Jan S. A. G. Schouten

Influence of SERTPR and STin2 in the serotonin transporter gene on the effect of selective serotonin reuptake inhibitors in depression: a systematic review.

Large differences in clinical response to selective serotonin reuptake inhibitors (SSRIs) are observed in depressive patients with different genotypes. Quantification of these differences is needed to decide if genetic testing prior to antidepressant treatment is useful. We conducted a systematic review of the literature on the influence of polymorphisms in the serotonin transporter gene (SERTPR (or 5-HTTLPR) and STin2) on SSRI response. Studies were identified by the use of MEDLINE, EmBase and PsycINFO, references of articles, reviews and information from pharmaceutical companies. Nine studies assessing the influence of SERTPR or STin2 on treatment response were included. Outcome was expressed as the percentage of decrease in depression score (HAM-D or MADRS) or as the percentage of responders (≥50% reduction on the depression scale). Both study methodologies and study outcomes showed large heterogeneity. Weighted mean decreases in depression score for patients with the s/s, s/l and l/l genotypes were 35.4, 46.3 and 48.0% at week 4, respectively, and 53.9, 54.6 and 48.3% at week 6. Among Caucasian patients, both mean decrease in depression score and response rate were lowest in the s/s group, while among Asian patients, results were inconsistent. Weighted response rates were 36.1% for the 10/12 genotype of the STin2 polymorphism and 80.7% for the 12/12 genotype (χ2=27.8, P<0.001) (only Asians). The available evidence points to a less favourable response to SSRI treatment among Caucasian patients with the SERTPR s/s genotype and among (Asian) patients with the STin2 10/12 genotype. In view of the scarcity and heterogeneity of the studies, however, current information is insufficiently reliable as a basis for implementing genetic testing in the diagnostic work-up of the depressive patient.

Facts and fiction of poor compliance as a cause of inadequate blood pressure control: a systematic review.

Objective(i) To obtain an overview of measured compliance with antihypertensive medication; (ii) to explore sources of variation in measured compliance percentages between studies; and (iii) to investigate whether studies can establish a relationship between compliance and achieved blood pressure.St

The relationship between visual field loss in glaucoma and health-related quality-of-life

PurposeTo investigate the relationship between visual field loss and health-related quality-of-life (HRQOL) in patients with ocular hypertension (OHT) or primary open-angle glaucoma (POAG).MethodsWe conducted a cross-sectional study among 537 OHT and POAG patients from seven hospitals in The Netherlands. Clinical information was obtained from medical files. Patients completed a questionnaire, containing generic HRQOL instruments (EQ-5D and Health Utilities Index mark 3), vision-specific National Eye Institute Visual Functioning Questionnaire (VFQ-25), and glaucoma-specific Glaucoma Quality-of-Life questionnaire (GQL-15). The impact of visual field loss on HRQOL scores was analysed with multiple linear regression analyses.ResultsA relationship between mean deviation (MD) and HRQOL was found after adjusting for age, gender, visual acuity, medication side effects, laser trabeculoplasty, and glaucoma surgery. We found interaction between MD in both eyes for GQL and VFQ-25 scores. The relationship between MD and utility was non-linear, with utility only affected at MD-values below −25 dB in the better eye. Visual acuity, side effects, and glaucoma surgery independently affected HRQOL. Binocular MD and MD in the better eye had similar impacts on HRQOL, whereas MD in the worse eye had an independent effect. HRQOL was affected more by binocular defects in the inferior than in the superior hemifield.ConclusionVisual field loss in progressing glaucoma is independently associated with a loss in both disease-specific and generic quality-of-life. It is important to prevent progression, both in early and in advanced glaucoma, especially in patients with inferior hemifield defects and severe defects in either eye.

A Systematic Review Of The Adverse Events Of Intravitreal Anti-vascular Endothelial Growth Factor Injections

Background: Intravitreal ranibizumab and pegaptanib are registered for neovascular age-related macular degeneration. No formal safety study has been conducted for intravitreal bevacizumab. These anti-vascular endothelial growth factor (anti-VEGF) drugs are being used on a large scale in daily practice for different ocular diseases. The objective of the present study was to systematically assess and compare the incidences of adverse events of anti-VEGFs. Methods: A systematic search was conducted in April 2009 with no date restrictions in PubMed, Embase, Toxline, and the Cochrane library. We used the terms pegaptanib, bevacizumab, ranibizumab, intravitreal, and specific and general terms for adverse events. Studies describing adverse events after anti-VEGF injections and the official safety data were included. Results: Two hundred and seventy-eight articles were included, and the incidences of adverse events were calculated separately for effect, safety, and specific side effect studies. The incidences of serious ocular and nonocular adverse events were approximately below 1 per 100 injections for intravitreal bevacizumab, intravitreal ranibizumab, and intravitreal pegaptanib. Most mild ocular adverse events were below 5 per 100 injections. Conclusion: The reported rates of serious adverse events were low after anti-VEGF injections. There is no sufficient evidence to conclude that there is a difference in incidences between the anti-VEGFs.

