Improving compliance in depression: a systematic review of narrative reviews.

BACKGROUND AND OBJECTIVE: Narrative reviews represent a popular source of information for clinicians, especially where the evidence on a given subject is sparse and analogies from other fields of medicine may help in filling the information gap. Unfortunately, narrative reviews often follow less stringent criteria for information selection and appraisal than systematic reviews, potentially leading to incomplete or biased recommendations. The objective of the present study was to examine the quality of the recommendations provided by narrative reviews on how to improve patient adherence to pharmacological treatment of unipolar depressive disorders. METHOD: We sought to locate all narrative review papers addressing adherence to treatment in unipolar depressive disorders. In order to do so, we searched Medline and PsychInfo from 1980 to December 2003, using the following keywords: review, depressive disorders, treatment, dropout, patient compliance and adherence. We inspected the title and the abstract, whenever available to identify the relevant reviews and obtained a full copy of the publications in this subset, and read the articles to identify further relevant reviews. These were in turn copied and reviewed, until no further references were found. RESULTS AND DISCUSSION: We identified 23 reviews, providing a total of 87 recommendations. The most common recommendation was for patient education (19 times), patient-physician empathy/alliance (14 times), and education of family (nine times). Reviewers' recommendations were based on the literature on depression 54 times, and on other medical conditions 17 times. A critical appraisal of the evidence base of the recommendations showed that randomized controlled trials or meta-analyses were quoted to support the recommendations only 23% of the times, while important interventions of proven efficacy in the field of depression or in other chronic conditions (e.g. medication clinics, training of nurses, psychological treatment, and telephone follow-up) were not mentioned. CONCLUSIONS: Narrative reviews on adherence to pharmacological treatment of depressive disorders suffer not only from the limited availability of good quality evidence, but also from an incomplete critical appraisal of available evidence on interventions both for depression and for other chronic disorders.

Patient adherence in the treatment of depression.

BACKGROUND: Non-adherence with antidepressant treatment is very common. Increasing adherence to pharmacological treatment may affect response rate. AIMS: To review and summarise quantitative evidence on factors associated with adherence and of adherence-enhancing interventions. METHOD: A systematic review of computerised databases was carried out to identify quantitative studies of adherence in depression. Papers retained addressed unipolar depression and considered adherence as the primary end-point. RESULTS: Of studies published between 1973 and 1999, 32 met the review criteria: epidemiological descriptive studies (n=14): non-random comparisons of control and intervention groups (n=3); randomised interventions (n=14); and meta-analysis (n=1). Patient education and medication clinics were the interventions most commonly tested, combined with a variety of other interventions. CONCLUSIONS: The studies did not give consistent indications of which interventions may be effective. Carefully designed clinical trials are needed to clarify the effect of single and combined interventions.

Dietary beta-carotene intake and the risk of epithelial ovarian cancer: a meta-analysis of 3,782 subjects from five observational studies.

OBJECTIVE: The etiology of epithelial ovarian cancer is unknown. Prior work suggests that high dietary beta-carotene intake is associated with a decreased risk of this tumor although this association remains speculative. A meta-analysis was performed to evaluate this suspected relationship. METHODS: Using previously described methods, a protocol was developed for a meta-analysis examining the association between high dietary beta-carotene intake versus low intake and the risk of epithelial ovarian cancer. Literature search techniques, study inclusion criteria and statistical procedures were prospectively defined. Data from observational studies were pooled using a general variance based meta-analytic method employing confidence intervals previously described by Greenland. The outcome of interest was a summary relative risk (RRs) reflecting the risk of ovarian cancer associated with high beta-carotene intake versus low dietary intake. Sensitivity analyses were performed when necessary to evaluate any observed statistical heterogeneity. RESULTS: Five observational studies enrolling 3,782 subjects were initially pooled in a meta-analysis subsequent to an analysis showing a lack of statistical heterogeneity. The meta-analysis showed a summary relative risk of 0.84 with a 95% confidence interval of 0.75-0.94, a statistically significant result. These data suggest that high (versus low) dietary intake of beta-carotene is associated with a sixteen percent decrease in ovarian cancer risk. Sensitivity analyses showed no impact of study design or differences in quantitative measure of beta-carotene intake across studies on the summary relative risk. CONCLUSIONS: High dietary intake of beta-carotene appears to represent a protective factor for the development of ovarian cancer although its magnitude is modest. Further work is needed to clarify factors that may modify the effects of beta-carotene in vivo.

