This study protocol was guided by the SPIRIT recommendations (Fig. 1 – study flowchart). The proposed prospective randomized study was duly registered at http://www.ensaiosclinicos.gov.br/org – Number: RBR-10b889rz/ UTN number: U1111-1287-9616 (February 13, 2022).
The clinical trial will be conducted in accordance with the precepts stipulated in the Declaration of Helsinki. The project received approval from the Ethics Committee for Research with Human Beings of the Federal University of Pernambuco (certificate number: 5.167.260 of 12/15/2021) and the Ethics Committee for Research with Human Beings of the Istituto de Medicina Integral Professor Fernando Figueira-IMIP (certificate number: 5.307.597 of 03/23/2022). All participants will be recruited from the psychiatry outpatient clinics of a Brazilian Public Hospital. We will evaluate adults of both genders (18 to 60 years old), with diagnosis of depression, insomnia and a history of suicidal ideation, in routine psychiatric clinic care, for a period of eight weeks.
Election criteria
Patients will be considered eligible if they:
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Present minimum age of 18 years and maximum of 60 years;
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Meet the criteria of the Diagnostic and Statistical Manual of Mental Disorders (5th edition, DSM-V Criteria) for Depressive Disorder and Comorbid Insomnia (APA, 2013).
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Present suicidal behavior according to the criteria proposed by the Columbia Suicide Risk Assessment Scale (POSNER et al., 2011);
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Have a total Insomnia Severity Index (ISI) score greater than 15.
Patients may be taking an antidepressant prescribed by their psychiatrist, but the insomnia medication of choice will be added to the study. The level of depression must be considered severe, as assessed by the psychiatrist. Individuals with cognitive impairment (as determined by the Mini-Mental Health Examination), those already under psychotherapeutic treatment or using another antidepressant, those with a history of psychiatric comorbidities, and pregnant or lactating women will be excluded from the study.
Operational procedures
All instructions will be accurate and written in manual form to ensure that all procedures determined for the clinical trial are performed, including patient recruitment, allocation to study groups, administration of the intervention, registration systems, criteria for stopping the intervention, etc. All activities to be carried out during the clinical trial will be previously established in the form of a list of tasks and distributed to the research team.
The initial assessment will consist of completing an identification form, a sociodemographic inventory, compilation of standardized medical records with anamnesis, physical examinations, standardized free and informed consent form, and a structured interview addressing depression using the Montgomey-Asberg Depression Rating Scale – scale that addresses the risk of suicide. The researcher will monitor the application of the depression and suicide risk scales.
Instruments for evaluating the measure of the primary outcomes
Assessment of Insomnia Severity
For this outcome, the Insomnia Severity Index (ISI) will be used, which is a 7-item insomnia measure of self-reported severity, commonly used in research. It has acceptable psychometric properties and is sensitive to treatment response. The questionnaire contains seven questions with scores ranging from zero to four. The specific items assess difficulties such as falling asleep, maintaining sleep, waking up in the morning, among others. The highest total score indicates severe sleep disturbance (Bastien, Valliãres, Morin, 2001; SADLER et al., 2018).
Assessment of suicidal behavior and suicide risk
For this outcome, the Columbia Suicide Risk Assessment Scale (C-SSRS) will be used, an instrument designed to assess suicidal behavior, developed by Kelly Posner and collaborators in New York, at Columbia University in 2007. This scale addresses the intensity of suicidal ideation and behavior, differentiating between behaviors with little probability of causing injuries and those with a higher probability of lethality (POSNER et al., 2011).
The instrument has an exclusive version for use in research of clinical trials focused on suicidal behavior outcomes. Currently, the scale is available in 103 languages, including Portuguese. It is one of the few tools which evaluates the entire spectrum of suicidal ideation, based on facts experienced by the individual and behavioral trends (POSNER et al., 2007). The Center for Disease Control and Prevention (CDC) and the Food and Drug Administration (FDA) recommend the use of this scale (POSNER et al., 2011). In this study, individuals who present a minimum score in any of the five sub-items of the scale during the follow-up period will be considered at risk of suicide.
