Evaluation of the Acceptability, Feasibility and Exploration of the Efficacy of an Integrated Care Pathway CARIBOU

A) THEORETICAL-CONCEPTUAL FOUNDATIONS AND STATE OF THE ART Definition and magnitude of the problem Major Depressive Disorder (MDD) is a distinct diagnosis outlined in the DSM-5, characterized by episodes lasting at least two weeks, often much longer, with changes in mood, thinking, and neurovegetative functions (sleep, appetite, and energy) and periods of remission between episodes. MDD symptoms are consistent and valid, classified into mild, moderate, and severe forms based on nine specific symptoms. Severity is determined by symptom count, intensity, and impairment level, with this classification method widely used in population studies and primary care settings. Mild depression involves fewer symptoms and minimal impairment, while severe depression includes all DSM-5 symptoms or severe impairment. Moderate depression falls in between. Most episodes last 3-6 months in community samples and 5-8 months in referred samples. However, 20% of adolescents may experience episodes lasting two years or more, with more than half having a recurrence within five years. Predictors of recurrence include poor treatment response, symptom severity and chronicity, previous episodes, comorbidity, negative cognitive style, family problems, low socioeconomic status, and exposure to family conflict or violence.

Major Depressive Disorder in adolescents (MDD-A) is common, with the National Comorbidity Survey-Adolescent Supplement (NCS-A) showing lifetime and 12-month prevalence rates of 11.0% and 7.5%, respectively, among adolescents aged 13 to 18. Prevalence increases significantly during adolescence, especially among females. Most cases involve psychiatric comorbidity and severe role impairment, with many reporting suicidality. Adolescents are considered to have severe MDD if they have at least five criteria plus a specific suicide plan, psychotic symptoms, a family history of bipolar disorder, or severe functional impairment.

Several studies have alerted about a significant deterioration in mental health among adolescents in the post-COVID-19 period. For instance, a recent study including 5,368 Canadian secondary school students who participated in three consecutive waves during the 2018-19, 2019-20, and 2020-21 school years, found that the proportion of adolescents with significant depressive (29.4%) and moderate-to-severe anxiety (17.6%) symptoms at baseline increased by 1.5 times, reaching 44.8% and 29.8% in the ongoing pandemic period, respectively.

In Chile, it is estimated that the prevalence at the national level of MDD in the adolescent population is 8.3%. There is concern regarding these figures because only between 20% and 50% of depressed adolescents finally access treatment. In a more recent study, 2,022 students from the first to the third grades of secondary education (9th to 11th grade) from 8 schools (average age, 15.2 years; 49.5% were women) were surveyed. Using the Patient Health Questionnaire-9 (PHQ-9) to explore depressive symptoms, 35.2% of the students had a score to be classified at risk of having a MDD-A (PHQ-9>10). There is no data on the prevalence of MDD-A in the post-COVID-19 period.

An MDD-A is debilitating, impacting the development in several areas. A recent meta-analysis of longitudinal studies found that adolescent depression was associated with outcomes including, but not limited to, failure to complete secondary school, unemployment, and pregnancy/parenthood. Additionally, MDD-A is also a risk factor for suicide. Some studies have shown that in primary care (PC), as many as 2 in 3 youth with depression are not identified and fail to receive any care. Treatment in any form was received by most adolescents with 12-month DSM-IV MDD (60.4%), but only a minority received treatment that was disorder-specific or from the mental health sector. Another study showed that 62% of individuals with a psychiatric disorder had not accessed any mental health services in the past year. This study also showed that these individuals exhibited fewer antisocial traits and disorders, more anxiety disorders, and less comorbidity compared to those receiving treatment. This suggests that individuals with anxiety disorders may be less likely to seek services and highlights that access to Child and Adolescent Mental Health Services (CAMHS) often requires more complex cases with high levels of comorbidity and impairment. In addition, the same longitudinal study found that among 14-year-old adolescents with a DSM-IV psychiatric disorder, those who used mental health services experienced a substantial reduction in depressive symptoms by the 36-month follow-up. By contrast, by age 17, adolescents who did not access mental health services were seven times more likely to report clinical-level depression symptoms compared to those who did seek help.

