Background
Treatment of depression in patients with cancer
Methods
Search strategy
Article selection and review strategy
Statistical methods (meta-analysis)
Results
Search results
Author | Year | Drug | Study design | Participants (n) | Duration | Type of cancer/Stages | Evaluation | Results |
---|---|---|---|---|---|---|---|---|
A. Head-to-head trials
| ||||||||
Holland | 1998 | Fluoxetine vs. Desipramine | Double blind RCT, ITT analysis, LOCF approach | n= 38 | 6 weeks | Breast cancer, Stages II, III, IV | HDRS Other: CGI, PGI, HAS, FLIC, MPAC, SF-36 HS | No significant difference between fluoxetine and desipramine. |
Pezella | 2001 | Paroxetine vs. Amitriptyline | Double blind RCT, ITT analysis, LOCF approach | n= 179 177 received medication | 8 weeks | Breast cancer, any stage | MADRS Other: CGI, FLIC, PGE | 38/88 subjects in the drug group and 33/87 in the amitryptiline group were responders (p= 0.441) |
Cancurtaran | 2008 | Mirtazapine vs. Imipramine vs. Control groupwithout medication | Double blind (for the participants of the two drug groups) RCT, completers’ analysis | n= 53 | 6 weeks | NR | SCID, HADS | Significant improvement in the mirtazapine group. No significant change in the other two groups. |
B. Placebo controlled studies
| ||||||||
Costa | 1985 | Mianserin | Double blind RCT, ITT analysis, LOCF approach | n= 73 | 4 weeks | Gynecological cancer, stages II, III, IV | ZSDRS, HDRS, CGI-S | 28/36 in the Mianserin group and 18/37 in the placebo group were responders (p< 0.025). |
Van Heeringen | 1996 | Mianserin | Double blind RCT, ITT analysis, LOCF approach | n= 55 | 7 weeks | Breast cancer, stages I, II | HDRS | 19/28 patients in the mianserin group and 10/27 in the placebo group were responders (p= 0.044). |
Razavi | 1996 | Fluoxetine | Double blind RCT, completers’ analysis | n= 91 | 5 weeks | Any kind of cancer, any stage | HADS Other: MADRS, HAS, SCL-90R, SQOLI | 18% in the fluoxetine group and 20% in the placebo group were responders (no significant difference) |
Fisch | 2003 | Fluoxetine | Double blind RCT, Completers’ analysis | n= 163 | 12 weeks | Any type of cancer, advanced stage | TQSS, FACT-G, BZRDS | Results available for 129 patients. 31/64 patients in the fluoxetine group and 23/65 in the placebo group were responders (p= 0.12). |
Musselmann | 2006 | Paroxetine vs Desipramine vs placebo | Double blind RCT, ITT analysis, LOCF approach | n= 35 | 6 weeks | Breast cancer, any stage | DSM-III-R- multiaxial evaluation HAD, HAS, CGI | 5/13 in the paroxetine group, 5/11 in the desipramine group and 6/11 in the placebo group were responders (no statistical significance). |
Navari | 2007 | Fluoxetine | Double blind RCT, completers’ analysis | n= 193 | Six months | Breast cancer, stages I, II | TQSS, BZDRS, FACT-G | 71/90 subjects in the fluoxetine group and 23/90 in the placebo group showed a significant (p< 0.01) improvement (p< 0.0005). |
Review of RCTs in depression
Meta-analysis
Effect size
Author | Year | Verum | Verum | Placebo | RR | ||
---|---|---|---|---|---|---|---|
Participants | Responders | Participants | Responders | ||||
Costa | 1985 | Mianserin | 36 | 28 | 37 | 18 | 1.60 |
Van Heeringen | 1996 | Mianserin | 28 | 19 | 27 | 10 | 1.83 |
Razavi | 1996 | Fluoxetine | 45 | 8 | 46 | 9 | 0.91 |
Fisch | 2003 | Fluoxetine | 64 | 31 | 65 | 23 | 1.37 |
Musselmann | 2006 | Paroxetine | 24 | 11 | 11 | 6 | 0.84 |
Navari | 2008 | Fluoxetine | 90 | 71 | 90 | 23 | 3.09 |
287 | 167 | 276 | 89 |
Heterogeneity
Subgroup analysis
Adverse effects and dropouts
Author | Year | Drug | Verum | Placebo | ||
---|---|---|---|---|---|---|
Participants | A.E. | Participants | A.E. | |||
Costa | 1985 | Mianserin | 36 | 17 | 37 | 11 |
Van Heeringen | 1996 | Mianserin | 28 | 11 | 27 | 17 |
Razavi | 1996 | Fluoxetine | 45 | 20 | 46 | 23 |
Fisch | 2003 | Fluoxetine | 64 | NR | 65 | NR |
Musselmann | 2006 | Paroxetine | 24 | NR | 11 | NR |
Navari | 2008 | Fluoxetine | 90 | NR | 90 | NR |
Author | Year | Verum | Placebo | RR | ||
---|---|---|---|---|---|---|
Participants | Dropouts | Participants | Dropouts | |||
Costa | 1985 | 36 | 7 | 37 | 15 | 0.48 |
Van Heeringen | 1996 | 28 | 6 | 27 | 15 | 0.39 |
Razavi | 1996 | 45 | 15 | 46 | 7 | 2.19 |
Fisch | 2003 | 83 | 19 | 80 | 15 | 1.22 |
Musselmann | 2006 | 24 | 10 | 11 | 5 | 0.92 |
216 | 57 | 201 | 57 |
0.86
|
Quality of life
Risk for bias and publication bias
Discussion
Depression and depressive symptoms
Side effects and interactions
Limitations
Conclusions
Appendixes
Appendix A
Listing of the studies
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Number of patients: 40 patients were recruited and 38 ones of these were randomized (21 patients to the fluoxetine and 17 to the desipramine group).
