F1000Research F1000Research 2046-1402 F1000 Research Limited London, UK 10.12688/f1000research.75764.1 Study Protocol Articles Effect of a collaborative multidimensional approach versus usual care on the resolution of adult depression in primary care in Chile: study protocol for a single blinded cluster randomized controlled trial

[version 1; peer review: 1 approved, 1 approved with reservations]

 VITRIOL VERONICA Conceptualization Data Curation Formal Analysis Funding Acquisition Investigation Methodology Project Administration Resources Supervision Validation Visualization Writing – Original Draft Preparation Writing – Review & Editing https://orcid.org/0000-0001-7406-4363 a 1 CANCINO ALFREDO Conceptualization Funding Acquisition Investigation Methodology Project Administration Resources Validation Visualization Writing – Original Draft Preparation Writing – Review & Editing 1 SCIOLLA ANDRES Conceptualization Investigation Methodology Resources Supervision Visualization Writing – Review & Editing 2 GUIÑEZ SERGIO Data Curation Formal Analysis Investigation Methodology Resources Software Supervision Validation Writing – Review & Editing 1 CALVO JORGE Data Curation Investigation Writing – Review & Editing 1 ORMAZABAL MARCELA Data Curation Investigation Writing – Review & Editing 3 KREITHER JOHANNA Data Curation Formal Analysis Investigation Methodology Resources Software Writing – Review & Editing 4 5 BALLESTEROS SOLEDAD Data Curation Investigation Resources Writing – Review & Editing 1 AYLWIN MARIA DE LA LUZ Conceptualization Data Curation Formal Analysis Funding Acquisition Investigation Methodology Project Administration Resources Software Supervision Validation Visualization Writing – Original Draft Preparation Writing – Review & Editing 4 6 Escuela de Medicina, Universidad de Talca, Talca, Maule, 3460000, Chile Department of Psychiatry and Behavioral Sciences School of Medicine, UC Davis Medical Center, Sacramento, Californa, 95616, USA Departamento Atención Primaria, Servicio de Salud del Maule,, Talca, Maule, 3460000, Chile Centro de Investigación en Ciencias Cognitivas, Universidad de Talca, Talca, Maule, 360000, Chile Centro de Psicología Aplicada, Universidad Talca, Talca, Maule, 3600000, Chile Centro de Investigaciones Médicas, Universidad de Talca, Talca, Maule, 3600000, Chile vvitriol@utalca.cl

No competing interests were disclosed.

 17 2 2022 2022 11 203 27 1 2022 Copyright: © 2022 VITRIOL V et al. 2022 This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Background: Major depression (MD) is a prevalent and disabling condition in Chile. Most MD cases are treated at the primary care level. In Chilean primary care, the authors have gathered evidence of a prevalent complex depression subtype associated with a worse prognosis and characterized by interpersonal difficulties, suicidality and trauma history. This MD presentation suggests the need for a multidimensional, trauma-informed and interprofessional approach.

The present study protocol describes the context, hypotheses and methods for a cluster randomized control trial (RCT) comparing a collaborative multidimensional approach and usual care in treatment outcomes of MD in primary care in Chile.

Methods: This is a two-arm, single-blinded, cluster RCT to compare the efficacy of a collaborative multidimensionalapproach for depression (CMAD) versus usual care to treat MD in primary care clinics in Chile. In total, 394 depressed adults from 18 to 65 years of age in twelve clinics located in Chile’s Maule Region will be consented to participate in the study. Patients and care teams from each clinic will be randomized to the intervention or to the control arm.

Interprofessional teams in the intervention arm will attend 27 hours of didactic and active learning sessions focused on clinical competences to effectively engage, treat and follow up patients with complex presentation of MD. Team in the control arm will receive 27 didactic sessions on current clinical guidelines for MD, profesionals in both arms will receive 27 hours of continued education.

Discussion: To improve treatment outcomes of MD in Chile, primary care teams should develop clinical competencies relevant to complex, difficult-to-treat types of MD within collaborative and trauma-informed approaches.

 Depression treatment primary care collaborative care trauma-informed care randomized controlled trial Agencia Nacional de Investigación y Desarrollo SA20I0031 The protocol of this study received funding for its execution from the Fondo Nacional de Investigación en Salud (FONIS), Agencia Nacional de Investigación y Desarrollo (ANID), ANID-FONIS SA20I0031. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Abbreviations

CMAD: Collaborative multidimensional approach for depression

GAD-7: General Anxiety Disorder Scale-7

GSES: General self-efficacy scale

ERS: Emotion regulation scale

MD: Major depression

MINI: Mini-International Neuro-psychiatric Interview

PHQ9: Patient Health Questionnaire

OQ-45: Outcome Questionnaire 45

RCT: Randomized controlled trial

 Background

Depression is the leading cause of disability worldwide, contributing significantly to the overall global burden of morbidity and mortality. 1 It is estimated that it affects almost 280 million people worldwide. 1 In Chile, depression constitutes a significant public health problem. 2 Findings before the SARS-CoV-2 pandemic showed that 18.2% of the adult Chilean population reported depressive symptoms, and 6.2% met the criteria for major depression (MD). 3 , 4 This prevalence is expected to increase with the pandemic. 5 Furthermore, it affects twice as many women as men, is the second leading cause of disability-adjusted life years and the first among women between 20 and 44 years. 2

Since 2001 there has been a Chilean national mental health program to treat MD. From 2006, this program has been known as Explicit Health Guarantees (Garantías Explícitas en Salud, GES, in Spanish), and is regulated by ministerial clinical guideline (Guía Clínica, 2013). 6 According to existing data, primary care treat 90% of MD cases. 7 Only those with current suicide attempts, suspected bipolarity or psychosis are referred to the specialty level. 2 , 7

Despite the implementation of the governmental guidelines, evidence shows limited competence in primary care teams to address MD, 7 with remission rates close to 50% at one year of follow-up. 8 , 9 There is also evidence of a high prevalence of comorbid anxiety disorders and reports of adverse life experiences in over 80% of patients with MD. 10 , 11 Using latent class analysis, our group found evidence of a complex depressive subtype. 12 This subtype, whose frequency is about half of the sample studied, is characterized by a history of suicide attempts, history of adverse life experiences, interpersonal difficulties, impairment in social functioning, and poor treatment response. 12 These characteristics, which have been reported in refractory depression, 13 can be understood in light of the neurobiological sequelae of exposure to psychological trauma. 14 Currently, there are a lack of recommendations in depression treatment guidelines regarding the needs of patients with this complex clinical picture.

