Part 1

When a research article is critiqued, it helps the appraiser picking the good quality of papers from the bad ones (Harrison, Reid, Quinn, & Shenkin, 2017). Critical appraisal exhibit understanding of the major health research logical perspectives and methodologies including their assumptions and practical applications. The appraisal also differentiate between different evidence types and research designs. The research question for the assignment is “In the target population of patients with major depressive disorder can the use of SSRI depressants improve symptoms as compared to standard treatment within 6 to 12 months?” This assignment critically reviews two research papers, one is a primary evidence which is an observational study while the other is a secondary evidence which is a systematic review. Same critiquing tool is used for both articles for the purpoe of critical appraisal. The appraisal for both the papers will include a review of the aim, research design, recruitment strategy, data collection and analysis methods, believability, implications of the study, clinical significance, and strengths and limitations of the article. Further, the appraisal will also include the relevance of the paper with the resarch question. Various critiquing tools exist for the purpose of critically appraising all types of studies. But in this assignment to appraise the primary and secondary evidence, Critical Appraisal Skills Programme (CASP) tools has been used. This tool has a strategic approach to evaluate the rigour of the research articles under consideration (Smith & Noble, 2016). In addition, the CASP tools are brief yet comprehensive by including every aspect needed for critical review of literature efficiently (Nadelson & Nadelson, 2014). In this assignment, the primary and secondary evidence are critically appraised to answer relevant and organized questions through the use of CASP tools. After the appraisal, the relevance of the paper to original research question is also identified.

The primary evidence used for critical appraisal relevant to the chosen topic is an observational study titled “Cognitive tolerability following successful long term treatment of major depression and anxiety disorders with SSRI antidepressants”.

The secondary evidence used for critical appraisal is a systematic review titled “Selective serotonin reuptake inhibitors versus placebo in patients with major depressive disorder. A systematic review with meta-analysis and Trial Sequential Analysis”.

Paper chosen for the critical appraisal- Jakobsen, J. C., Katakam, K. K., Schou, A., Hellmuth, S. G., Stallknecht, S. E., Leth-Møller, K., … & Krogh, J. (2017). Selective serotonin reuptake inhibitors versus placebo in patients with major depressive disorder. A systematic review with meta-analysis and Trial Sequential Analysis. BMC psychiatry, 17(1), 58. Doi: 10.1186/s12888-016-1173-2

1. A clearly focused question was addressed in the review?

The review is clearly focused and addresses a direct question. The focus in terms of population studied is the patients with the major depressive disorder. It is also focused in terms of the intervention given which is the Selective serotonin reuptake inhibitors in the target population. The review also focused on the comparison of the intervention which is placebo. The title of the article mentions the type of research study, that is systematic review. The mention of the study type in in the title, makes it easily searchable in the databse. The review question is clearly focused and explanatory and fulfil its key function of clarifying the aim of the study for the readers. Further, the abstract of the article provides a sharp overview of the background, methods, results and conclusion. By reading the abstarct of the article, readers will have a superficial idea of the in-depth study and can figure out if the paper is of their use, so whether they should keep on reading or stop.

1. Were right type of papers looked by the authors?

Primary Evidence

The key search terms that the authors included were “Depression”, “SSRI” and “Systematic Review”. Relevant studies were included with the most appropriate study design that is the randomized clinical trials which compared the effects of SSRIs versus placebo, ‘active placebo’ or no intervention. The trial that particularly randomised depressed participants with: a specific somatic disease, schizophrenia, or depression prior or post pregnancy were excluded from the research. Over 24000 studies were identified through database and after screening and exclusion 131 trials were included in the Meta analysis. Cochrane systematic review methodology, Trial Sequential Analysis, and measurement of Bayes factor were down. Subsequently, an eight-step process was done to evaluate if thresholds for statistical and clinical significance were met.