-
Type of cancer/Stages: Breast cancer. Stages: II, III, IV.
-
Duration: six weeks
-
Evaluation tools: the Hamilton Depression Rating Scale (17 item HAM-D), the Clinical and Patient’s Global Impression scales (CGI and PGI), the Hamilton Anxiety Rating scale (HAM-A), the Functional Living Index for Cancer (FLIC), the Memorial Pain Assessment Card (MPAC) and the SF-36 Health Survey.
-
Inclusion criteria: Major depressive episode or adjustment disorder with depressed mood and scores over 14 on the first 17 items of HAM-D.
-
Response criteria: a statistically significant baseline to endpoint change in HAM-D.
-
Design: double blind RCT with ITT analysis, LOCF approach.
-
Results: There was a significant improvement in the HAM-D scores in both group as evidenced by baseline-to-endpoint changes (p<0.001). ANOVA showed no significant difference between fluoxetine and desipramine. Similar improvement was also observed in the HAM-A. There were no significant differences in the dropout rates in the fluoxetine and desipramine group (28.6% and 41.2%, respectively). The only adverse effect revealing a significance difference was dry mouth reported by 14 (66.6%) patients in the fluoxetine group and 4 (23.5%) patients in the desipramine group.
-
Number of patients: 179 patients were randomized into either the paroxetine group (n= 89) or the amitiptyline group (n=90). 88 patients from the first and 87 from the second group received medication and were included in the ITT analysis.
-
Type of cancer/Stages: Breast cancer, any stage.
-
Duration: eight weeks
-
Evaluation tools: Montgomery and Asberg Depression Rating Scale (MADRS), the Clinical Global Impression (CGI), the functional living index: cancer (FLIC) and the patient’s global evaluation (PGE).
-
Inclusion criteria: The patients should fulfill the ICD-10 criteria for depressive episode and have a minimum score of 16 in the MADRS.
-
Response criteria: At least 50% decrease from baseline in MADRS score
-
Design: double blind RCT, ITT analysis, LOCF approach.
-
Results: 38 patients in the paroxetine group (43.7%) and 33 patients in the amitriptyline group (37.8%) were responders (p= 0.441). 47 patients in the first and 53 from the second group reported at least one adverse experience. There were 16 withdrawals in the paroxetine group and 19 withdrawals in the amitriptyline group. The study showed that paroxetine and amitriptyline were similar in efficacy and tolerability.
-
Number of patients: 53 patients participated in this study: 20 patients in the mirtazapine group, 13 patients in the imipramine group and 20 patients in a control group without medication or placebo (only supportive psychotherapy).
-
Type of cancer/Stages: The type and stage of cancer are not further specified.
-
Duration: six seeks
-
Evaluation tools: The patients were screened with the Structured Clinical Interview for Diagnostic (SCID). The Hospital Anxiety and Depression Scale (HADS) was administered for assessment of depression and anxiety during the study.
-
Inclusion criteria: Major depressive disorder, adjustment disorder, anxiety disorders.
-
Response criteria: The authors reported on the statistical significance of the rating differences between baseline and endpoint in each group.
-
Design: double blind RCT (not blinded for those who denied medication and received only psychotherapy), completers’ analysis.
-
Results: The patients in the mirtazapine group improved significantly after the six weeks in the total HADS scores (p=0.014), the anxiety subscale (p=0.04) and the depression subscale (p=0.008). The patients in the other two groups did not show any significant improvement.
-
Number of patients: 73 patients participated in this study (36 in the drug group and 37 in the placebo group).
-
Type of cancer/Stages: Gynecological cancers, stages II, III, IV
-
Duration: four weeks
-
Screening/Evaluation tools: Zung Self-Rating Depression Scale (ZSRDS), Hamilton Depression Rating Scale. Secondary tools measures: Clinical Global Impression of Illness Severity (CGI-S).
-
Inclusion Criteria: ZSRDS over 41 and HDRS score over 16.
-
Response criteria: nor reported.
-
Design: Double blind RCT, ITT analysis, LOCF approach.
-
Results: 28 of the 36 patients of the mianserin group were responders. There were only 18 responders among the 37 participants in the placebo group (response evaluated according to the CGI scores). This difference was statically significant (P<0.025, Chi squared= 6.62). The primary outcome was based on the scores of HDRS. There were 7 dropouts in the mianserin group and 15 in the placebo group. 17 patients from the drug group and 11 from the placebo group reported side effects. This difference was not statistically significant (Chi squared = 2.11).
