PBH91001 - SSRI Antidepressants in Treating Major Depression

This assignment provides a critical appraisal of Selective Serotonin Reuptake Inhibitors (SSRIs) for treating Major Depressive Disorder (MDD). It examines both primary and secondary research, including an observational study and a systematic review, using the Critical Appraisal Skills Programme (CASP) tools. The appraisal assesses the research design, recruitment, data analysis, clinical significance, and limitations of the selected studies. The systematic review, which included 131 randomized placebo-controlled trials, suggests that while SSRIs may have statistically significant effects on depression symptoms, they also increase the risk of adverse outcomes, potentially outweighing the clinical benefits. The appraisal highlights the importance of considering both the positive and negative effects of interventions in clinical practice, noting the high risk of bias in the included trials which limits the applicability of the findings to local populations. Desklib provides access to similar assignments and study tools.

Assessment 3 Critical Appraisal

Table of Contents
Part 1................................................................................................................................................3
Primary Evidence.........................................................................................................................4
Secondary Evidence.....................................................................................................................4
Part 2................................................................................................................................................4
Clinical significance of the article...............................................................................................9
Relevance to the original question...............................................................................................9
Strengths and limitations of the evidence....................................................................................9
Part 3..............................................................................................................................................11
Clinical significance of the article.............................................................................................13
Relevance to the original question.............................................................................................14
Strengths and limitations of the evidence..................................................................................14
References......................................................................................................................................14

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.

Primary Evidence
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”.
Secondary Evidence
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”.
Part 2
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.
2. Were right type of papers looked by the authors?
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.
3. 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.
4. 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.

5. 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.
6. 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.
7. Prescion of the results?
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.
8. 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).
9. Consideration of all the important outcomes?
I believe that all the significant outcomes were considered by the authors.
10. 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.

Clinical significance of the article
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.
Relevance to the original question
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.
Strengths and limitations of the evidence
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.
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.

Part 3
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.
2. 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.
3. 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.

4. 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.
5. Identification of the confounding factors by the authors?
I believe that major confounding factors were identified by the authors.
6. 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.
7. 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.
8. Application of the results to the local population?