According to a consensus of international experts, the clinical characteristics of patients with refractory depression are better conceptualized as difficult-to-treat depression. 13 This conceptualization implies an understanding of depression as a chronic disease, which requires a collaborative, multidimensional, biopsychosocial clinical approach and an orientation to the management of symptoms and functional recovery. 13 Working with similar populations, others have proposed the adoption of trauma-informed care principles and approaches, considering the cumulative interactions between trauma exposure, socioeconomic disadvantage, depression and suicidality 14 – 16

Both difficult-to-treat depression and trauma-informed care imply a collaborative organization health model similar to that proposed by Wagner et al in the management of chronic diseases, 17 including anxiety and depressive disorders as proposed by Archer et al. 18 It involves the presence of a case manager, a structured patient-centered approach, scheduled follow-up visits, the use of validated measures to monitor treatment response, and interprofessional communication between the different levels of care. 18 Considering all of the above, we hypothesize that a continuing education program for primary care teams that focuses on a biopsychosocial, trauma-informed care approach implemented in a collaborative model, will improve the outcomes of depression in comparison to usual care.

Specifically, we hypothesize that the collaborative multidimensional approach for depression (CMAD) in primary care will demonstrate greater efficacy relative to the standard treatment based on the clinical guidelines, considering:

Adult depressed patients in the CMAD arm will significantly improve depressive symptoms compared to the control group at 3 and 6 months after admission.

Adult depressed patients in the CMAD arm will significantly improve anxiety symptoms compared to the control group at 3 and 6 months after admission.

Adult depressed patients in the CMAD arm will significantly improve interpersonal dysfunction, social impairment, and emotional dysregulation compared to the control group at 3 and 6 months after admission

Adult depressed patients in the CMAD arm will achieve a significantly greater adherence than the control group at 3 and 6 months after admission.

We designed a cluster RCT protocol with two arms, single-blind to the outcome evaluator to compare the efficacy of a CMAD to improve the treatment outcomes of adult depression in primary care in Maule Region in Chile.

The general aim of this study is to compare the efficacy of a CMAD approach for MD with usual care according the standard treatment on the outcomes in primary care clinics in the Maule Region through a cluster RCT. The specific aims of this study are:

To design a CMAD treatment approach that imparts primary care teams with the competencies to recognize the clinical, functional and psychosocial dimensions associated with difficult-to-treat depression. This design includes trauma-informed principles and patient-centered care communication skills.

To implement the CMAD approach in primary care clinics in the Maule region, including a case manager, a structured patient-centered inter-professional management, a scheduled follow-up using validated instruments and continuous consultation with the specialty level.

To compare the depressive symptoms in adults treated for MD in primary care Maule clinics using the CMAD approach versus the standard treatment at baseline, three and six months.

To compare the anxiety symptoms in adult depressed patients treated for MD in primary care Maule clinics using the CMAD approach versus the standard treatment at baseline, three and six months.

To compare the symptoms of functional variables of emotional regulation, interpersonal and social functions in adult depressive patients treated for MD in primary care Maule clinics, using the CMAD approach versus the standard treatment at baseline, three and six months.

To compare the therapeutic adherence in adult depressive patients treated for MD in primary care Maule clinics using the CMAD approach and the standard treatment.

This study protocol is a cluster RCT, two parallel arms, single-blind to the outcome evaluator, which will compare the efficacy of a CMAD to improve the treatment outcomes of adult depression in primary care in the Maule Region in Chile.

 Methods Study setting

To meet the objectives of this protocol, primary care clinics belonging to the Maule Region in the municipalities of Talca, Curicó, Constitución, Sagrada Familia, Romeral and Pelarco will be invited to participate. These are centers that represent urban and rural areas of a disadvantaged region, including several rural areas where the socioeconomic and educational level is very low. 19 To obtain the sample, 12 centers were identified, which were matched according to similar average socioeconomic and educational characteristics. Moreover, selection considered that there will be no cross contamination between the patients in the control clinics and the intervention clinics. 34

Eligibility criteria

Adults between 18 and 65 years who enter treatment for depression in primary care clinics of the Maule Region will be invited for an evaluation after they sign a written informed consent statement. 34 Those with a confirmed diagnosis of MD, according to the Mini-international Neuro-psychiatric interview, will be included in the study. 20 On the other hand, those unable or unwilling to sign the informed consent, those with sensory disabilities, no access to a telephone, or who have been referred to a specialist level will be excluded from the study.

 Interventions

Eligible primary care clinics will be randomly assigned to the intervention and control arms of the study using a computer algorithm. Primary care teams of the intervention arm will receive training and implementation of the CMAD approach. Primary care teams of the control group will receive training in-line with the current clinical guideline for depression according.