-
Number of patients: 55 participants in the study (28 in the mianserin group and 27 in the placebo group)
-
Type of cancer/Stages: Breast cancer. Stages I, II
-
Duration: 7 weeks
-
Screening tool: Hamilton Depression Rating Scale (HDRS)
-
Inclusion Criteria: HDRS score over 16
-
Response criteria: 50% decrease in baseline HRDS scores
-
Design: double blind RCT, ITT analysis, LOCF approach.
-
Results: 19 patients from the 28 ones in the mianserin group and 10 patients from the 27 ones in the placebo group were responders. This difference was statistically significant (p=0.044, Fisher’s exact test). Significantly more placebo treated patients (n=15) than mianserin treated patients (n=6) terminated prematurely the study (P=0.014, Fisher’s exact test). No significant differences were found between numbers of patients complaining of at least one adverse effect (AE) at any assessment point. At day 42, 11 mianserin- and 17 placebo- treated patients reported AEs (P=0.14).
-
Number of patients: 91 patients participated in this study (45 in the fluoxetine group and 46 in the placebo group)
-
Type of cancer/Stages: Any kind of cancer (mainly gynecological), any stage (95% without metastases).
-
Duration: five weeks
-
Screening tool: Hospital Anxiety and Depression Scale (HADS). Other measures: the Montgomery and Asberg Depression Scale (MADRS), the Hamilton Anxiety Scale (HAS), the revised Symptom Checklist (SCL-90R) and the Spitzer Quality of Life Index (SQOLI).
-
Inclusion Criteria: a HADS score over 13
-
Response criteria: a 50% decrease or more in the baseline HADS scores
-
Design: double blind RCT, completers’ analysis.
-
Results: The HADS response rates were 18% in the fluoxetine group and 20% in the placebo group. The success rates (HADS scores under 8 at the end of the trial) were 11% (5 patients) and 7% (3 patients) in the drug and placebo group respectively. As a secondary outcome the author reported the response rates in both groups according to MADRS scale (50% improvement): these were 31% (14 patients) for the fluoxetine group and 33% (15 patients) in the placebo group. These differences were not statistically significant. Significantly more drop outs were observed in the drug group (n=15) than in the placebo group (n=7) (Chi Square test; P=0.04). 67% from the fluoxetine group reported at least one AE compared to 59% in the placebo group (not statistically significant difference: P= 0.43).
-
Number of patients: 163 patients participated in the study (83 patients in the fluoxetine group and 80 patients in the placebo group).
-
Type of cancer/Stages: Any type of cancer in advanced stage.
-
Duration: twelve weeks
-
Screening tool: The Two Question Screening Survey (TQSS) was used to assess mood and anhedonia. The two questions are: “During the past month have you been bothered by feeling down, depressed or hopeless?” and “During the past month have you been bothered by having little interest or pleasure in doing things?” There are five possible answers which are assigned values from 0 to 4:
-
0 not at all, 1 a little bit, 2 somewhat, 3 quite a bit, 4 very much.
-
For the evaluation of depression and quality of life in the participants the following tools were used: the Functional Assessment of Cancer Therapy General instrument (FACT-G), the Functional Assessment of Chronic Illness Therapy Spiritual and the Brief Zung Self administered Depression Rating Scale (BZDRS) with 11 items.
-
-
Inclusion Criteria: A TQSS score of 2 or greater. Patients with a major depressive episode were excluded.
-
Response criteria: A best change score of at least -3 in the BZDRS. A best change score is defined as the difference between the baseline score and the average of the best consecutive scores.
-
Design: Double blind RCT. Computations were made only on patients who completed the baseline questionnaires (n=159) and at least one follow up assessment (n=129). The authors used additionally the generalized estimating equation (GEE) method of regression.
-
Results: There were data for 129 patients at the end point (64 in the fluoxetine group and 65 in the placebo group). 48% (n=31) patients in the fluoxetine group and 36% (n=23) in the placebo group were responders. This difference was not statistically significant. Reevaluating the data with the GEE method of regression the authors found a significant improvement in the fluoxetine group. There were not any concrete data about the number of dropouts or reported adverse effects in each group.
-
Number of patients: 203 patients out of the 357 screened patients qualified for enrolment in this study. From the 193 who enrolled in the study the authors reported on the 180 patients who completed the six month assessment.
-
Type of cancer/Stages: Breast cancer, stages I, II
-
Duration: six months
-
Screening tool: The Two Question Screening Survey (TQSS) was used to assess mood and anhedonia. The two questions are: “During the past month have you been bothered by feeling down, depressed or hopeless?” and “During the past month have you been bothered by having little interest or pleasure in doing things?” There five possible answers which are assigned values from 0 to 4:
-
0 not at all, 1 a little bit, 2 somewhat, 3 quite a bit, 4 very much.
-
The quality of life was estimated using the Functional Assessment of Cancer Therapy-General (FACT-G) and the depression was estimated with the Brief Zung self administered Depression Rating Scale (BZDRS).
-
-
Inclusion Criteria: A TQSS score of 2 or greater. Patients with a major depressive episode were excluded.
-
Response criteria: “significant improvement” in the BZSRS (not further defined).
-
Design: double blind RCT, completers’ analysis.