Instruments for evaluating the measure of the secondary outcome
Assessment of depressive symptom severity
For this outcome, the Montgomery-Asberg Depression Scale, validated in 1979, will be used. The MADRS scale was chosen due to its greater sensitivity to changes in depressive symptomatology (MULDER, JOYCE, FRAMPTON, 2003). On this scale, scores less than or equal to 10 characterize the remission of the depressive episode. Higher MADRS scores indicate more severe depression, and each item yields a score from 0 to 6. The overall score ranges from 0 to 60. The questionnaire includes questions about the following symptoms: a) apparent sadness; b) expressed sadness; c) internal tension; d) reduced sleep; e) reduced appetite; f) concentration difficulties; g) lassitude; h) inability to feel; i) pessimistic thoughts; j) thoughts of suicide (MULDER, JOYCE,FRAMPTON, 2003).
Interventions
Medication Protocol for Insomnia
Both groups (Group A and Group B) will receive a drug protocol for insomnia. This will consist of Amitriptyline at a dosage of 25 mg, because it is a medication indicated for drug treatment in the 2019 Brazilian Consensus on Insomnia, and because of the availability of the medication in the Unified Health System.
CBTI protocol for insomnia
Only Group B will receive the CBTI protocol for insomnia. Cognitive Behavioral Therapy for Insomnia (CBTI) will be performed by a professional in the field of psychology who is trained to exercise specific psychotherapy for insomnia. CBTI, in particular, has been shown to be effective in reducing insomnia as well as mood and anxiety symptoms in several comorbid populations.
CBTI is an intervention normally carried out in face-to-face sessions, once a week for 30–40 minutes, for 6 to 8 weeks. Treatment manuals describe CBTI as consisting of three main components (Sleep Restriction Therapy, Stimulus Control Therapy, and Sleep-Specific Cognitive Therapy), along with sleep psychoeducation and sleep hygiene.
In this study, participants will receive weekly sessions of 60 to 90 minutes, for 8 weeks. The CBTI program will consider the guidelines of experts in the field, with session format and application of the treatment using a focused structure (SADLER et al., 2018). Actions proposed in the CBTI protocol will include, in the first four sessions, control stimuli (for example, going to bed only when feeling sleepy), sleep restriction (e.g. initially limiting the time spent in bed to increase the efficiency of the sleep), sleep hygiene (e.g. removing stimulating sources from the bedroom, such as television/radio/clock), and relaxation (e.g. diaphragmatic breathing, guided imagination). Cognitive restructuring of unhelpful sleep beliefs (e.g. thought diaries, behavioral experiments) and relapse prevention (e.g. summary of effective skills, maintaining progress) were included in the second half of the program (SADLER et al., 2018).
Data analysis
Data will be analyzed using statistical measures: mean and standard deviation values for numerical variables and percentage frequencies for categorical variables. Intergroup comparisons will be performed using Student's t test or Mann-Whitney test for numeric variables and Pearson's chi-square test for categorical variables. Intragroup comparisons of initial and final values will be performed using the paired Student's t test or the Wilcoxon test for paired data for numerical variables, and the McNemar test for categorical variables.
The unpaired and paired t tests will be used in situations where the data presents normal distribution, while the Mann-Whitney test and the Wilcoxon test for paired variables will be used in situations where it is normality rejected. The Shapiro-Wilk test will be used to determine data normality and Levene's F test will be used to determine the equality of variances.
The margin of error used in the decisions of the statistical tests will be 5%, and 95% confidence intervals will be calculated. Data will be entered into an EXCEL spreadsheet and the Statistical Package for the Social Sciences (SPSS version 23) will be used for all statistical calculations.
A statistician will perform the calculations and statistical analyses of the participants taking substances A and B. The masking will only be removed at the end of the statistical analyses.
Sample Size Calculation
The final sample will be calculated from a pilot study and conducted according to the guidelines proposed by Azevedo (2008). This will include the identification and classification of the variables of interest, the expected difference to be observed between the measures of these variables in the groups, the error probabilities called error type I (a) and error type II (b), whose values derive from the standardized Gaussian distribution scale (z table of the normal curve) (MASSAD, SILVEIA, ORTEGA, 2004), and finally the level of significance and the probability of correctly detecting a significant difference between groups. Thus, a formula for obtaining the sample related to the mean of the differences between the intervention groups will be adopted, namely:
Reducing the risk of bias
The dose of Amitriptyline for the treatment of chronic insomnia conditions meets the pre-established criteria, from previous trials, which showed positive results in reducing insomnia symptoms It has also been established by the current Consenso Brasileiro de Insônia 2019.