 Intervention arm

The intervention arm will include 27 hours of training in the CMAD approach for primary care teams of at least one physician, a psychologist and a social worker. This approach integrates knowledge, attitudes, and skills to manage clinical manifestations associated with adversity or trauma throughout the lifespan, which are common in patients with complex difficult-to-treat depression. These competencies will be integrated with, not substituted for, the diagnostic and treatment recommendations included in the current clinical guidelines for depression. The training will be conducted by a team of two professors from the Universidad de Talca and one professor from the University of California, Davis in a total of eight sessions, four recorded lectures and four online workshops using a video conference platform. After training, primary care teams will implement a collaborative treatment model with a case manager, an individual treatment plan, a follow-up using a combination of validated self-report and clinician-administered instruments, with continuous monthly group supervision by a psychiatrist. All patients enrolled in the clinics assigned to the intervention arm will be treated by the same intervention type according to the CMAD model of treatment. In this arm, patients will receive the usual pharmacological and behavioral treatment, but the health care team will impart the treatment according to the CMAD management model.

 Control arm

The control arm will include 27 hours of training for primary care teams consisting of at least one physician, a psychologist and a social worker on the current clinical guidelines for MD. This guideline outlines a staging algorithm according to severity for the treatment of MD. The training will be conducted by two professors from Universidad de Talca and take place in 5-recorded lectures and three online workshops. After the training, the primary care teams will treat the patients according to the usual treatment. Teams are expected to be familiar with the guidelines and apply them. However, as is the usual treatment, no formal implementation will be offered. All patients enrolled in the clinics assigned to the control arm will be treated according to the usual care. In this arm, patients will receive the usual pharmacological and behavioral treatment, and the health care team will impart the treatment according to the usual clinic management.

 Modifications

For a given trial participant, the assigned study intervention may need to be modified or discontinued by treatment teams for various reasons, including change in diagnosis, risk of suicidality, or withdrawal of participant consent. There will be no strategies to modify the patient’s adherence to treatment as part of this protocol.

 Concomitant care

Primary care teams will provide patients with the pharmacological and behavioral care that are mandatory in the primary health system for patients with MD.

 Outcomes measures

Primary outcome

Change in depressive symptoms

Difference in depressive symptoms between the two arms of the study will be assessed at baseline and three and six months, as shown in the participants timeline ( Table 1), using the Patient Health Questionnaire validated in Chile. 21 This questionnaire is a 9-item self-report survey that uses a 4-point Likert scale to screen for the presence of MD and monitor treatment effects. The total score ranges from 0 to 27, and a greater score means a greater severity of depression. The presence of five or more symptoms in at more than half the days in the last two weeks suggests MD.

Timeline of health care teams and patients’ measurements and actions as specified in the protocol.
Time Study
Teams Patients
Pre Training Post Enroll Study
0 3 m 6 m
Intervention X
Enrollment X
Informed Consent X     X      
Eligibility       X      
Evaluations              
PHQ X X X
GAD-7         X X X
OQ-45 X X X
ERS         X X X
Adherence Scale X X
GSES X X

Abbreviations: PHQ, Patient Health Questionnaire; GAD-7, General Anxiety Disorder Scale-7; OQ-45, Outcome questionnaire 45; ERS, Emotion regulation scale; GSES, General self-efficacy scale.

Secondary outcomes

Change in anxiety symptoms

Difference in anxiety symptoms between the two arms of the study will be evaluated at baseline and three and six months ( Table 1) by the Spanish validated version of the generalized anxiety disorder scale-7 (GAD-7). 22 The GAD-7 is a 7-item self-report survey that uses a 3-point Likert scale to screen for generalized anxiety disorder quantify symptom severity. The total score ranges from 0 to 21 points, and greater scores mean greater severity of anxiety.

Change in interpersonal dysfunction and social role difficulties

Difference in functional impairment in interpersonal and social areas between the two arms of the study will be evaluated at baseline, at three and at six months ( Table 1) by the subscales of the interpersonal functioning, and social role included in the Outcome Questionnaire 45 (OQ-45). 23 The OQ-45 has a 45-item self-report survey that uses a 4-point Likert scale originally developed to monitor patient progress during therapy and after termination. The OQ-45 comprises the subscales of symptom distress, interpersonal relations, and social role. The interpersonal relations subscale includes 12 items addressing loneliness, conflict with others, and marriage and family difficulties, with scores that range from 0 to 48. The social scale consists of nine items tapping into difficulties in the workplace, school or home duties, with scores that range from 0 to 36 points. Greater scores mean worse interpersonal and social functioning.

Change in emotion regulation

Difference in the difficulties in emotion regulation between the two arms of the study will be evaluated at baseline, three and six months ( Table 1) by the emotion regulation scale (ERS) validated in Spanish with cutoff scores for the Chilean population. 24 ERS contains five subscales addressing emotional rejection, dysregulation, interference, inattention, and confusion. This scale is a 28-item self-report survey that uses a 5-point Likert scale. The scores range from 0 to 140 points, and greater scores indicate increased difficulties with emotional regulation.

Therapeutic adherence

Difference in the adherence to treatment between the two arms of the study will be evaluated at three and six months ( Table 1) by the therapeutic adherence scale, 25 a 21-item self-reported survey to measure the percentage that patients assign the effectiveness of each behavior. A score of 100 represents the highest adherence possible.

Other outcomes

Self-efficacy of the primary care teams

The self-efficacy of the primary care team, in implementing the study model, will be evaluated at baseline and after training ( Table 1) by the general self-efficacy scale (GSES) validated in Chile. 26 The GSES is a 10-item self-report survey that uses a 7-point Likert scale to measure self-efficacy. Thus, greater scores mean greater self-efficacy.