-
Results: 71 patients from the fluoxetine group and 23 patients from the placebo group had a significant improvement in depressive symptoms (P<0.0005). There were not any data about adverse effects.
-
Number of patients: 35 patients participated in this study. They were divided into three groups and assigned to receive either paroxetine (n=13) or desipramine (n=11) or placebo (n=11).
-
Type of cancer/Stages: Breast cancer at any stage.
-
Duration: six weeks
-
Screening tool: a DSM-III-R multi-axial evaluation. Other rating scales used were the 21-item Hamilton Rating Scale for Depression (HAM-D), the 14-item Hamilton Rating Scale for Anxiety and the Clinical Global Impression Scale (CGI).
-
Inclusion Criteria: DSM-III-R criteria for major depression (except duration of illness had to be at least on month), HAM-D score of at least 14 in the first 17 items of the 21-item HAM-D.
-
Response criteria: A decrease of ≥50% from baseline HAM-D score or a CGI global improvement score ≤-2. Clinical remission was defined as a HAM-D score ≤7.
-
Design: double blind RCT, ITT analysis, LOCF approach
-
Results: The response rates were: 38% (5/13 patients) in the paroxetine group, 45% (5/11 patients) in the desipramine group and 55% (6/11 patients) in the placebo group (p= 0.91). The remission rates were: 23% (3/11 patients) in the paroxetine group, 45% (5/11 patients) in the desipramine group and 36% (4/11 patients) in the placebo group (p=0.55). There were 14 dropouts by week six: 5 in the paroxetine group, 4 in the desipramine group and 5 in the placebo group.
-
The most common adverse effects were:
-
Paroxetine: dry mouth (n=6), nausea (n=5), pain (n=5)
-
Desipramine: dry mouth (n=8), constipation (n=4), headaches (n=4), pain (n=4)
-
Placebo: headache (n=5), pain (n=5), dry mouth (n=3), constipation (n=3).
-
The difference in side effects among the groups was not significant.
Appendix B
Assessment of bias
Domain | Description | Review author’s judgement |
---|---|---|
Sequence generation | Describe the method used to generate the allocation sequence | Was the allocation sequence adequately generated? (Yes, No, Unclear) |
Allocation concealment | Describe the method used to conceal the allocation sequence | Was allocation adequately concealed? (Yes, No, Unclear) |
Blinding of participants, personnel, and outcome | Describe all measures used to blind participants and personnel | Was knowledge of the allocated intervention adequately prevented during the study? (Yes, No, Unclear) |
Incomplete outcome data | Describe the completeness of outcome data for each main outcome including attrition and exclusions from the analysis. | Were incomplete outcome data adequately addressed? (Yes, No, Unclear) |
Selective outcome reporting | State how the possibility of selective outcome reporting was examined by the review authors and what was found. | Are reports of the study free of suggestion of selective outcome reporting? (Yes, No, Unclear) |
Other sources of bias | State any important concerns about bias not addressed in the other domains. | Was the study apparently free of other problems that could put it at high risk of bias? |
Domain | Description | Review author’s judgement |
---|---|---|
Sequence generation | Randomized study, method not described. | “Unclear” |
Allocation concealment | Double dummy technique was used. Assignment envelopes are not described. | “Unclear” |
Blinding of participants, personnel, and outcome | Double blind study. More frequent anticholinegic AEs in the amitriptyline group, which could break blinding. | “Unclear” |
Incomplete outcome data | Main outcome was the MADRS score. 16 withdrawals in the paroxetine group and 19 in the amitriptyline group. 9 dropouts in the paroxetine group and 10 in the amitriptyline group due to AEs. Other reasons for withdrawals are not reported. Analysis according to ITT principle. Missing data imputation method: LOCF. | “No” |
Selective outcome reporting | Protocol is not available. All pre-specified outcomes of interest are reported in the pre-specified way. | “Yes” |
Other sources of bias | The study appears to be free of other sources of bias. | “Yes” |
Domain | Description | Review author’s judgement |
---|---|---|
Sequence generation | Randomized study, randomization method not described. | “Unclear” |
Allocation concealment | Method is not described. | “Unclear” |
Blinding of participants, personnel, and outcome | Double blind study. More frequent anticholinergic effects in the fluoxetine group. Issue is not sufficiently addressed by the authors. | “Unclear” |
Incomplete outcome data | The main outcome war the raw baseline to endpoint differences in HAM-D. There were 6 dropouts in the fluoxetine group, all due to AEs. There were 7 dropouts in the desipramine, 4 due to AEs, 3 to unknown reasons. Analysis according to ITT principle. Missing data imputation method: LOCF. | “No” |
Selective outcome reporting | Study protocol is not available. All pre-specified outcomes are reported in the pre-specified way. No response criteria were defined. Improvement was not pre-specified. | “No” |