1. Inclusion of all the important and relevant studies?

Suitable randomised clinical trials were searched in a range of databases namely The Cochrane Library’s CENTRAL, PubMed, EMBASE, PsycLIT, PsycINFO, Science Citation Index Expanded, clinical trial registers of Europe and USA, websites of pharmaceutical companies, the U.S. Food and Drug Administration (FDA), and the European Medicines Agency. These were screened for relevant papers published till January 2016. The data was extracted by minimum two independent reviewers. The included trials were used regardless of language, publication status, year and type. Unpublished trials were identified by searching clinical trial registers of Europe and USA, websites of pharmaceutical companies, websites of U.S. FDA and European Medicines Agency. USFDA was requested by the authors to offer all the information eligible for public release regarding the suitable trials of SSRIs that were proposed for marketing approval. Review authors worked on selecting the eligible trials and extracting the data in pairs and independently. A standardized data extraction form was utilized by the reviewers. A discussion was done among the reviewers in case some trial was identified by only one author regarding if the trial should be included or not. When a disparity came up, consultation from third reviewer was done. Review authors were contacted if important data was missing.

1. Were the quality of the included studies assessed throughly by the authors?

The potential effect of bias on the results of the study was assessed (Higgins & Green, 2011). Incomplete outcome data bias, which means possible effect of missing data was also evaluated through a ‘best-worst’ case scenario supposing that all respondents lost to follow-up in the SSRI group had a favorable outcome and all those with missing outcomes in the placebo group have had an adverse outcome (Jakobsen, Wetterslev, Winkel, Lange, & Gluud, 2014). Reverse ’worst-best-case’ scenario analysis was also performed. Risk of publication bias was also evaluated by visual inspection of funnel plots and by tests for funnel plot asymmetry.

1. Were the results of the review combined, was combining justified?

Results were combined and it was reasonable to combine them as the results were similar from study to study. But results from all the included studies are not presented in the paper.

1. The overall results of the study

The study included 131 randomised placebo-controlled trials which suggested inclusion of over 27,000 participants. Among the included trials, none of the trials used the control intervention of ‘active’ placebo or no intervention as discussed at the initial stage of research. Further, the reviewers reported that all the included trials had high risk of bias. The research identified four major effect of the SSRIs at the end of the treatment. It was found that at the end of the treatment from SSRIs, the Hamilton Depression Rating Scale (HDRS) was substantially declined. Bayes factor was found below predefined threshold (2.01*10−23). But, the effect estimate, lower than the predefined threshold for clinical significance of 3 HDRS points. SSRIs significantly reduced the chances of no remission but the Bayes factor which was 1426.81 was unable to verify this effect. SSRIs also considerably enhanced the chances of serious adverse outcomes. It was found that 31 in 1000 participants in SSRI group will face a serious adverse outcome while the figure was 22 in 1000 participants in control group. Lastly, SSRIs also considerably enhanced the number of minor adverse outcomes. 

1. Prescion of the results?

Secondary Evidence

The precision of the results can be established by looking at the confidence interval of the results. Suitable confidence can be established in the result that the estimated outcome will take place in the general population when the confidence interval is above 95. Further, the narrower the range included in the interval, the more precise the estimation of the result will be which will give a more valid estimate of the actual effect of the intervention, that is the SSRIs. For the first result, that is the HDRS decline showed a CI of 95% was found with a range of −2.50 to −1.37. For the second outcome of no risk remission, CI of 95% with range of 0.84 to 0.91 was found. Finally, for the outcome of enhanced chances of adverse effect 95% CI 1.08 to 1.75 was found. Therefore, it can be concluded that the results of this research study was adequately precise.

1. Application of the results to the local population?

It is unlikely that the results of the study can be applied to the local population as the included trials had high risks of bias. In addition, the conclusions of this study verified the results of other studies which queried the impacts of SSRIs (Gøtzsche, 2013), however, it contradicts the findings of other reviews which demonstrated that SSRIs are useful in treatment of depression (Cipriani, et al., 2009).

1. Consideration of all the important outcomes?

I believe that all the significant outcomes were considered by the authors.

1. Did the benefits outweig the harms and costs?

Since the study did not reach a clinically significant outcome, it can be said that the benefits of conducting the research may not be worth the costs of conducting it.