 Participant timeline Sample size

The estimation of the sample size considered a difference of 20% according to previous studies carried out in Chile, 27 – 29 based in a unilateral model, with an alpha of 5%, a power of 80%, a confidence level of 95% and a maximum variance of 50% resulted in 341 patients. Based on a previous study that determined the clinical and psychosocial variables associated with different evolutions in eight primary care clinics in the Maule region, 11 which showed retention of 85%, we adjusted the sample size to 394 patients. Based on a previous study we defined a group of at least 12 primary care clinics in the Maule Region, to be able to access the flow of adult patients with MD required for the feasibility of the study. 11

Recruitment

First, we will enroll the health care clinics through invitation to participate will be made to the health administration of the Maule region. Subsequently, those primary care clinics (Centro de Salud Familiar, in Spanish) authorized by their director will be invited to participate. A minimum of 12 primary care clinics will be enrolled, each with one team composed of a physician, a psychologist and a social worker.

The average socioeconomic level, adult population and patient’s income from 2019 will be used to match pairs of clinics. Later, the clinics will be assigned to the intervention or control groups using a pseudo-random algorithm (randi(2, [1 12], generates a 12-by-1 matrix of random integers between 1 and 2) in Matlab (MathWorks, Natick, MA, USA, RRID:SCR_001622).

A different researcher, not part of the training team, will make the list of pairs of clinics with similar characteristics in excel and assign each clinic to a number 1 or 2. Then, another researcher will assign the clinics corresponding to the randomization list (sequence of 1 and 2 numbers) to the intervention group and the remaining clinics of each pair to the control group. Finally, this last researcher will define a number code to the intervention and control groups, and a different group of researchers which, blinded to the arm assignments, will perform the data collection and analysis using the number code.

After the training phase, there will be a four month implementation of the CMAD approach in the clinic teams. After the implementation, patients who enter treatment for depression in their respective primary care clinic will be informed of the study and invited to participate by one person of each primary care team. Those who agree to participate, will be asked for their telephone number and researchers blind to the study arms will contact them, providing the informed consent form and then the questionnaires. An alphanumeric code will be assigned for each intervention arm, clinic and patient. Therefore, participants, outcome assessors, and data analysts will be blinded to the intervention allocation.

Patient recruitment is expected to begin on March 1, 2022. To achieve an adequate participant enrolment, each clinic will have a person in charge of inviting all the patients that meet the criteria for enrollment.

 Data collection, management and monitoring

The study will comply with all local research governance requirements for human data collection. A researcher team of psychiatry residents, blind to the intervention arms, will evaluate the participants at the beginning, at three and at six months using a set of instruments. The evaluation team will receive training for data gathering and standardization. The data from different instruments will be entered into a virtual worksheet located on SurveyMonkey by means of a tablet. Each evaluator will enter the data using a password, leaving no information on the devices. The data will be checked for correct entry every day and will be downloaded to the PI personal computer with a password located in an office with key. All data will be entered with the alphanumeric code, which prevents participant de-identification. The data from the participants that are referred to the specialist level will be eliminated from the study.

The data monitoring will be performed by the research team in charge of data collection and will meet every two weeks to evaluate the trial progression and data collection. A different research team in charge of data analysis will perform a checking of the data collected and perform preliminary data analysis to evaluate the progression of the data collection.

 Monitoring

Patients will first be monitored by their respective primary care teams as part of their treatment monthly. In high risk situations such as serious risk of suicide, psychosis and adverse effects of the medications are detected during the evaluations by the researchers (residents), the residents will inform to the researchers in charge of data collection, who in turn will inform the primary care teams. These patients will be excluded from the study as well as patients who do not want to continue with the evaluations.

We have not included plans for collecting, assessing, reporting, and managing solicited and spontaneously reported adverse events and other unintended effects of trial interventions as the medical treatment will not be modified from the national guidelines for MD. The interventions only modify the administration of the clinics’ treatment teams.

 Data analysis

An initial analysis of the sociodemographic and clinical characteristics of the sample will be carried out and the scores of the scales will be calculated. The results will be presented according to the Consolidated Standards of Reporting Trials guide for RCT, with its extensions to cluster interventions. Intention-to-treat analysis of the primary outcome will be performed. In the initial descriptive analysis, the differences in the characteristics of the clinics between the intervention groups will be estimated.

For the analysis of the primary outcome, linear multivariable regression will be used to establish differences at 3 and 6 months, adjusting the results according to the initial data in case of imbalance. In addition, a sensitivity analysis based on different assumptions will also be carried out to evaluate the possible effects of the lack of data. This analysis will also be done for secondary outcomes. Data analysis will be performed with SPSS software (IBM, Armonk, NY, United States, RRID:SCR_002865).

 Ethics approval and consent to participate

Ethical approval for this study was obtained from the institutional Ethics Committee (Comité Ético Científico, Universidad de Talca, protocol # 26-2020). The informed consent document will be available in a Mendeley Data repository. 34 Furthermore, informed written consent will be obtained from the participants (mental health team and patients). In case of protocol modifications (for example in the analyses or outcomes) the principal investigator should ask for an amendment to the original ethics informed consent to the Ethics Committee, and the changes should be communicated to all the study team.

The informed consent process will be performed by the research team in charge of the data collection. This team, made up of seven psychiatry residents, will obtained the informed consent in the health care clinic were the participant is admitted in a paper copy that will not have any information about the intervention assignment. During the informed consent procedure, an alphanumeric code will be assigned to the patient, and all the study information will be available under this code but it will not include any personal information that could help to obtain the identity of the participant. One researcher will have the list with the patient’s name and the assigned code in its personal computer secured with a password.

The final data set will be in the computer of the PI, and the researchers in charge of the analyses will have access to the data in the coded form. In case that the results of the study show significantly better outcomes in the intervention arm compared to the control arm, the primary care teams of the control arm will be trained in the CMAD approach.

 Dissemination

The principal investigator will communicate trial results to participants and healthcare professionals through workshops in the different clinics. The communication of the results to the general public, and other relevant groups will be performed trough seminars in the University of Talca. Finally, the communication of the results to the medical and scientific community will be done through the publication in specialized journals and the data sharing of the results in databases (eg, Mendeley). Moreover, the protocol will be available after the study has ended. Regarding the authorship legibility for the protocol, we will include all researchers that contributed significantly to the design, implementation the clinics training, data collection and analysis.