Other sources of bias | The study seems to be free from other sources of bias. | “Yes” |
Domain | Description | Review author’s judgement |
---|---|---|
Sequence generation | Randomization method is not described. Patients who refused to take medication formed a control group. The allocation by preference of the participants is problematic in randomized studies. | “No” |
Allocation concealment | Not described for the two drug groups. No blinding for the control group. | “No” |
Blinding of participants, personnel, and outcome | No blinding for the control group. | “No” |
Incomplete outcome data | The main outcome was the HAM-D score and single symptom scales score for nausea, pain, vomiting. 4 Dropouts in the mirtazapine group, 4 in the imipramine group, ten dropouts in the control group. No ITT analysis. Missing data imputation method: completers’ analysis. | “No” |
Selective outcome reporting | No study protocol available. All pre-specified outcomes are reported in the pre-specified way. No pre-specified criteria for response or improvement. | “No” |
Other sources of bias | The study seems to be free from other sources of bias. | “Yes” |
Domain | Description | Review author’s judgement |
---|---|---|
Sequence generation | The randomization method is not described. | “Unclear” |
Allocation concealment | Exact method is not described. | “Unclear” |
Blinding of participants, personnel, and outcome | Double blind trial. The issue is not adequately addressed. | “Unclear” |
Incomplete outcome data | The main outcome was the HDRS score. 7 dropout in the mianserin group (MG) and 15 in the placebo group (PG). Reasons for withdrawal: 1 in each group due to AEs, 2 in PG due to lack of efficacy, the treatment by one patient in the PG was interrupted by the investigator, 2 in MG and 4 MG ended the anticancer treatment, 2 in MG due to cancer complications, 1 in MG and 2 in PG due to temporary withdrawal from the anticancer treatment, 2 in PG refused anticancer therapy and were dismissed, 3 in PG had problems at home and 1 in MG died. The authors used an ITT analysis. Missing data imputation method: LOCF approach. Proportionally about one third (30%) of the patients were dropouts, which can induce bias in intervention effect estimate. | “No” |
Selective outcome reporting | No study protocol available. All pre-specified outcomes are reported in the pre-specified way. The response criteria are not pre-specified. | “No” |
Other sources of bias | The study seems to be free of other sources of bias. | “Yes” |
Domain | Description | Review author’s judgement |
---|---|---|
Sequence generation | The randomization method is not described | “Unclear” |
Allocation concealment | The exact method is not described. | “Unclear” |
Blinding of participants, personnel, and outcome | The study is defined as double blind. The issue is not addressed by the authors. | “Unclear” |
Incomplete outcome data | The main outcome was the HDRS score. There were 6 drop outs in the mianserin group and 15 dropouts in the placebo group. 2 patients in the mianserin group and 11 in the placebo group withdrew due to lack of efficacy. 2 dropouts in the mianserin group and 4 in the placebo group due to AEs. ITT analysis. Missing data imputation method: LOCF approach. Over one third of the patients withdrew from the study (38%), No study protocol available. All pre-specified outcomes are reported in the pre-specified way. | “No” |
Selective outcome reporting | No study protocol available. All pre-specified outcomes are reported in the pre-specified way. | “Yes” |
Other sources of bias | The study seems to be free of other sources of bias. | “Yes” |
Domain | Description | Review author’s judgement |
---|---|---|
Sequence generation | Randomization method is not described. | “Unclear” |
Allocation concealment | The exact method is not described. | “Unclear” |
Blinding of participants, personnel, and outcome | Double blind trial. The authors do not address this issue. | “Unclear” |
Incomplete outcome data | The main outcome was the number of patients with success criteria (HADS score≤8) and with response criteria (≥50% improvement in HADS score). There were 15 dropouts in the fluoxetine group (FG) and 7 dropouts in the placebo group (PG). The reasons for dropouts in the FG were: 7 due to AEs, 3 decided to interrupt their participation for unknown reasons, 1 due to alcohol abuse, and 4 for other reasons: | “Unclear” |
(Non-compliance, investigator’s decision, lost to follow-up). The reasons for dropouts in the PG were: 2 due to concomitant events, 4 for unknown reasons, 1 for psychiatric reasons. The authors used an ITT basis for the success and response rates. The exact missing data imputation method is not being reported. | ||
Selective outcome reporting | No study protocol available. All pre-specified outcomes are reported in the pre-specified way. | “Yes” |
Other sources of bias | The study seems to be free of other sources of bias. | “Yes” |
