Group 2 (c2 = 7.19; p < .05). A high percentage of patients showed depressive and anxious symptoms at t0, and GLM Repeated Measures showed significant differences in anxiety and depression scores between groups through time (Table 2). The same pattern of improvement of depression and anxiety levels in Group 1 and a worsening in Group 2 was evident for HDRS, HARS, and HADS; Group 3 remained stationary at every evaluation. Every patient in Group 1 and Group 2 showed depressive symptoms at t0 when measured through HDRS. There was a decrement of patients positive to HDRS in Group 1 at t2 while in Group 2 symptoms were not only
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Table 1. Sample Descriptiona Group 1 N = 15
Group 2 N = 14
Group 3 N = 14
Gender Female
10 (67)
10 (71)
11 (79)
Marital status Married Divorced Widow
13 (87) 0 2 (13)
13 (93) 0 1 (7)
11 (79) 2 (14) 1 (7)
0.515
2 (13) 7 (47) 3 (20) 3 (20)
5 (36) 1 (7) 6 (43) 2 (14)
1 (7) 6 (43) 4 (29) 3 (21)
9.053
Active worker (yes)
12 (80)
11 (79)
10 (71)
0.337
Stage of cancer (t0) I II III IV
1 (7) 5 (33) 9 (60) 0
0 2 (14) 7 (50) 5 (36)
5 (36) 7 (50) 2 (14) 0
***24.393
Metastasis (yes)
8 (53)
12 (86)
7 (50)
4.703
Cortisone therapy (yes)
9 (60)
12 (86)
13 (93)
5.278
Cancer familiarity (yes)
8 (53)
10 (71)
3 (21)
*7.190
Psychiatric familiarity (yes)
5 (33)
3 (21)
3 (21)
0.727
Education Elementary Middle school High school College
c2
aValues are presented as Frequencies (Percentages).
*p < .05; ***p < .001.
constant in all patients but the severity of depression worsened. Two-thirds of patients were positive to HARS at t0 (HARS ³ 18). Group 3 never scored higher than the threshold. Each of the 43 patients scored both HADS-D and HADS-A ³ 8 at each evaluation indicating that, even among these cancer patients for whom the clinician had not detected clinically relevant depressive symptoms (Group 3), at least a minimum perception of anxiety and depression was detected by selfreport scales (HADS-A and HADS-D). Nonetheless, multivariate analysis showed significant differences between groups where Group 2 showed a clear worsening at t2 when compared to the others. Depression levels (HADS-D) were always higher than anxiety levels (HADS-A) except for Group 3 at t1 and t2.
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Table 2. GLM Repeated Measures of HDRS, HARS, HADS, and Mini-MACa Tests of betweensubjects effects
Time
Group 1 N = 15
Group 2 N = 14
Group 3 N = 14
HDRS
t0 t1 t2
18.1 (3.5) 11.9 (4.4) 10.8 (6.0)
19.9 (3.5) 22.9 (3.5) 24.2 (3.6)
6.5 (1.7) 6.0 (1.6) 6.7 (1.9)
***113.3005
HARS
t0 t1 t2
22.0 (6.7) 14.4 (7.7) 14.3 (7.9)
22.4 (5.2) 25.6 (6.5) 29.1 (5.1)
10.9 (3.8) 9.3 (3.5) 10.1 (3.5)
***36.417
HADS-D
t0 t1 t2
18.1 (3.4) 16.1 (3.3) 14.4 (3.5)
19.2 (3.3) 21.2 (3.3) 20.9 (2.9)
10.9 (1.7) 11.0 (2.1) 10.0 (2.1)
***16.443
HADS-A
t0 t1 t2
19.4 (4.0) 15.1 (3.8) 14.3 (4.1)
18.4 (2.7) 19.8 (3.1) 20.4 (3.0)
12.3 (2.3) 12.5 (2.0) 11.7 (2.4)
***15.698
Mini-MAC HelplessHopeless
t0 t1 t2
19.9 (4.7) 17.1 (7.2) 17.6 (8.1)
19.6 (7.8) 19.6 (7.5) 21.6 (7.0)
10.6 (2.3) 11.2 (3.0) 11.4 (2.9)
***13.148
Mini-MAC Anxious preoccupations
t0 t1 t2
24.3 (6.5) 23.0 (5.3) 22.1 (5.5)
26.5 (4.4) 26.1 (4.5) 26.6 (4.3)
19.4 (6.2) 20.0 (8.0) 20.3 (6.8)
**6.250
Mini-MAC Fighting spirit
t0 t1 t2
11.5 (2.2) 12.1 (3.4) 12.5 (3.0)
11.4 (2.8) 11.6 (2.8) 11.9 (3.0)
14.0 (2.1) 14.1 (1.9) 13.8 (2.3)
*3.842
Mini-MAC Cognitive avoidance
t0 t1 t2
14.4 (7.4) 12.1 (2.6) 15.0 (7.3)
12.9 (2.3) 12.9 (2.5) 12.6 (1.7)
11.5 (4.0) 11.9 (4.0) 12.9 (3.5)
0.761
Mini-MAC Fatalism
t0 t1 t2
15.5 (2.6) 15.9 (3.9) 16.7 (2.7)
16.6 (2.4) 17.8 (2.1) 17.2 (2.2)
16.9 (3.3) 15.4 (3.7) 15.9 (4.0)
1.109
aValues are presented as Means (SD). *p < .05; **p < .01; ***p < .001.