 Study status

This study has concluded the health clinics’ recruitment as well as the health care team’s informed consent and training in both study arms. Patient recruitment is expected to begin on March 1, 2022.

 Discussion

Collaborative models have proven to be the most effective to improve the outcomes for the treatment of MD in primary care. 18 However, in Chile, a single study that applied this model on the current government clinical guideline's recommendations showed no significant efficacy in the resolution of depressive symptoms. 28 As far as we know, there is no evidence on the efficacy of a collaborative model on the complex, difficult-to-treat depression subtype, which includes the recognition by primary care teams of clinical and functional variables associated with exposure to adversity and trauma. 13 , 29 , 30

This project seeks to test a clinical approach that includes a comprehensive, multidisciplinary clinical evaluation, and promotes the synergy of the entire health team, so that patients with difficult-to-treat depression, with neurobiological and psychological vulnerabilities associated with a history of biographical adversity, receive consistent treatment over time. It also entails close collaboration between the primary and secondary health system levels, which may reduce emotional distress in the treating professionals themselves.

Among the limitations, it should be noted that the continued education intervention will recruit team members who wish to participate. The sample of health care professionals may not be representative of health care professionals working in primary care in Chile. Professionals who are especially motivated in their continued education may be overrepresented among those who consent to participate. In addition, it is possible that this group of providers may have a higher-than-average competency level in some of the skills and attitudes fostered by the proposed approach.

As an additional limitation, results from this randomized trial involving many low income, rural and semi-rural patients in central Chile may not be extended to other more socioeconomically advantaged populations or patients living elsewhere in the country. Surveys using nationally representative samples have found up to 15-fold differences in prevalence between richer and poorer regions even if at the country level prevalence of MD has not changed significantly in the period of observation. 31 Furthermore, Chile’s income inequality gap is also more than 65% wider than the average in a group of mostly rich countries, 32 and meta-analysis data demonstrate greater risk of MD in populations with higher income inequality relative to populations with lower inequality. 33 Overall, the focus on primary care in the Maule Region of Chile seems justified on population health and social justice considerations. We hope that results from this trial will help address the existing low remission rates of MD in primary care, especially in patients presenting with difficult-to-treat, complex clinical presentations.

 Consent for publication

Not applicable.

 Data availability Underlying data

No underlying data are associated with this article.

 Extended data

Mendeley Data: Collaborative multidimensional approach to improve the resolution of depression in primary care in Chile https://doi.org/10.17632/jdftfbpvkn.1 34

This project contains the following extended data:

InformedConsent

Acta de aprobación V. Vitriol.pdf (Minutes of the Institutional Ethic Committee reporting the approval of the Informed Consent documents)

Consentimiento informado aprobado CEC.pdf (Informed consent document for participants)

Consentimiento informado profesional aprobado CEC.pdf (Informed consent document for primary care teams)

Primary Care Clinic Lists

Primary Care clinics.pdf (Clinics selected for trial).

Project Acceptance Letter

Carta N°988 Adj. XVII Fonis U. de Talca.pdf (Allocation of Funds for the study)

Reporting guidelines

Mendeley Data: Collaborative multidimensional approach to improve the resolution of depression in primary care in Chile https://doi.org/10.17632/jdftfbpvkn.1 34

This project contains the following reporting guidelines:

SPIRIT-Checklist-31 Dec 2021.pdf

Data are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).

 Roles and responsibilities

The research team responsible for this study belong to the School of Medicine of the University of Talca and the University of Davis, in collaboration with the Maule Health Service.

Principal Investigator: Verónica Vitriol

Study design: Verónica Vitriol, Alfredo Cancino, Andrés Sciolla and Maria de la Luz Aylwin

Clinic recruitment: Marcela Ormazábal, Sergio Guiñez

Clinic Team Data collection: Sergio Guiñez, Johanna Kreither

Pairing and assignment: Marcela Ormazábal, Maria de La Luz Aylwin

Training Primary Care Teams CMAD: Veronica Vitriol, Alfredo Cancino, Andres Sciolla

Training Primary Care Teams Depression Clinical Guideline: Jorge Calvo

Patient recruitment: Marcela Ormazábal, Soledad Ballesteros

Patient data collection and monitoring: Marcela Ormazábal, Soledad Ballesteros

Data analysis and interpretation: Veronica Vitriol, Alfredo Cancino, Andres Sciolla and Johanna Kreither

Research report writing: Veronica Vitriol, Alfredo Cancino, Andres Sciolla, Maria de la Luz Aylwin, Sergio Guiñez, Johanna Kreither, Jorge Calvo

 Authors' information

Verónica G. Vitriol MD, Escuela de Medicina, Universidad de Talca, Talca, Chile

Alfredo Cancino MD, Escuela de Medicina, Universidad de Talca, Talca, Chile

Andrés Sciolla MD, Department of Psychiatry, Medical School, UC Davis, USA

Sergio Guiñez PhD, Escuela de Medicina, Universidad de Talca, Talca, Chile

Jorge Calvo MD, Escuela de Medicina, Universidad de Talca, Talca, Chile

Marcela Ormazábal Ms, Departamento APS, Programas y Ciclo Vital, Subdirección de Gestión Asistencial, Dirección Servicio de Salud del Maule, Talca, Chile

Johanna Kreither PhD, Centro de Investigación en Ciencias Cognitivas, Centro de Psicología Aplicada Facultad de Psicología, Universidad Talca, Talca Chile

Soledad Ballesteros MD, Escuela de Medicina, Universidad de Talca, Talca, Chile

María de la Luz Aylwin PhD, Centro de Investigaciones Médicas, Escuela de Medicina, PIA Ciencias Cognitivas, Centro de Investigación en Ciencias Cognitivas, Universidad de Talca, Talca, Chile

Acknowledgements

We thank the Regional Health Secretary and the Health Departments of the Municipality of Curicó, Constitución, Linares, Pelarco, Romeral, Sagrada Familia, and Talca and all the mental health teams and directors of the primary care clinics who contributed to this project. We also thank Ms. Carmen Gloria Blanco for her assistance with project management.

