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Research Proposal

Project Title: 
Psychiatric Symptoms as Adverse Events of Topiramate Therapy: Systematic Review and Meta-Analysis
Scientific Abstract: 

Background: Topiramate (TPM) is used in many contexts & has many off-label uses. This is despite the fact that its product information lists many possible psychiatric adverse events (PAE). However, up to now no one has worked on systematically categorising those PAE & linking them to certain risk groups of individuals.
Objective: The aim of our study is to systematically review all available studies employing TPM in patients with a broad range of issues such as somnolence, anorexia & concentration problems & to analyse both qualitatively & quantitatively whether there are groups associated with greater risk for these events.
Study Design: Our study is a systematic review & meta-analysis of both published & unpublished data on patients using TPM. Studies are collected after a literature search in three scientific databases (PubMed, WebOfScience, Embase) & two Clinical Trial Registries (ClinicalTrials, eudract). Data from unpublished studies are sought by contacting study authors/manufacturers. Total numbers of exposed patients & frequencies of PAE of them are extracted, categorized & reviewed.
Participants: As project is review, participant data will be extracted from resulting lit. search
Main Outcome: Frequencies of psychiatric or psychosomatic PAE for Statistical Analysis (Odds Ratios). For placebo-controlled studies, meta-analyses are calculated for PAE during TPM vs. Placebo, as well as comparing TPM to other agents.
Statistical Analysis: Comparison of Odds Ratios between different populations of patients, differing in demographics & associated disorders.

Brief Project Background and Statement of Project Significance: 

Topiramate is a well-established drug in the treatment of epilepsy and migraine prevention, but which is also often used off label to treat a broad array of issues, including, but not limited to weight loss, neuropathy and aiding smoking secession. For those off-label usages, there are no reports of adverse events available in the product information.
Our project is to evaluate the risk of psychiatric or psychosomatic adverse events by the means of a systematic review and meta-analysis. If the results of our independent study show that there are groups of individuals with a greater susceptibility to mental health issues as a result of Topiramate usage, it may help raise awareness of the suitability of Topiramate in such instances and to develop alternative treatment options with a lower risk of impeding adverse mental health outcomes.
We are aware of the fact, that the general psychothrophic adverse event profile is already established, however, it has not yet been established, whether different groups of patients for which TPM has been used experimentally or in clinical use are affected to the same degree: on the one hand patients with differential diagnosis, and on the other hand patients of different age groups. As this is a question not yet discussed in the scientific literature we believe to be contributing in a substantial way.

Specific Aims of the Project: 

Aim of our project is to systematically investigate and review how a therapy with Topiramate is associated with psychiatric adverse events. Product information mentions psychiatric adverse events during treatment with Topiramate in case of epilepsy. We want to support with evidence which risk factors may underlie patients using Topiramate in order to improve treatment for such risk groups. Our hypothesis is that based on the occurrence of psychiatric symptoms in Topiramate treatment of epilepsy, treatment of other disorder should also cause psychiatric symptoms, depending on several factors such as disorder being treated. To evaluate or hypothesis we will extract data on psychiatric (including psychosomatic) adverse events from interventional studies using Topiramate, determine their frequencies across studies, and meta-analytically compare the frequencies of psychiatric adverse events during Topiramate to those during placebo, controlling for factors such as age, gender and disorder treated.

In order to accomplish this we need the CSR data only with the AE case numbers for the different study arms.

What is the purpose of the analysis being proposed? Please select all that apply.: 
New research question to examine treatment safety
Confirm or validate previously conducted research on treatment safety
Summary-level data meta-analysis
Summary-level data meta-analysis pooling data from YODA Project with other additional data sources
Software Used: 
I am not analyzing participant-level data / plan to use another secure data sharing platform
Data Source and Inclusion/Exclusion Criteria to be used to define the patient sample for your study: 

For literature search, we used 3 databases (PubMed/MEDLINE, WebOfScience & Embase) and 2 clinical trials registries (ClinicalTrials & eudract). Keywords were: “topiramate AND double AND (blind OR dummy OR masked)”
Literature selection was performed manually using pre-defined criteria. We included interventional, double blind, placebo or other active agent controlled trials on humans w/ at least 1 treatment arm of TPM that reported at least 1 psychiatric adverse event (PAE). Trials include NCT00802412, NCT01859013, NCT01581281, NCT0184369
The following terms represent PAE we are interested in: “Anorexia/Reduced Appetite/Appetite Loss”, “Cognitive Impairment”, “Increased Appetite”, “Insomnia/Decreased Sleep/Sleeping Difficulties”, “Nervousness”, “Reduced Libido”, “Somnolence”, “Drowsiness”, “Suicidal Ideation/suicide attempt”, “Depression”, “Mood problems”, “Memory impairment”, “Increased sleep”, “Concentration issues”, “Anxiety”, “Confusion”, “Irritability”, “Restlessness”, “psychomotor retardation”, “Attention disturbance”, “Language problems”, “Cognitive Problems”, “Amnesia”, “psychosis”, “Thinking abnormalities”, “Behavioural problems”, “personality disorder”, “Hallucinations”.

Main Outcome Measure and how it will be categorized/defined for your study: 

Our study investigates frequencies of psychiatric adverse events during treatment with Topiramate in all included studies and analysis of risk groups. All randomized, placebo-controlled studies will be part of meta-analysis.