Domain | Description | Review author’s judgement |
---|---|---|
Sequence generation | Randomization by means of a preprinted randomization table. | “Yes” |
Allocation concealment | The exact method is not described. | “Unclear” |
Blinding of participants, personnel, and outcome | “The issue is not addressed by the authors. | “Unclear” |
Incomplete outcome data | 163 patients were randomized and 159 allocated to receive medication. The patients were included in the analysis if they provided data at least two assessments (baseline and one of the next four). 64 patients were evaluable in the fluoxetine group and 65 in the placebo group. The reasons for dropouts are not fully presented. The authors used a modification of completers’ analysis. The missing data imputation method was the best change score, which is defined as the difference between the baseline score and the average of the best consecutive scores. According to the authors’ opinion this is a valid statistical method for longitudinal data. To our opinion the best change score belongs to the inappropriate imputation methods. | “No” |
Selective outcome reporting | No study protocol available. All pre-specified outcomes are reported in the pre-specified way. | “Yes” |
Other sources of bias | There were many loss of data especially at the fourth assessment. This could influence the intervention effect estimate. | “No” |
Domain | Description | Review author’s judgement |
---|---|---|
Sequence generation | The randomization method is not described. | “Unclear” |
Allocation concealment | The exact method is not described. | “Unclear” |
Blinding of participants, personnel, and outcome | Double blind trial. The issue is not addressed by the authors. | “Unclear” |
Incomplete outcome data | The main outcome was the scores on FACT-G and BZSDS. 193 patients enrolled in the study, 183 were available at the first follow-up and 180 at the second. The reasons for dropouts are not reported. The authors used a completers’ analysis, which was not pre-specified in the description of the study. | “No” |
Selective outcome reporting | The scores of the FACT-G and BZSDS are not reported. The results are presented as numbers of patients with significant improvement, which is not pre-specified in the description of the study. The AEs are also not reported. | “No” |
Other sources of bias | The study seems to be free from other sources of bias. | “Yes” |
Domain | Description | Review author’s judgement |
---|---|---|
Sequence generation | The randomization method is not described | “Unclear” |
Allocation concealment | The exact method is not described. | “Unclear” |
Blinding of participants, personnel, and outcome | Double blind study. The issue is not addressed by the authors. | “Unclear” |
Incomplete outcome data | The main outcome was the number of patients with response (≥50% improvement in the HAM-D scale) and with remission (HAM-D≤7). There were 14 dropouts in a total of 40 participants (40%). Reasons for dropouts were: AEs (2 in paroxetine group, 1 in desipramine group and 2 in placebo group), lack of efficacy (2 in paroxetine and 2 in placebo group), patients’ wish to discontinue (2 in placebo group), one was lost to follow-up and one from the placebo group could not ingest any medication. The analysis was done on an ITT base. The missing data imputation method was the LOCF. | “No” |
Selective outcome reporting | No study protocol available. All pre-specified outcomes are reported in the pre-specified way. | “Yes” |
Other sources of bias | Small number of participants. | “No” |
Appendix C
Subgroup analysis after outlier exclusion
Author | Year | Verum | Verum | Placebo | ||
---|---|---|---|---|---|---|
Participants | Responders | Participants | Responders | |||
Group A: Clinical depression as an inclusion criterion
| ||||||
Costa | 1985 | Mianserin | 36 | 28 | 37 | 18 |
Van Heeringen | 1996 | Mianserin | 28 | 19 | 27 | 10 |
Razavi | 1996 | Fluoxetine | 35 | 8 | 46 | 9 |
Musselmann | 2006 | Paroxetine/desipramine | 24 | 11 | 11 | 6 |
Total
| 133 | 66 | 121 | 43 | ||
Group B: Clinical depression not as an inclusion criterion
| ||||||
Fisch | 2003 | Fluoxetine | 64 | 31 | 65 | 23 |
Total
| 64 | 31 | 65 | 23 |
Author | Year | Drug | Verum | Placebo | ||
---|---|---|---|---|---|---|
Participants | Responders | Participants | Responders | |||
Group A: Analyses by ITT
| ||||||
Costa | 1985 | Mianserin | 36 | 28 | 37 | 18 |
Van Heeringen | 1996 | Mianserin | 28 | 19 | 27 | 10 |
Musselmann | 2006 | Paroxetine/desipramine | 24 | 11 | 11 | 6 |
Total
| 88 | 58 | 75 | 34 | ||
Group B: analyses not by ITT
| ||||||
Fisch | 2003 | Fluoxetine | 64 | 31 | 65 | 23 |
Razavi | 1996 | Fluoxetine | 45 | 8 | 46 | 9 |
Total
| 109 | 39 | 111 | 32 |
Author | Year | Drug | Verum | Placebo | ||
---|---|---|---|---|---|---|
Participants | Responders | Participants | Responders | |||
Group A: Any or advanced cancer stage
| ||||||
Costa | 1985 | Mianserin | 36 | 28 | 37 | 18 |