Impact of intravesical chemotherapy on recurrence rate of recurrent superficial transitional cell carcinoma of the bladder: results of a meta-analysis.

BACKGROUND: The impact of in tranvesical chemotherapy on preventing recurrence of superficial transitional cell carcinoma of the bladder is controversial. The objective of this report is to present a meta-analysis of the available clinical trial data to quantify the effect of intravesical chemotherapy on tumor recurrence following trans-urethral resection (TURB) in patients with recurrent superficial bladder cancer. METHODS: A prospective study protocol outlining a meta-analysis was developed followed by a thorough search of the existing published literature using strict eligibility criteria. Eight randomized trials were found which met protocol specifications. These studies contained data on 1,609 patients which were statistically combined using a fixed effects model (Peto). The outcome of interest was the proportion of patients with tumor recurrence at one, two and three years post-TURB. RESULTS: Combining all 8 studies using 1 year recurrence as the outcome measure yielded a Peto odds ratio (ORp) of 0.62, demonstrating a 38% reduction in one year recurrence among patients treated with intravesical chemotherapy versus TURB alone. Using 2 and 3 year recurrence as the outcome measure yielded ORp's of 0.46 and 0.35 respectively, favoring TURB + intravesical chemotherapy versus TURB alone. A statistical test for heterogeneity (Q) showed the 2 and 3 year outcome data to be heterogeneous (i.e. the studies are not measuring an effect of the same magnitude). Sensitivity analyses showed that drug type appeared to account for the observed heterogeneity with a stratified analysis demonstrating that adriamycin is less effective in reducing subsequent tumor recurrences than all other drugs studied. CONCLUSION: Intravesical chemotherapy appears to have a major impact on decreasing the chance of recurrence of recurrent superficial bladder cancer. Three year recurrence is decreased by as much as 70% when compared with TURB alone. These data are in contrast to prior analyses suggesting only modest efficacy of such treatment in this clinical setting.

Meta-analysis to assess the efficacy of interferon-alpha in patients with follicular non-Hodgkin's lymphoma.

The authors wanted to determine whether adding interferon-alpha (IFN-alpha) to chemotherapy regimens, in either induction or maintenance settings, provides additional survival benefits in follicular non-Hodgkin's lymphoma (NHL). A meta-analysis was performed based on published data from randomized controlled clinical trials involving nine separate study populations. Patients receiving IFN-alpha (in either induction or maintenance therapy) had significantly increased 5-year and progression-free survival rates at 3 and 5 years compared with concurrent controls. The advantages of IFN-alpha therapy were most marked in studies using anthracycline-containing induction chemotherapy; in these studies, patients who received IFN-alpha had approximately 20% increased progression-free survival rates compared with controls and a lesser survival advantage. The available literature did not allow a determination of the relative benefit of IFN-alpha in induction or maintenance treatments for NHL or a determination of the optimum duration of IFN-alpha treatment. Although questions remain about its optimal use. IFN-alpha appears to prolong survival time in patients with follicular NHL.

Dietary fat intake and risk of epithelial ovarian cancer: a meta-analysis of 6,689 subjects from 8 observational studies.

The etiology of epithelial ovarian cancer is unknown. Prior work suggests that high dietary fat intake is associated with an increased risk of this tumor, although this association remains speculative. A meta-analysis was performed to evaluate this suspected relationship. Using previously described methods, a protocol was developed for a meta-analysis examining the association between high vs. low dietary fat intake and the risk of epithelial ovarian cancer. Literature search techniques, study inclusion criteria, and statistical procedures were prospectively defined. Data from observational studies were pooled using a general variance-based meta-analytic method employing confidence intervals (CI) previously described by Greenland. The outcome of interest was a summary relative risk (RRs) reflecting the risk of ovarian cancer associated with high vs. low dietary fat intake. Sensitivity analyses were performed when necessary to evaluate any observed statistical heterogeneity. The literature search yielded 8 observational studies enrolling 6,689 subjects. Data were stratified into three dietary fat intake categories: total fat, animal fat, and saturated fat. Initial tests for statistical homogeneity demonstrated that hospital-based studies accounted for observed heterogeneity possibly because of selection bias. Accounting for this, an RRs was calculated for high vs. low total fat intake, yielding a value of 1.24 (95% CI = 1.07-1.43), a statistically significant result. That is, high total fat intake is associated with a 24% increased risk of ovarian cancer development. The RRs for high saturated fat intake was 1.20 (95% CI = 1.04-1.39), suggesting a 20% increased risk of ovarian cancer among subjects with these dietary habits. High vs. low animal fat diet gave an RRs of 1.70 (95% CI = 1.43-2.03), consistent with a statistically significant 70% increased ovarian cancer risk. High dietary fat intake appears to represent a significant risk factor for the development of ovarian cancer. The magnitude of this risk associated with total fat and saturated fat is rather modest. Ovarian cancer risk associated with high animal fat intake appears significantly greater than that associated with the other types of fat intake studied, although this requires confirmation via larger analyses. Further work is needed to clarify factors that may modify the effects of dietary fat in vivo.