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Regarding Mini-MAC scores, the highest difference between groups was found in the Helpless-Hopeless dimension: Group 3 showed the lowest and most stable scores, Group 1 a decrease and Group 2 an increase at the end of the study. A similar pattern was observed for Anxious Preoccupations while the Fighting Spirit improved only in Group 1. No differences in Cognitive Avoidance and Fatalism were found between groups across the evaluation.
DISCUSSION The requests for psychiatric consultation by the oncologists were appropriate in the group of cancer patients included in the present study as all patients in Groups 1 and 2 had at least moderate symptoms of anxiety and depression. Data have also demonstrated a minimum perception of anxiety and depression in Group 3. This fact stands out once again of the different perception and evaluation of the symptoms by the clinician and the patient [10, 25], even if the symptoms remained stable at a subclinical level for the duration of the study in the control group. As previously demonstrated [26, 27], anxiety, depression, and mental maladjustment to cancer were present but modifiable by antidepressant treatment: ADT significantly reduced the levels of anxiety and depression among the depressed oncological patients that accepted the treatment and, contrarily, anxiety and depression worsened without pharmacological therapy in the group of depressed patients that rejected the antidepressant treatment. Data related to depressed oncological patients who refused antidepressant therapy (Group 2) were particularly interesting. They had a greater family history of cancer and were in a more advanced stage of cancer even if they were the same age as the other groups [28]. Although patients in more advanced stages of cancer are less likely to receive antidepressant therapy compared to patients in earlier stages, or the antidepressants are often prescribed too late in the final two weeks of life [26], it should be investigated if the previous oncological family experience of cancer patients can undermine the expectation of improvement and result in the rejection of ADT. It could explain that more advanced stage of illness together with the untreated depression results in worse adjustment to cancer, i.e., higher helpless-hopeless and fatalism and lower fighting spirit. Hope and optimism have been negatively correlated to cancer patients’ level of anxiety and depression [29, 30]. In our study there was a parallel change in the levels of anxious and depressive symptoms and in the adaptation to cancer disease, with major reduction in the Helpless-Hopeless and Anxious Preoccupations dimensions and a significant increase of the Fighting Spirit component that we consider related to a better adherence to cancer treatment as described by others [31].
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Clinical Implications These results let us not consider depression as a normal reaction to cancer but to recommend a specialized evaluation with further therapy if necessary in depressed oncological patients. The mental adaptation to cancer should not be considered dependent on the illness itself but on the patient’s affective state, so the improvement of patients’ anxiety and depression through ADT could enhance their coping skills with cancer. Limits The most important limit of this study was the small sample size. This was due, in part, to the restrictive inclusion criteria; that is, a specific population of oncological patients with anxious-depressive symptoms referred by the oncologists for psychiatric consultation and secondly to the large number of drop-outs. Therefore, a more complex statistical analysis of the data could not be carried out. REFERENCES 1. Pasquini M, Biondi M. Depression in cancer patients: A critical review. Clinical Practice and Epidemiology in Mental Health 2007;3:2. doi: 10.1186/1745-0179-3-2 2. Caplette-Gingras A, Savard J. Depression in women with metastatic breast cancer: A review of the literature. Palliative & Supportive Care 2008;6:377-387. doi: 10.1017/ S1478951508000606 3. Wein S, Sulkes A, Stemmer S. The oncologist’s role in managing depression, anxiety, and demoralization with advanced cancer. The Cancer Journal 2010;16:493-499. doi: 10.1097/PPO.0b013e3181f28b64 4. Salvo N, Zeng L, Zhang L, Leung M, Khan L, Presutti R, Nguyen J, Holden L, Culleton S, Chow E. Frequency of reporting and predictive factors for anxiety and depression in patients with advanced cancer. Clinical Oncology 2012;24:139-148. doi: 10.1016/j.clon.2011.05.003 5. Fulcher CD, Badger T, Gunter AK, Marrs JA, Reese JM. Putting evidence into practice: Interventions for depression. Clinical Journal of Oncology Nursing 2008; 12:131-140. doi: 10.1188/08.CJON.131-140 6. 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. General Hospital Psychiatry 2008;30:112-126. doi: 10.1016/j.genhosp psych.2007.10.008 7. Theobald DE, Kirsh KL, Holtsclaw EBA, Donaghy K, Passik SD. An open label pilot study of citalopram for depression and boredom in ambulatory cancer patients. Palliative & Supportive Care 2003;1:71-77. doi: 10.1017/S1478951503030037 8. American Psychiatric Association. Diagnostical and statistical manual of mental disorders (4th ed.; text revision). Washington, DC: American Psychiatric Press, 2000. 9. Spoletini I, Gianni W, Repetto L, Bria P, Caltagirone C, Bossù P, Spalletta G. Depression and cancer: An unexplored and unresolved emergent issue in elderly
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