Fisch | 2003 | Fluoxetine | 64 | 31 | 65 | 23 |
Razavi | 1996 | Fluoxetine | 45 | 8 | 46 | 9 |
Musselmann | 2006 | Paroxetine/desipramine | 24 | 11 | 11 | 6 |
Total
| 169 | 78 | 159 | 56 | ||
Group B: Early cancer stages
| ||||||
Van Heeringen | 1996 | Mianserin | 28 | 19 | 27 | 10 |
Total
| 28 | 19 | 27 | 10 |
Author | Year | Drug | Verum | Placebo | ||
---|---|---|---|---|---|---|
Participants | Responders | Participants | Responders | |||
Group A: SSRIs
| ||||||
Fisch | 2003 | Fluoxetine | 64 | 31 | 65 | 23 |
Razavi | 1996 | Fluoxetine | 45 | 8 | 46 | 9 |
Musselmann | 2006 | Paroxetine | 13 | 5 | 11 | 6 |
Total
| 122 | 44 | 122 | 38 | ||
Group B: Mianserin
| ||||||
Costa | 1985 | Mianserin | 36 | 28 | 37 | 18 |
Van Heeringen | 1996 | Mianserin | 28 | 19 | 27 | 10 |
Total
| 64 | 47 | 64 | 28 |
Appendix D
Article | Assessment |
---|---|
Goldberg RJ. Management of depression in the patient with advanced cancer. JAMA.246(4):373–6, 1981. | Review |
Costa D, Mogos I, Toma T. Efficacy of mianserin in the treatment of depression of women with cancer. Acta Psychiatrica Scandinavica. 72 (suppl. 320): 85–92, 1985. |
RCT included in the review
|
Mathé G, Lopez MD, Fréchet M, de Vassal F, Brienza S, Gastiaburu J. A comparative trial of a MAOI, iproniazide, and a polycyclic agent, mianserine, for the search of the most rapidly and frequently active treatment of depressive syndromes in an oncology service. Biomedicine and Pharmacotherapy.41(1):13–26, 1987. | No double blind RCT |
Maguire P, Hopwood P, Tarrier N, Howell T. Treatment of depression in cancer patients. Acta Psychiatrica Scandinavica Suppl. 320:81–4, 1985. | Antidepressant therapy was administrated together with anxiolytic and supportive psychotherapy |
Evans DL, McCartney CF, Nemeroff CB, Haggerty JJ Jr, Simon JS, Pedersen CA, Holmes V, Droba M, Mason GA, Raft D, et al. Depression in cancer patients. Diagnostic and treatment considerations. North Carolina Medical Journal.49(10):546–8, 1988. | Review |
Silberfarb PM. Psychiatric treatment of the patient during cancer therapy. CA; A Cancer Journal of Clinicians. 38(3):133–7, 1988. | Review |
Evans DL, McCartney CF, Haggerty JJ Jr, Nemeroff CB, Golden RN, Simon JB, Quade D, Holmes V, Droba M, Mason GA, et al. Treatment of depression in cancer patients is associated with better life adaptation: a pilot study. Psychosomatic Medicine. 50(1):73–6, 1988. | No control group. |
Van Heeringen K, Zivkov M. Pharmacological treatment of depression in cancer patients. A placebo controlled study of Mianserin. British Journal of Psychiatry. 169: 440.443, 1996. |
RCT included in the review
|
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 Psychiatrica Scandinavia. 94: 205–210, 1996. |
RCT included in the review
|
Holland JC, Romano SJ, Heiligenstein JH, Tepner RG, Wilson MG. A controlled trial of fluoxetine and desipramine in depressed women with advanced cancer. Psycho-Oncology. 7: 291–200, 1998 |
RCT included in the review
|
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. The Journal of International Medical Research. 27(6):264–72, 1999. | The efficacy of trazodone cannot be safely proven when it is compared to a benzodiazepine. Depression was not an eligibility criterion. |
Musselmann DL, Lawson DH, Gumnick JF, Manatunga AK, Penna S, Goodkin RS, Greiner K, Nemeroff CB, Miller AH. Paroxetine for the prevention of depression induced by high dose interferone alpha. The New England Journal of Medicine. Vol 344, No 13, 2001 | Prevention study, thus prevention was not an eligibility criterion. |
Pezella G, Moslinger-Gehmayr R, Contu A. Treatment of depression in patients with breast cancer: a comparison between paroxetine and amitrptyline. Breast Cancer Research and Treatment. 70: 1–10, 2001 |
RCT included in the review
|
Passik SD, Kirsh KL, Theobald D, Donaghy K, Holtsclaw E, Edgerton S, Dugan W. Use of a depression screening tool and a fluoxetine-based algorithm to improve the recognition and treatment of depression in cancer patients. A demonstration project. Journal of Pain and Symptom Management. 24(3):318–27, 2002. | No RCT. |
Carr D, Goudas L, Lawrence D, Pirl W, Lau J, DeVine D, Kupelnick B, Miller K. Management of cancer symptoms: pain, depression, and fatigue. Evidence Report/Technology Assessment. 61:1–5, 2002. | Review. |
Davis MP, Khawam E, Pozuelo L, Lagman R. Management of symptoms associated with advanced cancer: olanzapine and mirtazapine. A World Health Organization project. Expert Review of Anticancer Therapy. 2(4): 365–76, 2002.
| Recommendation |
Fisch MJ, Loehrer PJ, Kristeller J, Passik S, Jung SH, Shen SH, Arquette MA, Brames MJ, Einhorn LH. Fluoxetine versus Placebo in advanced cancer outpatients: a double-blinded trial of the Hoosier oncology group. Journal of Clinical Oncology. Vol 21, No 10: 1937–1943, 2003. |
RCT included in the review
|
Theobald DE, Kirsh KL, Holtsclaw E, Donaghy K, Passik SD. An open label pilot study of citalopram for depression and boredom in ambulatory cancer patients. Palliat Support Care. 2003 Mar;1(1):71–7.