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Stress. 2021 Feb 9;34:1139–1148. 33561310 10.1002/jts.22658 Lathan EC Selwyn CN Langhinrichsen-Rohling J : The "3 Es" of trauma-informed care in a federally qualified health center: Traumatic Event- and Experience-related predictors of physical and mental health Effects among female patients. J. Community Psychol. 2021 Mar;49(2):703–724. 33301611 10.1002/jcop.22488 Wagner EH Austin BT Korff MV : Organizing Care for Patients with Chronic Illness. Milbank Q. 1996;74(4):511. 10.2307/3350391 Archer J Bower P Gilbody S : Collaborative care for depression and anxiety problems. Cochrane Database Syst. Rev. 2012;10:Cd006525. 10.1002/14651858.CD006525.pub2 Descripción sociodemográfica de la región del Maule: Reference Source Lecrubier Y Sheehan DV Weiller E : The Mini International Neuropsychiatric Interview (MINI). A short diagnostic structured interview: Reliability and validity according to the CIDI. Eur. 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Guzmán-González M Mendoza-Llanos R Garrido-Rojas L : Cut-off points of the difficulties in Emotion Regulation Scale for the Chilean population. Rev. Med. Chil. 2020;148:644–652. 33399757 10.4067/S0034-98872020000500644 Soria Trujano R Vega Valero CZ Nava Quiroz C : Escala de adherencia terapéutica para pacientes con enfermedades crónicas, basada en comportamientos explícitos. 2009;14:89–103. Clavijo M Yévenes F Gallardo I : The general self-efficacy scale (GSES): Reevaluation of its reliability and validity evidence in Chile. Rev. Med. Chil. 2020;148:1452–1460. 33844715 10.4067/S0034-98872020001001452 Rojas G Martínez P Vöhringer PA : Comprehensive technology-assisted training and supervision program to enhance depression management in primary care in Santiago, Chile: study protocol for a cluster randomized controlled trial. Trials. 2015;16:311. 26201546 10.1186/s13063-015-0845-4 Rojas G Guajardo V Martínez P : A Remote Collaborative Care Program for Patients with Depression Living in Rural Areas: Open-Label Trial. J. Med. Internet Res. 2018;20:e158. 29712627 10.2196/jmir.8803 Vitriol V Sciolla A Cancino A : Cuidado Informado En Trauma: Un Modelo Emergente Para El Abordaje Del Subtipo Depresivo Con Historia De Adversdad Infantil. 2020;58:348–362. Sciolla AF : An Overview of Trauma-Informed Care. Cham: Springer International Publishing;2017;165–181. Markkula N Zitko P Peña S : Prevalence, trends, correlates and treatment of depression in Chile in 2003 to 2010. Soc. Psychiatry Psychiatr. Epidemiol. 2017 Apr;52(4):399–409. 28197670 10.1007/s00127-017-1346-4 Chile economic snaphot: Upcoming Economic Forescat update. 1 December 2021. Reference Source Patel V Burns JK Dhingra M : Income inequality and depression: a systematic review and meta-analysis of the association and a scoping review of mechanisms. World Psychiatry. 2018;17(1):76–89. [published correction appears in World Psychiatry. 2018 Jun;17(2):235]. 29352539 10.1002/wps.20492 Vitriol V Aylwin M :2022. Collaborative multidimensional approach to improve the resolution of depression in primary care in Chile. Mendeley Data. V1. 10.17632/jdftfbpvkn.1 10.5256/f1000research.79682.r281255 Reviewer response for version 1 Eplov Lene F. 1 Referee Ustrup Marte 2 Co-referee Copenhagen Research Center for Mental Health - CORE, Mental Health Centre Copenhagen, Copenhagen, Denmark Copenhagen Research Unit for Recovery, Mental Health Centre Amager, Copenhagen, Denmark

Competing interests: No competing interests were disclosed.

 12 9 2024 Copyright: © 2024 Eplov LF and Ustrup M 2024 This is an open access peer review report distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. recommendation approve-with-reservations

The paper is a study protocol for a cluster randomized controlled trial evaluating the effect of a collaborative multidimensional approach for major depression (MD). This is an important study, as MD constitutes are large burden in Chile and because the research group has previously observed a complex depressive subtype with poor response to standard treatment.

The rationale for the study is clearly described.

The choice of a multidimensional, collaborative, and trauma-informed approach is well-justified and seems an appropriate choice, based on the literature and the groups previous studies.

Overall, the study protocol is clearly structured and conforms with the CONSORT guidelines.

However, there are some major issues as well as minor issues that needs to be addressed.

Major issues

Abstract:

The primary outcome is not described in the section “Methods” in the abstract. This is essential information and should be provided here.

Background:

The section clearly describes the scientific background and rationale. However, the authors use a lot of space to describe a subgroup among people with MD and although this is interesting, the RCT is investigation the effect of the intervention on the whole population with MD in primary care. Furthermore, it doesn’t look like they are going to do a subgroup analysis on the mentioned subgroup and the power calculation is based on wanting an analysis of the effect on the whole group, leading to the fact that there is not enough power to examine the effect of the intervention on the mentioned subgroup. Therefore, the introduction needs to have the main focus on describing the need of the intervention for the whole group of people with MD in primary care.