Legal tools and Clinical Guidelines for depression among adolescents in Chile in a nutshell In 2001, the Program for Screening, Diagnosis, and Comprehensive Treatment of Depression (PSDCTD) was established to provide effective treatment for depressive disorders in primary care clinics. By 2005, the program was extended to all primary care clinics nationwide. In 2006, it was supplemented by the Explicit Health Guarantees (GES) plan, which included coverage for depressive disorders in individuals over 15 years old. The GES plan guarantees coverage by Fonasa and Isapres, ensuring timely and comprehensive treatment by accredited providers. Financial coverage varies by income, covering 100% for the lowest income households and up to 80% for higher income groups and Isapre affiliates. Patients are informed about GES coverage options for depression and can choose between private providers and the free-choice system.

In 2013, the Clinical Guide for Depression (CGD) for individuals aged 15 and older provided treatment recommendations, including active detection of at-risk individuals, reducing complications and relapses through early and continuous evidence-based treatment, and promoting cost-effective interventions tailored to patients' specific conditions. However, it lacked recommendations for adolescents. The Chilean Ministry of Health recently introduced the Clinical Practice Guideline for Addressing Depression in Adolescents (CGD-A), offering detailed recommendations for all healthcare professionals involved in adolescent depression care, such as general practitioners, psychiatrists, psychologists, and others.

The PSDCTD, GES Plan, CGD, and CGD-A are good tools for health professionals to help adolescents with depression. However, no evaluation of their effectiveness and implementation has been done.

Treatment of Depression for Adolescents:

Several treatments are available for depression, including different types of psychotherapy, medications, family involvement, or a combination of these. Treatment may also involve collaboration with the adolescent's school or participation in peer support or self-help groups. The professionals in charge of the treatment should create a comprehensive treatment plan tailored to the specific situation and adolescent's needs, incorporating the recommended treatment approaches. Additionally, the professionals should thoroughly explain the treatment plan's risks and benefits to you and your child.

There are limited studies on the effectiveness of medications for depression in adolescents. Fluoxetine (Prozac) and escitalopram (Lexapro) are Selective Serotonin Reuptake Inhibitors (SSRIs) and the only medications approved by the FDA for treating depression in children and adolescents aged 8 and older and 12 and older, respectively. Other SSRIs, like sertraline, and non-SSRIs, such as venlafaxine, although not FDA-approved for this age group, are commonly used off-label by physicians to treat depression in children and adolescents, which is a standard clinical practice.

On the other hand, the efficacy of psychological treatments for depression in children and adolescents gained traction in 1980 following the American Psychiatric Association's clarification on the similarity of major depressive episodes across age groups. That year, the first trial on the treatment of childhood depression was published, and six years later, the first study of the treatment of depression in adolescents was published. Initial trials indicated cognitive behavioral therapy (CBT) as an effective treatment adapted for adolescents, though early comparisons with relaxation training showed no significant differences in outcomes. The first randomized controlled trial (RCT) in adolescents diagnosed with depression was conducted in 1990. A recent meta-analysis revealed that psychotherapies are effective compared to control conditions. Yet, over 60% of youths receiving therapy do not respond, indicating the need for more effective treatments and strategies. Additionally, a gap exists between research-based interventions and their clinical implementation. Despite approximately 20% of adolescents experiencing major depression, evidence-based treatments remain underutilized, highlighting the need to bridge the gap between research findings and clinical application.

Effectiveness of medication and when combined with psychotherapy The Treatment for Adolescents with Depression Study (TADS), funded by the National Institute of Mental Health and published in 2004, evaluated fluoxetine (Prozac), cognitive-behavioral therapy (CBT), and their combination in treating moderate to severe depression in adolescents. After 12 weeks, 71% of those receiving the combined treatment improved significantly, compared to 35% for placebo, 43% for psychotherapy, and 61% for medication alone. The combined treatment also enhanced functioning and quality of life, making it the preferred approach for faster recovery and remission. All treatments reduced suicidal thoughts and behaviors, but fluoxetine alone was linked to increased suicidal ideation. After three months, suicidal thoughts and behaviors significantly decreased across all treatments, with no completed suicides. This study underscores the effectiveness of medication and suggests that combined treatment may help protect against suicidal thoughts and behaviors, though this effect is not consistently found in all studies.