Paternal smoking during pregnancy and the risk of childhood brain tumors: results of a meta-analysis.

OBJECTIVE: Prior epidemiological studies suggest a possible association between paternal smoking during pregnancy and risk of childhood brain tumors (CBT). A meta-analysis was performed statistically pooling all available observational studies on this topic in order to evaluate this suspected association. METHODS: Using previously described methods, a protocol was developed for a meta-analysis examining the association between paternal smoking during pregnancy and subsequent development of primary brain tumors in their offspring. Literature search techniques study inclusion criteria and statistical procedures were prospectively defined. Data from epidemiological studies were pooled using a general variance based meta-analytic method employing confidence intervals previously described by Greenland. The outcome of interest was a summary relative risk (RRs) reflecting the risk of childhood brain tumor development associated with father's smoking during the index pregnancy. Sensitivity analyses were performed when necessary to explain any observed statistical heterogeneity and/or to evaluate the impact of demographic or study characteristics on the summary estimate of effect. RESULTS: Seven observational studies meeting protocol specified inclusion criteria were obtained via a comprehensive literature search. These studies enrolled a total of 3,600 patients. Analysis for homogeneity demonstrated that the data were homogeneous (P = 0.52) and could be statistically combined. Pooling all seven reports yielded a RRs of 1.29 (1.07-1.53), a statistically significant result suggesting a 29% increased risk of brain tumor development associated with paternal smoking during pregnancy. An analysis of father's smoking impact on CBT risk based on "ever" versus "never" smoking history gave a RRs of 1.14 (0.98-1.34), a marginally non-statistically significant result. CONCLUSION: The available epidemiological data suggest an association between paternal smoking during pregnancy and pediatric brain tumor development. Although this association is biologically plausible, limitations in study designs limit definitive conclusions based on available data.

Use of topical sunscreen and the risk of malignant melanoma. Results of a meta-analysis of 9,067 patients.

PURPOSE: Prior epidemiological studies suggest that the use of sunscreen preparations is associated with increased risk of cutaneous malignant melanoma (CMM) although the data are conflicting. A meta-analysis was performed to evaluate this suspected association.METHODS: A protocol was developed for a meta-analysis examining the association between frequent sunscreen use versus non-use and the development of CMM. Data from observational studies were pooled using a general variance based meta-analytic method employing confidence intervals. The outcome of interest was a summary relative risk (RRs) reflecting the risk of melanoma associated with sunscreen use versus non-use. Sensitivity analyses were performed when necessary to explain any observed statistical heterogeneity.RESULTS: Eleven case-control studies enrolling 9,067 patients were combined in a meta-analysis. This yielded a RRs of 1.11 (CI = 0.37-3.32), a non-statistically significant result, (i.e. no association between sunscreen use and melanoma risk). Since the data were found to be heterogeneous, i.e. Q = 42.0 (p < 0.001), a series of sensitivity analyses were performed to explore possible sources of heterogeneity. Stratifying studies based on study design, i.e. hospital based versus population based, showed that hospital derived data were highly heterogeneous (Q = 36.9, p < 0.001) while the population registry data were not (Q = 4.9, p = 0.18). Combining those studies using population based data gave a RRs of 1.01 (95% CI = 0.46-2.28) indicating no association between sunscreen use and the development of CMM.CONCLUSIONS: The available epidemiological data do not support the existence of a relationship between topical sunscreen use and an increased risk of CMM.