 Methods:

The section “Modifications” is hard to understand. Is the modification made in the treatment, then move the section up to the description of the “intervention arm”, if it is part of the must conduct the analyses then move the section to “Data analysis”. Be aware then that you can’t write that you will perform intention-to-treat analysis, as described under the section “Data analysis”.

Sample size: It is unclear if the sample size calculation takes the cluster design of the RCT into account. There is no mentioning of assumptions, such as approximate equal-sized clusters, or intra-class correlation (ICC).

Data analysis: As for the sample size calculation, it is unclear if and how the analyses take the clustering of individuals in clinics into account.

 Minor issues

Abstract:

The section “Discussion” is more of a conclusion, as if the trial has already been completed and analyzed. Instead, rephrase to e.g., “This trial will provide information on whether…”.

If the trial has been registered, e.g., at ClinicalTrials.gov, please provide registration number and date at the end of the Abstract.

 Hypotheses and aims:

Instead of listing five aims and four hypotheses, only list those related to the primary outcome, i.e. aim 3. The protocol only describes the RCT and therefore it is not an aim to, for example, design the intervention (aim 1), unless this process is also described in details.

Hypotheses 1 and 2: Change the wording “improve depressive symptoms” to “a reduction in depressive symptoms”, as this is more specific.

Aim 3: To make the aim and outcome clearer, emphasize that it is the change in depressive symptoms between baseline and follow-up, which is compared between the two groups, e.g., “To compare the changes in depressive symptoms…”.

The two sentences before the aims (“We designed a cluster RCT…”) and the two below the aims (“This study protocol is a cluster RCT…”) are both related to the methods and should be moved (and merged, as they repeat the same information) from the section “Background” to the section “Methods”, for example as a sub-heading “Design” at the beginning of the section.

 Methods:

Study setting: The last two sentences (“To obtain the sample…”) should be moved to the section “Recruitment”, as it is confusing here how centers were identified and matched.

Study setting: For international readers, it would be informative with a short description of the healthcare system in Chile, i.e. are the primary care clinics public or private and free of charge or with user payment.

Eligibility criteria: Are there any exclusion criteria related to e.g., comorbidity, alcohol or substance misuse, somatic illness?

Interventions: The first sentence (“Eligible primary care clinics will…”) should be moved to the section “Recruitment”. It would also make more sense when reading, if the section “Recruitment” came before this section on “Interventions”, and if the heading was changed to “Recruitment and randomization”.

Intervention arm: The intervention could be described in more details, as each element is not clearly described, but merely listed. For example, what is the role of the case manager (scheduled meetings with the patient and/or the primary care team? Inter-professional communication? Monitoring of follow-up assessments?), and how are the individual treatment plans developed (based on which instructions/guidelines or principles of care? Stepped care algorithm? Treatment modalities?).

Outcome measures: Emphasize that the change in symptoms between baseline and follow-up is the measure: “Difference in depressive symptoms change”. Same for the secondary outcomes.

All about blinding and randomization must be move to a separate section called “Blinding and randomization”. Together with the already given information, the authors need to address the fact that all the outcomes are self-report, which can lead expectation bias.   

Recruitment: When is the recruitment expected to end (length of inclusion period)?

Monitoring: Here the authors write “ These patients will be excluded from the study as well as patients who do not want to continue with the evaluation. Are the patients excluded from the treatment or the study as a whole. If the first change the wording, if he last, remove the phases about using intention-to treat under “data analysis”, as this is not the case.  

 References: Please check the reference list carefully, as:

Several of the references link to URLs that does not exist.

Some institution names are incorrect.

Links to web pages should list access date or publication date.

Reports and documents should list name of institution/publisher and location.

 Formatting: There are several phrasing and grammatical errors, which confuse the reading, such as:

Phrasing: In the title, the term “on the resolution of adult depression” is unspecific. Replace with “on the treatment of”.

Proofreading: Please carefully proofread the entire paper again, as there are several errors, such as a word missing in a sentence or an extra word at the end of a sentence, which should be deleted.

Grammatical errors: Please carefully go through the text and check for grammatical errors, as there are quite a few of these, such as the word “The” missing, or plural “s” missing, or confusion between are/is.

Efficacy versus effect are used interchangeably, please use the correct wording in all places.

Conclusion

The manuscript needs major revision before it can be indexed.

Is the study design appropriate for the research question?

Yes

Is the rationale for, and objectives of, the study clearly described?

Yes

Are sufficient details of the methods provided to allow replication by others?

Partly

Are the datasets clearly presented in a useable and accessible format?

Not applicable

Reviewer Expertise:

psychiatry, mental health, recovery, interventions, implementation, collaborative care

We confirm that we have read this submission and believe that we have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however we have significant reservations, as outlined above.

VITRIOL VERONICA Universidad de Talca, Chile

Competing interests: There are no competing interests

 27 9 2024

Dear Reviewers,

Lene F Eplov and Marte Ustrup

We would like to extend our sincere gratitude for your thoughtful and detailed feedback on our manuscript. Your comments and suggestions have been instrumental in improving both the structure and content of the paper. We have carefully considered each of your points and made the necessary revisions to enhance the clarity and overall quality of the manuscript.

Please note that this manuscript was originally submitted in 2021, prior to the commencement of the project. Since then, the study has been completed, and we are now in the process of publishing the results in the Annals of Family Medicine.

Below, we have provided specific responses to your comments:

Primary Outcome in the Abstract

Comment: The primary outcome is not described in the “Methods” section of the abstract.

Response: We have added a description of the primary outcome in the "Methods" section of the abstract. Both the primary and secondary outcomes are now clearly outlined in the Methods section of the main text for better clarity.

Background

Comment: The focus in the Background section on a specific subgroup of people with Major Depression (MD) is unnecessary, as the study focuses on the entire population with MD in primary care.