The rationale of conducting the study was the concern prevalent among public about the effects of SSRIs. It has been previously found that the harms of antidepressants outweigh the benefits (Andrews, Thomson, Amstadter, & Neale, 2012). This study also demonstrated that SSRIs substantially enhanced the risks serious as well as minor outcomes and the harmful impacts appear to prevail over the possible little beneficial clinical impacts of SSRIs. The clinical significance of this study is also questionable due to the high risk of bias among the included trials and therefore it will be unlikely to use this review to guide clinical practice.

The study found that SSRIs have statistically considerable impacts on the symptoms of depression as opposed to placebo. It also found that enhanced the risk of both serious and minor adverse outcomes and that when SSRIs are given for major depression, the harmful effects outweigh the small potential beneficial effects. This is relevant to the original research question as it aimed to find out the benefits of the SSRIs as opposed to standard treatment in patients of major depression. Its essential that not only the positive effects of an intervention are identified but the posible serious as well as non-serious events should also be recognised.

The most important strength of the article had been the inclusion of 131 studies with only randomized control trial design to reduce risk of bias and use of both meta-analysis and tri-sequential analysis, which enhanced the quality and reliability of the data. In addition, the data was double-extracted by independent authors which lowered the risk of erroneous data extraction, and the risk of bias in every trial was evaluated as per Cochrane. Moreover, Trial Sequential Analysis was made use of to regulate the likelihood of random errors (Wetterslev, Thorlund, Brok, & Gluud, 2008). When the primary outcomes were analysed it was found that the accumulated data assizes were adequate. Additionally, visual assessments of forest plots and statistical test exhibited restricted indications of heterogeneity in statistics. So, it can be said that the findings of the study were quite valid and that the results were consistent in various trials.

Part 2

But the secondary evidence had various limitations as well. Firstly, the HDRS mean differences were averaged impacts. So, it would not be appropriate to deduce the conclusion that SSRIs do not have clinically significant impacts on all the participants with depression. Further, the included trials were at high risk of bias per several bias risk domains and particularly the risk of incomplete outcome data, selective outcome reporting, and inadequate blinding bias can prejudice the results of the review. The GRADE assessments demonstrated that the quality of the evidence was low because of the high risks of bias of the trials. The high risks of bias also doubts the validity of the findings of the meta-analysis because the trials at high risk of bias have a tendency to overvalue the benefits and undervalue the harms. Further, the authors also included very constrained data on the impacts of SSRIs on long-term results, suicidal tendency, and quality of life, so the impacts of SSRIs on these aspects remains uncertain. The eight-step process used in the review to check if the threshold is met or not has not yet been validated in empirical studies and is not accepted universally which is a limitation in the research methodology.

Paper used for the appraisal: Popovic, D., Vieta, E., Fornaro, M., & Perugi, G. (2015). Cognitive tolerability following successful long term treatment of major depression and anxiety disorders with SSRi antidepressants. Journal of affective disorders, 173, 211-215. Doi: 10.1016/j.jad.2014.11.008

1. A clearly focused question was addressed in the review?

The study is focused in terms of the intervention which is SSRi antidepressants. It is clear that the study has attempted to identify side effects the intervention in terms of cognitive tolerability. It doesn’t mention the population and the time frame is described as long-term.

1. Appropriateness of the recruitment strategy?

The cohort included the population who were successfully treated with SSRIs in monotherapy for at least six months for major depression or anxiety disorder. Further, no control group was recruited for this study.

1. Was the exposure accurately measured to minimise bias?

The effect of the SSRIs were measured on the population subjectively. The focus of this study was on cognition and therefore subjective measuring increased the chances of the bias. But all the participants were exposed to SSRIs treatment for at least 6 months.

1. Was the outcome accurately measured to minimise bias?

Since the study aimed to measure cognitive tolerability and subjective measurement is frequently faced with cognitive biases, it makes the outcome exposed to a major bias which cannot be reduced. There was no control group to make comparison of the outcomes between two groups and draw conclusions.

1. Identification of the confounding factors by the authors?

I believe that major confounding factors were identified by the authors.