Most adolescents with depression (about 60%) improve with initial SSRI antidepressant treatment, but around 40% do not respond. The TORDIA study investigated alternative therapies for these SSRI-resistant adolescents, including switching to a different SSRI, switching to a non-SSRI (venlafaxine), combining a different SSRI with CBT, and combining a non-SSRI with CBT. The most improvement was seen in those who switched medications and added CBT, proving more effective than medication alone. Switching to another SSRI was as effective as switching to venlafaxine but had fewer side effects. These findings suggest that adolescents not responding to initial SSRI treatment may benefit from switching to another SSRI combined with CBT. It is important to allow 6-8 weeks to assess the initial treatment's effectiveness before considering alternatives. Optimal treatment often involves a combination of psychotherapy and medication.

What happened in the real world? Treatment approaches used in real-world clinical practice are heterogeneous, often with limited patient follow-up frequency, low resolution, and insufficient evidence support in the primary care system. There are several steps to bridge the gap between research and practice in treating MDD-A. Firstly, to establish a broad consensus on evidence-based treatments for MDD-A. High-quality Clinical Practice Guidelines (CPGs) are designed to fulfill this role; they are defined as "statements that include recommendations aimed at optimizing patient care based on a systematic review of evidence and an assessment of the benefits and harms of alternative care options." Only recently, in Chile (in 2021), the Chilean Ministry of Health published the CPG for adolescents. In 2018, the American Academy of Pediatrics published the Guidelines for Adolescent Depression in Primary Care (GLAD-PC), Part I and Part II. Regarding the GLAD-PC, these guidelines strongly support that Primary Care (PC) clinicians should recommend scientifically tested and proven treatments (i.e., psychotherapies, such as CBT or Interpersonal Psychotherapy, or antidepressant treatment, such as SSRIs) whenever possible to achieve the goals of the treatment plan. These GLAD-PCs also provide recommendations for managing adolescent depression in primary care, including 1) active monitoring of mildly depressed youth, 2) using evidence-based medications and psychotherapeutic methods for moderate and severe depression, 3) closely monitoring side effects, 4) consulting and co-managing care with mental health specialists, 5) continuously tracking outcomes, and 6) taking specific actions in cases of partial or no improvement after starting treatment. One might question whether primary care (PC) clinicians should identify and diagnose adolescent depression, given the limited availability of psychiatric services for referrals. Despite this concern, the growing consensus is that, at the very least, PC clinicians should be equipped with the necessary guidance to support the initial management of adolescent depression. However, due to the varying levels of readiness among practitioners and their clinical settings in identifying and managing adolescent depression, significant time and flexibility will likely be needed before these guidelines are systematically or universally implemented. Secondly, the gap in how CPG recommendations should be implemented in clinical settings must be narrowed. Greater adherence to care standards in the treatment of depressive disorders in adolescents treated in primary care has been associated with improved outcomes. As mentioned above, specific evidence-based treatments, such as antidepressant medication and CBT, have shown limited effectiveness, with up to 40% of adolescents remaining unremitted at follow-up. This is why there has been a call for more comprehensive care, where, in addition to medications and therapy, they could be integrated into other strategies, such as psychoeducation about sleep, exercise, diet, and family involvement. There is evidence that a multifaceted approach to mental health consultation may improve the management of depression in Primary Care settings. In this sense, Integrated Care Pathways (ICPs) serve as an implementation tool: they are decision-support aids based on CPG recommendations designed to guide clinical choices during patient care. No studies have explored the effectiveness of ICPs in guiding the comprehensive delivery of care for MDD-A in Chile and Latin American countries. ICPs aim to standardize and personalize patient management by enabling comprehensive, multidisciplinary care through a sequence of decision points and treatment steps. The ultimate goal of ICPs is to optimize evidence-based care by balancing research evidence, expert clinical judgment, and patient/family values within the constraints of available resources. Finally, the patient's progress must be monitored following successive CPG recommendations, ensuring that the patient improves or alerts physicians when treatment is ineffective and needs adjustment. Measurement-Based Care (MBC) provides this approach; it "involves systematic administration of symptom rating scales and uses the results to drive clinical decision-making at the individual patient level." To our knowledge, only one ICP has been studied among adolescents with MDD. It is called The CARIBOU pathway, which stands for "Care for Adolescents who Receive Information 'Bout Outcomes" (first iteration), which includes several components for youth: 1) a structured assessment focusing on self-harm risk, bullying exposure, and caregiver mental illness, 2) a group education session called "Mood Foundations" discussing depression, sleep hygiene, exercise, and diet with youth and caregivers, 3) 16 sessions of group CBT, chosen over individual therapy due to resource availability and evidence of similar efficacy, 4) an 8-session caregiver group focusing on validating communication and collaborative problem-solving, 5) a medication algorithm with fluoxetine as the first-line treatment and sertraline as the second-line, and 6) all within a framework of measurement-based care (MBC). In a recent pilot parallel non-randomized controlled clinical trial, two centers participated, one implementing CARIBOU in 35 adolescents and the other assigned to Treatment As Usual (TAU) with 31 participants. Recruitment met the target sample size over 15 months. High clinician fidelity (95%) and adolescent engagement (80%) were observed in the ICP components based on checklists. Baseline and 20-week endpoint data for depressive symptoms as the primary outcome, measured by the Children's Depression Rating Scale-Revised (CDRS-R), were collected for 83% of the participants. Analysis using linear mixed-effects modeling showed a consistent decrease in CDRS-R scores over 4-week intervals up to the 20-week endpoint in both groups (β = -2.07; 95% CI -3.14 to -1.01). The study concluded that implementing CARIBOU was feasible. Still, more research is needed to explore the effectiveness of this ICP model in a larger randomized controlled trial (RCT).

