Efficacy and safety profile of oral creatine monohydrate in add-on to cognitive-behavioural therapy in depression: An 8-week pilot, double-blind, randomised, placebo-controlled feasibility and exploratory trial in an under-resourced area

Table of Contents

Overall Summary

Overview

In this randomized, double-blind, placebo-controlled pilot study (N=100), participants with depression received either creatine (5g/day) or placebo alongside biweekly CBT for 8 weeks. The creatine + CBT group showed a statistically significant reduction in PHQ-9 scores (mean difference = -5.12) compared to the placebo + CBT group. Both groups had similar dropout rates (40%) and adverse event profiles, with creatine associated with more gastrointestinal issues and muscle cramps. ITT and PP analyses confirmed the primary outcome. Secondary outcomes (treatment acceptability, tolerability, safety) showed no significant differences between groups.

Key Points

Clear Presentation of Main Findings (written-content)
The abstract clearly presents the main finding of reduced PHQ-9 scores in the creatine + CBT group.
Section: Abstract
Expand on Methodology (written-content)
The abstract lacks crucial methodological details like study design, sample size, and specific interventions, limiting its informativeness.
Section: Abstract
Clear Rationale and Context (written-content)
The introduction effectively establishes the context and rationale by highlighting the prevalence of depression and limitations of current treatments.
Section: Introduction
Clarify Research Gap and Question (written-content)
The introduction could be strengthened by explicitly stating the research gap and primary research question.
Section: Introduction
Comprehensive Description of Study Design (written-content)
The methods section provides a comprehensive description of the study design, including randomization, blinding, and placebo control, enhancing rigor.
Section: Methods
Provide More Details about the CBT Intervention (written-content)
The methods section lacks detailed information about the CBT intervention, limiting reproducibility.
Section: Methods
Clear Presentation of Primary Outcome and Participant Flow (written-content)
The results section clearly presents the primary outcome and participant flow, enhancing transparency.
Section: Results
Enhance Visuals and Adverse Event Reporting (written-content)
The results section would benefit from a visual representation of the primary outcome data and more detailed adverse event information.
Section: Results
Clear and Accurate Participant Flow Chart (graphical-figure)
Figure 1 clearly presents participant flow, adhering to CONSORT guidelines and accurately representing the study design.
Section: Results
Comprehensive Baseline Characteristics Table (graphical-figure)
Table 1 effectively summarizes baseline characteristics, demonstrating comparability between groups.
Section: Results
Improve Clarity and Readability of Outcome Table (graphical-figure)
Table 2 presents key outcome data but could be improved by clarifying the presentation of PHQ-9 scores and separating raw numbers from percentages for secondary outcomes.
Section: Results
Effective Contextualization and Transparency (written-content)
The discussion effectively connects the findings to existing literature and acknowledges study limitations.
Section: Discussion
Explore Mechanisms and Clinical Implications (written-content)
The discussion could be enhanced by elaborating on potential mechanisms of creatine-CBT synergy and discussing clinical implications.
Section: Discussion

Conclusion

This pilot study presents promising, albeit preliminary, evidence supporting the potential of creatine supplementation as an adjunct to CBT for depression. The randomized, double-blind, placebo-controlled design, and the use of ITT analysis are methodological strengths. The significant reduction in PHQ-9 scores in the creatine + CBT group compared to the placebo + CBT group is a noteworthy finding. However, the high dropout rate, lack of detailed information on the CBT protocol, limited visual representation of results, and the absence of p-values for secondary outcomes raise concerns. While the study's findings align with previous research on creatine's antidepressant effects, the limited sample size and potential confounding factors necessitate cautious interpretation. Larger, more rigorous trials with longer follow-up periods are needed to confirm these findings, explore the mechanisms of creatine-CBT synergy, and determine the clinical implications for diverse patient populations.