1. The overall result of the research?

The results reported more than 20% of the patients who had major depression and anxiety disorder for more than 6 months with SSRIs recounted cognitive symptoms which included fatigue, inattentiveness, poor concentration, memory deficiency and apathy. Recall memory inadequacy, attention insufficiency and somnolence were most often ranked as moderate or severe.

1. Believability of the results?

Since, the sample size is small, it can be regarded as a flaw in the design. However, in that population size as well the outcome was observed in major proportion which enhances the believability.

1. Application of the results to the local population?

Selection of the Paper

Due to the subjective measuring of cognition, the subjective perceptions may change in different culture and their population. So, the local setting may vary from that in the study. Further, the sample size was also extremely small to consider the results to generalize it for entire population.

1. Do the results of this study fit with other available evidence?

Previous studies conducted to find the tolerability of physical or cognitive symptoms by using antidepressants for long term have reported certain symptoms which may represent the side-effects of the antidepressants rather than the residual symptomatology.

1. Implications of this study in practice?

The study found that a huge percentage of the patients having depression or anxiety who received treatment with SSRIs for over six months stated cognitive, affective, motivational symptoms. Such symptoms may represent SSRI side effects instead of residual symptoms of depression indicating towards the side-effects of using SSRIs for long-term.

Since, a single observational study can seldom offer adequately robust evidence to recommend changes to clinical, it can be said that the study should be supported by other evidences in order to be clinically significant.

This study and its outcome are relevant to the original question as the question aimed to identify in the target population of patients with major depressive disorder can the use of SSRI depressants improve symptoms as compared to standard treatment within 6 to 12 months. For improvement of symptoms, it is essential that the intervention does not produce its own side-effects, so the measurement of side-effects on cognition as well as physical symptoms is relevant. Further, since the study included both depression as well as anxiety patients, it is a deviation from the original question. But no considerable differences were found in SSRI cognitive side effects reports of both the groups of the patients.

The most notable strength of this article is the novel insight it is providing on the side effects of this treatment option, this is the first article to assess side effects of the SSRI along with judging its efficacy in treating symptoms, which is a very important aspect of biomedical research when considering the efficacy of a treatment option. However, it has certain limitations also such as the cognitive functioning can only be measured through subjective means. Subjective measurement may contain several cognitive and economic biases (Jahedi & M´endez, 2013). Further. The sample size taken in this study was limited. In addition there was a lack of a control group.

References

Andrews, Thomson, Amstadter, & Neale. (2012). Primum Non Nocere: An Evolutionary Analysis of Whether Antidepressants Do More Harm than Good. Front Psychol, 3(117).

Cipriani, Furukawa, Salanti, Geddes, Higgins, Churchill, . . . McGuire. (2009). Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis. Lancet, 373(9665), 746–58.

Gøtzsche. (2013). Deadly Medicines and Organised Crime: How Big Pharma Has Corrupted Healthcare. Radcliffe Medical Press ltd.

Harrison, J. K., Reid, J., Quinn, T. J., & Shenkin, S. D. (2017). Using quality assessment tools to critically appraise ageing research: a guide for clinicians. Age and Ageing, 46(3), 359-365.

Higgins, & Green. (2011). The Cochrane Handbook for Systematic Reviews of Interventions, Version 5.1.0. Retrieved from The Cochrane Collaboration: https://www.cochrane-handbook.org/

Jahedi, S., & M´endez, F. (2013). On the Advantages and Disadvantages of Subjective Measures. 

Jakobsen, Wetterslev, Winkel, Lange, & Gluud. (2014). Thresholds for statistical and clinical significance in systematic reviews with meta-analytic methods. BMC Med Res Methodol, 14(1), 120.

Nadelson, & Nadelson. (2014). Evidence-Based Practice Article Reviews Using CASP Tools: A Method for Teaching EBP. Evidence-Based Nursing, 11(5).

Smith, J., & Noble, H. (2016). Reviewing the literature. Evidence-Based Nursing, 19, 2-3.

Wetterslev, Thorlund, Brok, & Gluud. (2008). Trial sequential analysis may establish when firm evidence is reached in cumulative meta-analysis. J Clin Epidemiol, 61(1), 64-75.