There is an urgent need to assess the acceptability, feasibility, and efficacy/effectiveness of Integrated Care Pathways like CARIBOU for treating Major Depressive Disorder (MDD) in adolescents in resource-constrained countries such as Chile and other Latin American nations. In Chile, 18% of individuals needing mental health treatment are underserved. Recent initiatives by the Chilean Ministry of Health, such as an updated national plan to prevent adolescent suicide in educational settings and the promotion of collaboration between schools and primary care clinics to minimize support delays and reach all those in need, give support to this proposal. Furthermore, the Ministry supports the implementation of CARIBOU by advocating for depression screening in primary care settings for adolescents and promoting group over individual psychological interventions to optimize resources in already constrained settings such as primary care clinics.

Inclusion criteria

• Adolescents aged 15 to 18 years (up to their 19th birthday).
• Presenting at one of the participating primary care centers.
• The primary care physician considers depressive symptoms to be a priority treatment target.
• PHQ-9 score ≥5 at screening.
• Meet DSM-5 criteria for Major Depressive Disorder or Persistent Depressive Disorder, confirmed using the MINI-KID.
• Able to read and write in Spanish.
• Able to provide informed assent/consent, with parent or legal guardian consent when applicable.

Exclusion criteria

• Severe depressive symptoms (PHQ-9 score ≥20).
• Active psychotic symptoms (persistent delusions, hallucinations, or disorganized speech affecting functioning).
• Bipolar disorder (type I or II).
• Moderate or severe substance use disorder.
• Autism spectrum disorder or intellectual disability.
• Moderate or severe eating disorder.
• Imminent suicide risk requiring immediate intervention (e.g., hospitalization).
• Inability to read or write in Spanish.
• Inability to provide informed consent/assent.
• Under the care of state-based institutions without available family support.
• Receiving ongoing individual psychotherapy or pharmacotherapy for depression or anxiety at another healthcare center