Section Analysis

Abstract

Key Aspects

Strengths

Suggestions for Improvement

Introduction

Key Aspects

Strengths

Suggestions for Improvement

Methods

Key Aspects

Strengths

Suggestions for Improvement

Results

Key Aspects

Strengths

Suggestions for Improvement

Non-Text Elements

Fig. 1. Study flow chart.
First Reference in Text
Of these, 60 participants reached the study endpoint at 8 weeks (Fig. 1).
Description
  • Overall structure and purpose: The flow chart depicts the journey of participants through a randomized controlled trial (RCT). It starts with the initial pool of participants assessed for eligibility and follows them through the various stages of the study. The chart is organized chronologically, starting with the assessment for eligibility and proceeding through randomization, allocation to treatment groups, follow-up assessments, and finally, inclusion in the analysis. Each stage is represented by a box, and the connecting lines indicate the flow of participants. The number of participants at each stage is clearly indicated within or alongside each box. The chart also specifies the reasons for dropout at each time point, which may be unfamiliar to a layperson but is clearly denoted in the chart.
  • Treatment arms and allocation: The chart uses a color-coding system to differentiate between the two treatment arms of the RCT. One arm is represented by red boxes, while the other arm is represented by green boxes, consistently throughout the chart. This clear color distinction aids in visualizing the participant flow within each treatment arm independently. The allocation of participants to these two arms is determined through a process called 'randomization', a technique used in RCTs to ensure that participants are assigned to either treatment group by chance rather than by any other factor, with the aim of minimizing bias.
  • Dropout and study endpoint: The flow chart also illustrates the number of dropouts at each follow-up time point. 'Dropout' refers to the discontinuation of a participant's involvement in a study before its completion. The chart depicts dropouts as branches diverting from the main flow, with the number of participants who dropped out at each assessment indicated in the corresponding branch. The reasons for dropout are also specified, such as loss to follow-up (participants no longer contactable), side effects (adverse events), or discontinued intervention (participant chose to end their involvement). Dropouts are a common occurrence in clinical trials and understanding their reasons can help interpret the results of the study. In the reference text, the term 'study endpoint' refers to the final assessment time point of the trial, which in this case is 8 weeks.
Scientific Validity
  • CONSORT guidelines adherence: The flow chart adheres to the CONSORT (Consolidated Standards of Reporting Trials) guidelines, which represent a set of evidence-based recommendations for reporting randomized controlled trials. Adherence to these guidelines enhances the transparency and completeness of reporting, which is crucial for evaluating the validity and generalizability of trial results. The clear depiction of participant flow, including randomization, allocation, follow-up, and analysis, ensures that readers can fully comprehend the study's methodology and potential biases.
  • Study design representation: The chart accurately represents the study design as a randomized, parallel-arm, placebo-controlled, double-blind trial. This clear presentation of the study design strengthens the study's rigor and validity. The explicit mention of randomization and allocation procedures, as well as the use of a placebo control and blinding, highlights the study's efforts to minimize bias and enhance the reliability of the findings. The inclusion of follow-up time points and reasons for dropout provides further insights into the conduct and results of the trial.
  • Sample size accuracy: The flow chart correctly indicates the sample size at each stage of the study, providing a transparent and accurate representation of the study population. This detailed breakdown of participant numbers allows readers to assess the potential impact of attrition (dropout) on the study results and to gauge the representativeness of the final sample. The clear representation of sample sizes enhances the transparency and reproducibility of the study.
Communication
  • Clarity and organization: The flow chart clearly presents the flow of participants through the different stages of the study. The color-coding effectively distinguishes between the two treatment arms, and the use of concise labels makes the chart easy to follow. The figure effectively communicates the sample size at each stage, including the number of participants screened, randomized, allocated to each treatment arm, dropped out, and completed the study. This transparent presentation of participant flow enhances the credibility of the study by allowing readers to understand how the final sample size was reached and the reasons for attrition.
  • Accessibility and conciseness: The figure's caption is concise yet informative, providing context and clearly indicating the content of the chart. The labels within the chart are also clear and unambiguous, avoiding jargon and technical terms that might confuse a non-expert reader. The visual simplicity of the flow chart, combined with clear and concise labeling, makes the information readily accessible to a broad audience, including those without specialized knowledge in clinical trials.