Prognostic significance of p53 mutations in non-small cell lung cancer: a meta-analysis of 829 cases from eight published studies.

Mutation of the p53 tumor suppressor gene is considered a possible marker of poor survival among patients with non-small cell lung cancer (NSCLC). This report presents the results of a meta-analysis of the available data addressing this issue. Using previously described methods, a protocol was developed for a meta-analysis examining the prognostic significance of p53 mutations in NSCLC. Two-year survival data derived from 829 patients in eight published studies were analyzed using a general variance-based method employing confidence intervals described by Greenland (Epidemiol. Rev. 9 (1986) 1-30). The outcome of interest was a summary relative risk (RRs) reflecting the risk of death at 2 years associated with p53 mutation positive versus p53 negative disease. Prior to calculation of a RRs, an analysis for homogeneity (Q) showed Q to equal 22.3. With 8 degrees of freedom, this yielded a P value corresponding to P<0.005. This indicated substantial heterogeneity across studies in terms of their estimate of effect. Although a RRs of 1.52 was found when all eight studies were combined (favoring a negative prognostic role for p53 mutation), the validity of this estimate is questionable since the existing heterogeneity indicates that factors other than p53 mutation account for the variability in RRs across studies. Sensitivity analyses suggested that selection bias might represent an important source of variability in that p53 mutations may differ in their effects on biological behavior of NSCL tumors. Other possible confounders include smoking history, race, geographic location of study and socio-economic status. The available data do not support a clear role for p53 mutation as a prognostic marker in NSCLC. It appears that multiple sources of bias may contribute to spurious association of p53 mutation status and survival. Future analyses must control for possible confounders in order to determine whether certain p53 mutations are truly associated with poor clinical outcome.

Epidermal growth factor receptor gene amplification as a prognostic marker in glioblastoma multiforme: results of a meta-analysis.

Amplification of the epidermal growth factor receptor (EGFR) gene occurs in approximately 40% of cases of glioblastoma multiforme (GBM) and is considered a possible marker of poor prognosis. This report presents the results of a meta-analysis of the available data addressing this issue. Using a prospective protocol, a meta-analysis was designed to assess the possible prognostic importance of EGFR gene amplification in GBM. One-year survival data derived from seven published studies were analyzed using a general variance based method employing confidence intervals described by Greenland. The outcome of interest was a summary relative risk (RRs) reflecting the risk of death at 1 year from diagnosis associated with EGFR amplification-positive versus -negative disease. Prior to calculation of a RRs, an analysis for homogeneity (Q) showed Q to equal 9.21. With 6 df this yielded a P value of 0.12, indicating that the data were homogenous and could be combined in a meta-analysis. Pooling all available studies gave a RRs of 1.13 with a 95% confidence interval of 0.71-1.80, a nonstatistically significant result. The data suggest that the available studies are insufficient for determining whether EGFR gene amplification is of prognostic value in GBM. Important potential confounding factors are the influence of underlying EFGR gene mutation on patient survival and lack of control for important known clinical prognostic indicators in many studies. Future work must incorporate these parameters in multivariate analyses to determine whether EGFR gene alterations are truly associated with poor clinical outcome.

Effectiveness of antidepressants. Meta-analysis of dose-effect relationships in randomised clinical trials.

BACKGROUND: Antidepressant drugs are usually prescribed at low doses, possibly to avoid adverse reactions. No comprehensive review has addressed the issue of dose, clinical response and tolerability in a quantitative way. AIMS: To determine whether high doses of antidepressants are more effective than low doses, and how safety is affected by dose. METHOD: Trials comparing two or more doses of the same antidepressant were located, and all antidepressants administered were converted to the equivalent dose of imipramine. Generalised estimating equations were used to analyse percentage improvement and adverse event rate according to dose level. RESULTS: Thirty-three studies were identified. The dose level 100-200 mg imipramine equivalents showed an average improvement of 53% by 'intention-to-treat'. Higher doses were not accompanied by increased efficacy, while lower doses showed reduction in efficacy. Adverse events significantly increased with dose. CONCLUSIONS: With a low dose of antidepressants, clinicians trade off a slightly reduced chance of improvement for a higher chance of avoiding adverse reactions.