Main Predictor/Independent Variable and how it will be categorized/defined for your study: 

For the review, the predictor for the outcome of interest is treatment with Topiramate vs. Placebo / other active agents. For the meta-analysis, the predictor for the outcome of interest is treatment (with Topiramate vs. Placebo / other active agents).
Terms which represent psychiatric adverse events and we are interested in to conduct the frequencies of, are the following: “Anorexia/Reduced Appetite/Appetite Loss”, “Cognitive Impairment”, “Increased Appetite”, “Insomnia/Decreased Sleep/Sleeping Difficulties”, “Nervousness”, “Reduced Libido”, “Somnolence”, “Drowsiness”, “Suicidal Ideation/suicide attempt”, “Depression”, “Mood problems”, “Memory impairment”, “Increased sleep”, “Concentration issues”, “Anxiety”, “Confusion”, “Irritability”, “Restlessness”, “psychomotor retardation”, “Attention disturbance”, “Language problems”, “Cognitive Problems”, “Amnesia”, “psychosis”, “Thinking abnormalities”, “Behavioural problems”, “personality disorder”, “Hallucinations”.

Other Variables of Interest that will be used in your analysis and how they will be categorized/defined for your study: 

Frequencies of the following specified psychiatric advers events symptoms: “Anorexia/Reduced Appetite/Appetite Loss”, “Cognitive Impairment”, “Increased Appetite”, “Insomnia/Decreased Sleep/Sleeping Difficulties”, “Nervousness”, “Reduced Libido”, “Somnolence”, “Drowsiness”, “Suicidal Ideation/suicide attempt”, “Depression”, “Mood problems”, “Memory impairment”, “Increased sleep”, “Concentration issues”, “Anxiety”, “Confusion”, “Irritability”, “Restlessness”, “psychomotor retardation”, “Attention disturbance”, “Language problems”, “Cognitive Problems”, “Amnesia”, “psychosis”, “Thinking abnormalities”, “Behavioural problems”, “personality disorder”, “Hallucinations”.

Statistical Analysis Plan: 

In the systematic review, data will be analyzed qualitatively. In the meta-analysis, odds-ratios will be calculated for the different adverse effects occurring under Topiramate vs. Placebo using RevMan 5 in order to identify the risks for adverse events across populations as wekk as perfoming sub group analyses of risks for adverse events. For that matter, frequencies of PAE will be taken from the CSR-data and pooled with data already collected (for examples see section data source) and supplemented with the data provided by YODA. No IPD will be used in our analyses. We consider the analyses taken to be a substantial contribution in order to describe the safety profile of TPM.

Narrative Summary: 

Topiramate which is mainly used to treat epilepsy and to prevent migraine, has frequently been associated with psychiatric adverse events such as somnolence, anorexia and concentration problems. Yet, it is frequently prescribed for a broad range of issues, including weight loss and neuropathia that are not at all linked with its main uses. The aim of this study is to systematically review studies employing Topiramate to analyse whether or not there there are certain risk factors such as age or disorder being treated that predict a higher suspectability for psychiatric adverse events. Adverse events of interest include but are not limited to somnolence, anorexia and concentration problems.

Project Timeline: 

Our project is in the midst of completion. All aforementioned databases and clinical trial registries were searched and the studies were scanned and categorized and will be analysed further. Frequencies will extracted and evaluated. We will also contact several authors of studies that did not report adverse events in their publications. The requested studies in YODA are among the last in our attainment of white literature to gain a most complete set of data. We agree that it's a long term project and would adopt our time frame, but we'd like you to consider that we already performed the searches for published literature and clinical databases and extracted the data.

Project start date: 01.11.2019
Analysis completion date: 01.09.2020 (but still waiting for additional and more detailed data from YODA)
Manuscript drafted date: 30.11.2020
Results reported back date: 01.12.2020
Publication date: 01.02.2021

Dissemination Plan: 

Our project is part of a master thesis for a M.Sc. in Psychology. It was agreed with the supervisors of the project that the thesis will from the start be written in style of a scientific paper as per the submission guidelines of our target journal: "Human Psychopharmacology: Clinical and Experimental".
Before submission, you will receive a copy of the manuscript.


A short selected enumeration of included studies:

Anthenelli, R. M., Heffner, J. L., Wong, E., Tibbs, J., Russell, K., Isgro, M., ... & Doran, N. (2017) / Pubmed ID: 28029173
de Brito, A. M. C., de Almeida Pinto, M. G., Bronstein, G., Carneiro, E., Faertes, D., Fukugawa, V., ... & Tavares, H. (2017) / Pubmed ID: 27256372
Johnson, B. A., Ait-Daoud, N., Wang, X. Q., Penberthy, J. K., Javors, M. A., Seneviratne, C., & Liu, L. (2013) / Pubmed ID: 24132249
Elkashef, A., Kahn, R., Yu, E., Iturriaga, E., Li, S. H., Anderson, A., ... & Serpi, T. (2012) / Pubmed ID: 22221594
Yeh, M. S., Mari, J. J., Costa, M. C. P., Andreoli, S. B., Bressan, R. A., & Mello, M. F. (2011) / Pubmed ID: 21554564
Jankovic, J., Jimenez-Shahed, J., & Brown, L. W. (2010) / Pubmed ID: 19726418
Rosenstock, J., Hollander, P., Gadde, K. M., Sun, X., Strauss, R., & Leung, A. (2007). / Pubmed ID: 17363756
Muehlbacher, M., Nickel, M. K., Kettler, C., Tritt, K., Lahmann, C., Leiberich, P. K., ... & Loew, T. H. (2006) / Pubmed ID: 16788338
Ondo, W. G., Jankovic, J., Connor, G. S., Pahwa, R., Elble, R., Stacy, M. A., ... & Hulihan, J. F. (2006) / Pubmed ID: 16436648
Loew, T. H., Nickel, M. K., Muehlbacher, M., Kaplan, P., Nickel, C., Kettler, C., ... & Bachler, E. (2006) / Pubmed ID: 16415708

General Information

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Full CSR

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