Efficacy and safety of femtosecond laser-assisted corneal endothelial keratoplasty: a randomized multicenter clinical trial.

Background. To evaluate the efficacy and safety of femtosecond laser-assisted endothelial keratoplasty (FLEK) versus penetrating keratoplasty (PK) in patients with corneal endothelial disease. Methods. A randomized multicenter clinical trial of 80 eyes of 80 patients with corneal endothelial disease were randomized to FLEK or PK. Clinical outcomes (astigmatism and visual acuity) and incidence of postoperative complications were compared between the two groups. Results. At 12 months, the percentage of eyes with a refractive astigmatism less than or equal to 3 diopters was higher in the FLEK group in comparison with the PK group (86.2% vs. 51.3%, P=0.004). The mean postoperative best corrected visual acuity was 20/70±2 lines in the FLEK group and 20/44±2 lines in the PK group (P<0.001), but the gain in the best corrected visual acuity between the two groups was not significantly different. The endothelial cell loss in the FLEK and PK group was 65±12% and 23±15% (P<0.001). The most common postoperative complication in the FLEK group was graft dislocation (27.8%). Wound healing related problems occurred in six eyes (15%) in the PK group and in none of the FLEK eyes. Conclusions. FLEK effectively reduces postoperative astigmatism and results in an absence of wound healing related problems in patients with endothelial disease. However, visual acuity is lower as compared with conventional PK, and the high level of endothelial cell loss warrants a modification of the insertion technique of the endothelial graft.

An evidence-based review of prognostic factors for glaucomatous visual field progression.

PURPOSE To examine which prognostic factors are associated with glaucomatous visual field progression. DESIGN Knowledge of prognostic factors helps clinicians to select patients at risk of glaucomatous visual field progression and intensify their treatment. METHODS By consulting relevant databases, we identified 2733 articles published up to September 2010, of which 85 articles investigating prognostic factors for visual field progression in patients with open-angle glaucoma (OAG) were eligible. We summarized results for each factor in tables, noting the direction of the association between the prognostic factor and progression, and the accompanying P value. Four authors, working blind to the factors, independently judged the extent to which a prognostic factor was associated with glaucomatous visual field progression. If there were different associations for normal-tension glaucoma (NTG) studies, they were judged separately. Consensus was reached during group meetings. MAIN OUTCOME MEASURES A ranking of all studied prognostic factors for glaucomatous visual field progression according to their likelihood of being prognostic. RESULTS A total of 103 different prognostic factors were investigated in 85 articles. The following factors were clearly associated with glaucomatous visual field progression: age, disc hemorrhages (for NTG), baseline visual field loss, baseline intraocular pressure (IOP), and exfoliation syndrome. An association was unlikely for family history of glaucoma, atherosclerosis, systemic hypertension, visual acuity, sex (for NTG), systolic blood pressure, myopic refractive error (for NTG), and Raynauds phenomenon. CONCLUSIONS The factors we found clearly associated with progression could be used in clinical practice and for developing clinical prediction models. For many other factors, further research is necessary.

A network meta-analysis combined direct and indirect comparisons between glaucoma drugs to rank effectiveness in lowering intraocular pressure

OBJECTIVE It is difficult to rank treatments according to their effect size when several treatments are available and not all treatments have been compared directly. The purpose of this study was to show a new statistical technique (network meta-analysis) to address this problem and to rank glaucoma drugs according to their intraocular pressure (IOP)-reducing effect. STUDY DESIGN AND SETTING Network meta-analysis of randomized controlled trials was used to combine direct and indirect estimates of the effect of eight drugs and placebo from 28 randomized controlled trials in patients with primary open-angle glaucoma or ocular hypertension patients, 6,841 for the peak effect and 6,953 patients for the trough effect. RESULTS All drugs differ from placebo in lowering IOP. At the peak, the rank order from high to low in terms of the mean IOP reduction reached is bimatoprost, travoprost and latanoprost, brimonidine, timolol, dorzolamide, betaxolol, brinzolamide. At the trough, this rank order is bimatoprost, latanoprost, travoprost, timolol, betaxolol, dorzolamide, brinzolamide, brimonidine. The results based on direct or indirect estimates were similar. This ranking differed from the ranking based on the mean IOP change from baseline of all arms including the study drug from all randomized controlled trials. CONCLUSIONS A network meta-analysis can be used to combine direct and indirect treatment effects in a formal way. Applied to glaucoma medications, it shows that there is a rank order in treatment effects on IOP.