Table 1. Baseline characteristics per study arm.
First Reference in Text
Participants' baseline characteristics were comparable between study arms (Table 1).
Description
  • Overall structure and purpose: The table presents the baseline characteristics of the participants enrolled in the randomized controlled trial (RCT), categorized by the treatment arm to which they were allocated. 'Baseline' refers to the status of the participants before any intervention is administered, allowing researchers to understand the initial characteristics of the groups being compared. The table is organized with rows representing different characteristics and two columns, one for each treatment arm: 'creatine + CBT' and 'placebo + CBT'. 'CBT' stands for Cognitive Behavioral Therapy, a type of psychotherapy. The table aims to demonstrate that the two groups were similar at the beginning of the study, minimizing the chance that observed differences in outcomes are due to pre-existing differences rather than the treatment itself.
  • Specific characteristics presented: The characteristics presented in the table include demographic information like age, sex, body mass index (BMI), relationship status, years of education, and employment status. These characteristics provide a general profile of the participants in each group. It also includes the baseline PHQ-9 (Patient Health Questionnaire-9) score. The PHQ-9 is a self-reported questionnaire used to assess the severity of depressive symptoms. A higher score indicates more severe depression.
  • Data presentation format: For categorical variables such as sex, relationship status, and employment status, the table presents both the number (N) of participants in each category and the corresponding percentage of the total number within each treatment arm. For continuous variables like age, BMI, and PHQ-9 score, the table presents the mean (average value) and standard deviation (SD), which shows how spread out the values are from the mean. Presenting both means and SDs allows for a better understanding of the distribution of these variables within each group.
Scientific Validity
  • Randomization effectiveness: The inclusion of baseline characteristics is a standard practice in randomized controlled trials and strengthens the internal validity of the study. Comparing baseline characteristics ensures that the randomization process has effectively distributed potential confounding factors across the treatment groups, minimizing the risk of selection bias. This helps to ensure that any observed differences in outcomes can be more confidently attributed to the intervention rather than pre-existing differences between the groups.
  • Relevance of characteristics: The choice of baseline characteristics is appropriate and relevant to the study's focus on depression. The inclusion of age, sex, BMI, socioeconomic indicators (education, employment), and baseline depression severity (PHQ-9) allows for a comprehensive assessment of potential confounding variables that could influence the outcome. This comprehensive assessment strengthens the validity of the study's findings.
  • Statistical rigor: The statistical measures used to describe the baseline characteristics are appropriate and correctly applied. Reporting means and SDs for continuous variables and frequencies and percentages for categorical variables is standard practice and provides a clear and accurate summary of the data. The use of these appropriate descriptive statistics strengthens the credibility of the presented data.
Communication
  • Clarity and formatting: The table is well-organized and easy to read, with clear column headings and consistent formatting. The use of descriptive labels for each characteristic and the inclusion of both raw numbers and percentages for categorical variables makes the data readily interpretable. The presentation of means and standard deviations for continuous variables is appropriate and facilitates comparison between the two study arms. The clear legend further enhances readability by explaining the abbreviations and statistical measures used.
  • Informativeness: The table effectively summarizes the baseline characteristics of the participants in each study arm, allowing for direct comparison and assessment of baseline comparability. The presentation of demographic and clinical characteristics, including age, sex, BMI, relationship status, education, employment status, and baseline PHQ-9 score, provides a comprehensive overview of the study population. This comprehensive presentation allows readers to assess the potential influence of these baseline characteristics on the study outcomes.
  • Conciseness: While the table presents a good amount of information, it remains concise and avoids overwhelming the reader with unnecessary details. The focus on key baseline characteristics relevant to the study's objectives ensures that the table serves its purpose effectively without being overly complex. The use of a clear and concise legend further aids in conveying the necessary information without cluttering the table itself.
Table 2. Study outcomes at 8 weeks (study endpoint).
First Reference in Text
Outcome data at study endpoint for both creatine + CBT and placebo + CBT arms are available in Table 2.
Description