Response: Thank you for this suggestion. We have revised the introduction to focus on the general population with MD, aligning with the study's objective of evaluating the intervention for all individuals with MD in primary care, rather than emphasizing a specific subgroup.

Methods

Comment: The “Modifications” section is unclear and misplaced.

Response: We have removed the “Modifications” section and incorporated relevant details into other sections for improved clarity and coherence.

Comment: It is unclear if the sample size calculation takes the cluster design into account.

Response: In this version, we have elaborated on the sample size calculation, including assumptions such as equal-sized clusters and intra-class correlation (ICC).

Comment: It is unclear how data analysis accounts for clustering of individuals within clinics.

Response: The data analysis section now clearly explains how clustering is handled, including conducting an intra-cluster correlation prior to the regression analyses.

Minor Issues

Comment: The "Discussion" section reads more like a conclusion.

Response: We have rephrased the "Discussion" section to reflect that the trial is ongoing, using language such as "This trial will provide information on whether...".

Comment: Please include the registration number for the trial.

Response: The trial registration number and date have been added at the end of the abstract.

Hypotheses and Aims

Comment: Only list aims and hypotheses related to the primary outcome.

Response: The aims and hypotheses have been revised to focus on those related to the primary and secondary outcomes. Aims such as designing the intervention (aim 1) have been removed unless explicitly described.

Comment: Change "improve depressive symptoms" to "a reduction in depressive symptoms."

Response: This wording change has been implemented for greater specificity.

Comment: Clarify that the aim is to compare changes in depressive symptoms between baseline and follow-up.

Response: The aim now explicitly states that we compared changes in depressive symptoms between baseline and follow-up in the two groups.

Comment: Sentences regarding the study design should be moved from “Background” to “Methods.”

Response: We have moved and merged the relevant sentences under a new sub-heading titled "Design" in the Methods section for clarity and to avoid repetition.

Study Setting

Comment: Move the last two sentences regarding recruitment to the “Recruitment” section.

Response: These sentences have been moved to the "Recruitment" section for better organization.

Comment: Provide a brief description of the healthcare system in Chile.

Response: A brief description of Chile’s healthcare system, including the public/private structure and costs to users, has been added.

Comment: Are there any exclusion criteria related to comorbidity, substance misuse, or somatic illness?

Response: Exclusion criteria for this protocol were  bipolar disorder, suicide attempt, or severe drug dependence and consequently, they have been included in the updated version.

Interventions

Comment: The intervention could be described in more detail.

Response: The intervention arm has been elaborated, with a clearer description of the role of the case manager and the development of individual treatment plans.

Outcome Measures

Comment: Emphasize that the measure is the change in symptoms between baseline and follow-up.

Response: We have clarified that the measure is the change in depressive symptoms between baseline and follow-up, and similar wording has been applied to secondary outcomes.

Comment: All details regarding blinding and randomization should be in a separate section.

Response: A separate section titled "Blinding and Randomization" has been added, addressing the use of self-reported outcomes and the potential for expectation bias. Additionally, patients will be followed in a blinded manner by residents administering the follow-up surveys, which will be independent of self-reported information provided to the treatment team.

Recruitment

Comment: When is recruitment expected to end?

Response: The recruitment timeline, including the expected end date and the length of the inclusion period, has been specified.

Monitoring

Comment: Clarify whether patients are excluded from treatment or the study as a whole. Response: Patients may discontinue treatment or evaluations but will still be included in the analysis based on the intention-to-treat principle. The wording has been updated to reflect this distinction.

References

Comment: There are several issues with the reference list.

Response: The reference list has been reviewed and updated. All URLs have been checked for accuracy, institutional names have been corrected, and links to web pages now include access or publication dates. Reports and documents list the appropriate institution or publisher and location.

Formatting

Comment: There are phrasing and grammatical errors, and the terms "efficacy" and "effect" are used interchangeably.

Response: The manuscript has been thoroughly proofread to correct phrasing, grammatical errors, and consistency issues. The terms “efficacy” and “effect” have been replaced with “effectiveness,” where appropriate, to ensure proper usage.

Once again, we are grateful for your time and valuable input, which have greatly improved the manuscript. We hope the revised version meets your expectations.

                                                                                 Sincerely,

                                                                         Dr. Veronica Vitriol

                                                                          Profesor of Psychiatry

  27/Sept/2024                                                      Universidad de Talca

 10.5256/f1000research.79682.r188474 Reviewer response for version 1 Dagnino Paula 1 2 Referee https://orcid.org/0000-0002-4923-9827 Psychology, Universidad San Sebastian, Concepción, Bío Bío Region, Chile Millennium Institute for Research on Depression and Personality, Santiago, Chile

Competing interests: No competing interests were disclosed.

 31 7 2023 Copyright: © 2023 Dagnino P 2023 This is an open access peer review report distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. recommendation approve

I emphasize the importance of this study. It considers a central pathology, such as depression, specifically patients who are difficult to treat. The fact that the study will include complementary variables to the symptomatology, such as emotional regulation, comorbidity, interpersonal relationships, etc., is in the most updated line of research in this field, in personalized or patient-centered treatment. The training of health professionals in Chile needs to be improved in this type of complexity and also in interdisciplinary, community, and network treatment. Knowing that this is "the" way of treating patients, the CMAD protocol will significantly contribute to primary care.

The document is well-written and clear in each of the sections. I will be looking forward to the results.

Is the study design appropriate for the research question?

Yes

Is the rationale for, and objectives of, the study clearly described?

Yes

Are sufficient details of the methods provided to allow replication by others?

Yes

Are the datasets clearly presented in a useable and accessible format?

Yes

Reviewer Expertise:

Research in clinical psychology. Research in Depression and Personality. Research in patients treatment

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.