Pharmacological management of primary open-angle glaucoma: second-line options and beyond

Glaucoma is one of the leading causes of blindness worldwide. Increased intraocular pressure (IOP) is considered to be the most important risk factor. Major outcome studies from recent years have shown that lowering IOP is beneficial in primary open-angle glaucoma and ocular hypertension. The introduction of new classes of IOP-lowering drugs (α2-adrenoceptor agonists, topical carbonic anhydrase inhibitors and hypotensive lipids) in the last decade has contributed to a change in the drug prescription pattern. Together with β-adrenoceptor antagonists (β-blockers), these drugs are now considered to be first-choice classes, giving ophthalmologists ample opportunities to choose from a broad spectrum of IOP-lowering drugs. The number of possible medical treatment combinations has increased likewise.We review medical treatment combinations of two, three or four drugs from the four major first-choice glaucoma drug classes and provide an overview of the scientific evidence for IOP efficacy of second-line medical options when first-line therapy has been effective but additional IOP lowering is necessary. A systematic search of the literature initially revealed 2729 publications. After a thorough selection process, 42 studies were found to be eligible for inclusion in the review. Publications were excluded if the primary endpoint of the study was not IOP or if glaucoma topics other than IOP lowering of drugs were studied. In addition, studies that reported results for monotherapies only were excluded. The vast majority of study arms reported on combinations of a β-blocker with either a carbonic anhydrase inhibitor or a hypotensive lipid. For a number of treatment combinations no eligible studies were available or could be included.This review shows that combining drugs from the different first-choice classes results in an additional IOP decrease. The exact magnitude of this additional decrease and the patients to whom it applies remain unclear. In many studies, no information on IOP before the run-in phase was available. However, such data are important in order to determine whether patients with high untreated IOP or patients non-responsive to the run-in drug(s) were preferentially included. Another issue that hampers interpretation is the fact that the timepoints of measurements of IOP before and after adding a drug should be related to the peak and trough times of the drugs. Finally, differences between concomitant use and fixed combined use of drugs may have consequences for the interpretation of results.

The influence of 5-HTTLPR and STin2 polymorphisms in the serotonin transporter gene on treatment effect of selective serotonin reuptake inhibitors in depressive patients.

Background Serotonin transporter gene (SLC6A4) variations have been proposed as an explanation for interindividual differences in selective serotonin reuptake inhibitors (SSRIs) effects. Quantitative assessment of genetic influences is necessary to evaluate whether genetic testing before antidepressant prescription would lead to earlier treatment effects. This study evaluates the influence of two polymorphisms (5-HTTLPR and STin2) on SSRI treatment outcome in depression. Methods We included 50 SSRI nonresponders (cases) and 164 referents meeting Diagnostic and Statistical Manual Of Mental Disorder-IV criteria for major depression and using an SSRI for at least 6 weeks. Blood samples or buccal swabs were gathered to determine 5-HTTLPR (N=48 for cases and 161 for referents) and STin2 (N=50 for cases and 162 for referents) genotypes. The association between genotype and SSRI response was assessed by use of logistic regression. Results Patients with the 5-HTTLPR s-allele had a nonsignificantly increased risk of SSRI nonresponse; odds ratio (OR) 1.60, 95% confidence interval (CI) 0.66–3.89. 5-HTTLPR effects were strongest in female patients (OR 3.54, 95% CI 1.05–11.92), and for male patients 5-HTTLPR seemed to have no effect (OR 0.29, 95% CI 0.04–2.34). An age-dependent effect of 5-HTTLPR was observed; patients under 44 years of age had an increased nonresponse risk (OR 9.34, 95% CI 1.41–61.98). STin2 genotype had no clear influence on treatment outcome. Conclusion Our findings indicate that women with the 5-HTTLPR s-allele have a less favorable response to SSRI treatment. To our knowledge, this is the first time that a gender-dependent influence of 5-HTTLPR is reported. More research is needed, particularly in subgroups of patients, before implementation of genetic testing can be recommended.

Modeling Complex Treatment Strategies: Construction and Validation of a Discrete Event Simulation Model for Glaucoma

OBJECTIVE Discrete event simulation (DES) modeling has several advantages over simpler modeling techniques in health economics, such as increased flexibility and the ability to model complex systems. Nevertheless, these benefits may come at the cost of reduced transparency, which may compromise the models face validity and credibility. We aimed to produce a transparent report on the construction and validation of a DES model using a recently developed model of ocular hypertension and glaucoma. METHODS Current evidence of associations between prognostic factors and disease progression in ocular hypertension and glaucoma was translated into DES model elements. The model was extended to simulate treatment decisions and effects. Utility and costs were linked to disease status and treatment, and clinical and health economic outcomes were defined. The model was validated at several levels. The soundness of design and the plausibility of input estimates were evaluated in interdisciplinary meetings (face validity). Individual patients were traced throughout the simulation under a multitude of model settings to debug the model, and the model was run with a variety of extreme scenarios to compare the outcomes with prior expectations (internal validity). Finally, several intermediate (clinical) outcomes of the model were compared with those observed in experimental or observational studies (external validity) and the feasibility of evaluating hypothetical treatment strategies was tested. RESULTS The model performed well in all validity tests. Analyses of hypothetical treatment strategies took about 30 minutes per cohort and lead to plausible health-economic outcomes. CONCLUSION There is added value of DES models in complex treatment strategies such as glaucoma. Achieving transparency in model structure and outcomes may require some effort in reporting and validating the model, but it is feasible.