Ethical considerations
The project received approval from the Ethics Committee for Research with Human Beings of the Federal University of Pernambuco (certificate number: 5.167.260 of 12/15/2021) and the Ethics Committee for Research with Human Beings of IMIP (certificate number: 5.307.597 of 03/23/2022). For the proper execution of the activities related to the research, it will be necessary to meet the following demands in sequence of occurrence:
Letter(s) of consent(s) from the institutions: to obtain participants and carry out the treatments.
Consent of the Research Ethics Committee (REC): in compliance with the recommendations expressed in resolution No. 466 of 2012, of the National Health Council.
Confidentiality Agreement of those responsible for the research: in order to ensure that the data shared in the activities is protected and reserved only for the purposes proposed in the project; those responsible for the research will sign confidentiality terms.
Completion of the terms of consent: all participants will be informed about the objectives of the research, the necessary steps and the risks and benefits that will arise with the acceptance of participation. The right to freely choose whether or not to participate in the research will be assured and withdrawal will be allowed at any time. There will be anonymity regarding all information contained in the dissemination of the study results. The acceptance of the participant will be finalized through due and complete clarification of these terms, and ensured by the voluntary signature of the Free and Informed Consent Form.
Criteria for Suspension and Termination of Research: The participant is assured the right to withdraw from participation at any time, as well as to have complete access to the information acquired and analyzed. Participants will have their participation suspended or terminated if any casuistry criterion is found that is not in compliance and has not been declared, such as, for example, the finding of a pregnancy. The decision on suspension and conclusion of the individual's participation in the research will be carried out considering the well-being and health of the patient and the integrity and reliability of the research and its results.
Benefits: The study presents the benefits of evaluating the psychotherapeutic intervention of CBTI in patients with depression, insomnia and suicidal behavior.
Risks: This research presents minimal risk, which concerns the discomfort of volunteers when approached by unknown people to answer the questionnaires, as well as the deviation or loss of any of the instruments, causing harm and/or embarrassment to the volunteer. In order to minimize any embarrassment, the place of the interview will be private for the interviewees and researchers. Only the researchers will have access to the evaluation instruments. It is at the discretion of the volunteer during the research to allow a trusted companion to be present in the environment chosen for the research. After the period of 8 sessions, if the volunteer still has symptoms, he will be referred to the psychiatry service for a new, more careful evaluation.
Primary outcomes
Prior to each of the treatments, participants will complete self-report questionnaires. The evaluator, blinded to group allocation, will ask participants to complete outcome measures in a separate location from the treatment room.
1- Therapeutic effects of CBTI on insomnia, evaluated by the Insomnia Severity Index - ISI;
2- CBTI therapeutic effects on depressive symptoms assessed by the Montgomery-Asberg Depression Scale.
Secondary outcomes
1- Therapeutic effects of CBTI in reducing the risk of suicide, as assessed by the Columbia-Suicide Severity Rating Scale.
2- Reduction in the frequency of suicidal thoughts and ideation evaluated by the Columbia-Suicide Severity Rating Scale.
Analysis plan and outcome measurement
1-Insomnia – The mean change in the Insomnia Severity Index score from the beginning to the end of the intervention, measured for all participants, starting from non-significant insomnia (scores from 0 to 7 points), or from the lower limit for insomnia (scores from 8 to 14 points) – ISI reference;
2-Depression – Reduction of the total score obtained using the Montgomery-Asberg Depression Scale represented by scores less than or equal to 10 points, which characterize the remission of the depressive episode. MONTGOMERY, A.S.; Åsberg, M. – New Depression Scale Designed to be Sensitive to Change. British Journal of Psychiatry 134, pp382-389, 1979.
3-Suicide risk – Reduction in the total score obtained in the Columbia-Suicide Severity Rating Scale evaluation, represented by the absence of a minimum score in any of the five sub-items of the scale. POSNER, K.; BROWN, G.K.; STANLEY, B. et al. The Columbia–Suicide Severity Rating Scale: initial validity and internal consistency findings from three multisite studies with adolescents and adults. American journal of psychiatry, v.168, n.12, p. 1266-77, 2011.