  • Overall structure and purpose: The table presents the results of the study at the 8-week endpoint, summarizing both the primary and secondary outcome measures. The primary outcome, PHQ-9 depression symptom severity, is presented as mean and standard deviation (SD) for both the creatine + CBT and placebo + CBT groups. Secondary outcomes include the proportion of participants discontinuing treatment due to any cause (acceptability), due to adverse events (tolerability), and the proportion experiencing at least one adverse event (safety). 'Study endpoint' refers to the final assessment point in a clinical trial, which is 8 weeks in this study. CBT stands for Cognitive Behavioral Therapy, a type of psychotherapy.
  • Types of analysis: The table includes the results of both an intention-to-treat (ITT) and a per-protocol (PP) analysis. ITT analysis includes all randomized participants, regardless of whether they completed the study or adhered to the assigned treatment, preserving the benefits of randomization. PP analysis, on the other hand, only includes participants who completed the study according to the protocol. Including both analyses provides a more comprehensive understanding of the treatment effect and accounts for potential bias introduced by dropouts or non-compliance.
  • Specific measures and statistics: For the primary outcome (PHQ-9 score), the table presents the baseline mean and SD alongside the endpoint mean and SD for both treatment arms. Additionally, the adjusted mean difference (aMD) between the two groups is presented along with its 95% confidence interval (CI). The CI provides a range of values within which the true population mean difference is likely to lie. For the secondary outcomes, the table presents the number (N) and percentage (%) of participants experiencing each outcome in both treatment arms. Adjusted odds ratios (aOR) with their respective CIs are also reported for the secondary outcomes. The aOR represents the odds of an event occurring in one group compared to the other, after adjusting for other variables. Beta (β) coefficients are regression coefficients that help understand the impact of various predictor variables on an outcome. The inclusion of baseline PHQ-9 score helps in assessing the change from baseline in each treatment group.
Scientific Validity
  • ITT and PP analyses: The inclusion of both ITT and PP analyses is commendable as it strengthens the study's robustness and allows for assessing the impact of missing data. The ITT analysis preserves the benefits of randomization and provides a more conservative estimate of the treatment effect. The PP analysis offers insights into the treatment's efficacy in those who adhered to the protocol. Presenting both analyses allows readers to compare the results and consider potential biases introduced by participant dropout or non-compliance.
  • Effect size and confidence intervals: Reporting aMDs and aORs with 95% CIs for both primary and secondary outcomes is appropriate and provides crucial information about the precision and statistical significance of the observed effects. The use of appropriate statistical methods, including adjustment for potential confounders, strengthens the validity of the findings. However, the absence of p-values for secondary outcomes makes it difficult to assess the statistical significance of these results and could be improved by including them.
  • Baseline and endpoint data: The table clearly presents the baseline and endpoint PHQ-9 scores for both treatment arms, allowing for a direct comparison of the change in depression severity. This clear presentation of both baseline and endpoint data, alongside the effect size and CI, facilitates a thorough evaluation of the treatment effect. However, the use of mixed units (mean ± SD for the PHQ-9 score and N events (%) for other variables) in the results section, while potentially reflecting different data types, could benefit from clarification to avoid potential confusion. Ensuring consistent reporting units across outcomes would enhance clarity and comparability.
Communication
  • Clarity and formatting: The table is generally well-organized, but the presentation of both baseline and endpoint data for the PHQ-9 scores within the same cell can be slightly confusing. Separating these values into different rows would improve clarity. Additionally, the inclusion of both raw event numbers (N) and percentages (%) for the secondary outcomes is helpful, but the placement of both within the same cell adds to the visual clutter. Presenting these values in separate columns would enhance readability.
  • Informativeness: The table provides essential information about the primary and secondary outcomes of the study, including effect sizes and confidence intervals, which are crucial for interpreting the results. The inclusion of both intention-to-treat (ITT) and per-protocol (PP) analyses for the primary outcome strengthens the robustness of the findings. However, the lack of p-values for the secondary outcomes makes it difficult to assess the statistical significance of these results, which limits the ability to draw definitive conclusions.
  • Accessibility: The use of abbreviations like aMD, aOR, β, and CI, while standard in scientific literature, might not be immediately clear to all readers. Including a brief explanation of these terms in the table legend would enhance accessibility. The dense presentation of data, particularly the combination of means, SDs, and baseline values within the same cell, can make it challenging for readers to quickly grasp the key findings. Streamlining the presentation and separating these values would improve readability.

Discussion

Key Aspects

Strengths

Suggestions for Improvement

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