| No RCT. |
Morrow GR, Hickok JT, Roscoe JA, Raubertas RF, Andrews PLR, Flynn PJ, Hynes HE, Banerjee TK, Kirschner JJ, King DK. Differential effects of paroxetine on fatigue and depression: a randomized, double blind trial from the University of Rochester Cancer Center Community Clinical Oncology Program. Journal of Clinical Oncology. Vol 21, No 24: 4635–4641, 2003 | Depression was not an eligibility criterion |
Pae CU, Kim YJ, Won WY, Kim HJ, Lee S, Lee CU, Lee SJ, Kim DW, Lee C, Min WS, Kim CC, Paik IH, Serretti A. Paroxetine in the treatment of depressed patients with haematological malignancy: an open-label study. Human Psychopharmacology. 19(1):25–9, 2004. | No RCT. |
Coyne JC, Palmer SC, Shapiro PJ. Prescribing antidepressants to advanced cancer patients with mild depressive symptoms is not justified. Journal of Clinical Oncology. 1;22(1):205–6; author reply 206–8, 2004. | Comment. |
Thangathurai D, Roffey P, Mogos M, Riad M, Mikhail M. Usefulness of desipramine in ICU cancer patients for acute depression. Journal of Palliative Care. 20(4):326, 2004. | Comment. |
Ladd CO, Newport DJ, Ragan KA, Loughhead A, Stowe ZN. Venlafaxine in the treatment of depressive and vasomotor symptoms in women with perimenopausal depression. Depression and Anxiety. 22(2):94–7, 2005. | No RCT. |
Roscoe JA, Morrow GR, Hickok JT, Mustian KM, Griggs JJ, Matteson SE, Bushunow P, Qazo R, Smith B. Effect of paroxetine hydrochloride on fatigue and depression in breast cancer patients receiving chemotherapy. Breast Cancer Research and Treatment. 89: 243–249, 2005. | Depression was not an eligibility criterion. |
Musselmann 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, IV) with major depression. Journal of Clinical Psychiatry. 67: 288–296, 2006. |
RCT included in the review.
|
Kimmick GG, Lovato J, McQuellon R, Robinson E, Muss HB. Randomized, double-blind, placebo-controlled, crossover study of sertraline (Zoloft) for the treatment of hot flashes in women with early stage breast cancer taking tamoxifen. The Breast Journal. 12(2):114–22, 2006.
| Depression was a secondary outcome. |
Moss EL, Simpson JS, Pelletier G, Forsyth P. An open-label study of the effects of bupropion SR on fatigue, depression and quality of life of mixed-site cancer patients and their partners. Psychooncology. 15(3):259–67, 2006. | No RCT. |
Loibl S, Schwedler K, von Minckwitz G, Strohmeier R, Mehta KM, Kaufmann M. Venlafaxine is superior to clonidine as treatment of hot flashes in breast cancer patients--a double-blind, randomized study. Annals of Oncology. 18(4):689–93, 2007.
| No measures for depression were included. |
Stockler MR, O´Connel R, Nowak AK, Goldstein D, Turner J, Wilcken NRC, Wyld D, Abdi EA, Glasgow A, Beale PJ, Jefford M, Dhillon H, Heritier S, Carter C, Hickie IB, Simes RJ. Effect of sertraline on symptoms and survival in patients with advanced cancer, but without major depression: a placebo controlled double-blind randomized trial. Lancet Oncology. 8: 603–612, 2007. | Depression was not an eligibility criterion. |
Raji MA, Barnum PD, Freeman J, Markowitz AB. Mirtazapine for depression and comorbidities in older patients with cancer. Annals of Pharmacotherapy.41(9):1548–9, 2007.
| No RCT. |
Cankurtaran ES, Ozalp E, Soygur H, Akbiyik DI, Tuhan L, Alkis N. Mirtazapine improves sleep and lowers anxiety and depression in cancer patients: superiority over imipramine. Supportive Care in Cancer. 16: 1291–1298, 2008. |
RCT included in the review.
|
Torta R, Siri I, Caldera P. Sertraline effectiveness and safety in depressed oncological patients. Supportive Care in Cancer. 16(1):83–91, 2008. | No RCT. |
Okamura M, Akizuki N, Nakano T, Shimizu K, Ito T, Akechi T, Uchitomi Y. Clinical experience of the use of a pharmacological treatment algorithm for major depressive disorder in patients with advanced cancer. Psychooncology. 17(2):154–60, 2008.
| No RCT. |
Ersoy MA, Noyan AM, Elbi H. An open-label long-term naturalistic study of mirtazapine treatment for depression in cancer patients. Clinical Drug Investigation. 28(2):113–20, 2008.
| No RCT. |
Kim SW, Shin IS, Kim JM, Kim YC, Kim KS, Kim KM, Yang SJ, Yoon JS. Effectiveness of mirtazapine for nausea and insomnia in cancer patients with depression. Psychiatry and Clinical Neuroscience. 62(1):75–83, 2008.
| No RCT. |
Lydiatt WM, Denman D, McNeilly DP, Puumula SE, Burke WJ. A randomized placebo- controlled trial of citalopram for the prevention of major depression during treatment for head and neck cancer. Archives of Otolaryngology- Head and Neck Surgery. Vol. 134 (No 5), 2008. | Prevention study, thus depression was not an eligibility criterion. |
Navari RM, Brenner MC, Wilson MN. Treatment of depressive symptoms in patients with early stage breast cancer undergoing adjuvant therapy. Breast Cancer Research and Treatment. 112: 197–201, 2008. | RCT included in the review. |
Thangathurai D, Roby J, Roffey P. Treatment of resistant depression in patients with cancer with low doses of ketamine and desipramine. Journal of Palliative Medicine. 13(3):235, 2010. | The authors report on two patients |