RESEARCH LINES
EPIDEMIOLOGY AND RISK FACTORS
It is estimated that approximately 5% of the global population experiences a depressive episode at some point during any 12-month period. According to the Global Burden of Disease study, 280 million people were facing depression in 2019. Within the age range of 10 to 24 years, depression ranks as the second most significant cause of years lived with disability, meaning years lived without full health.
Although much is already known about depression, this knowledge is mostly based on data from high-income countries. A lot less is known about adolescents living in low or middle-income countries like Brazil, where doing research is more difficult. However, it is exactly in these countries that most adolescents around the world live.
Considering these aspects, the Prodia team studies the profile of adolescents, especially in Brazil, to better understand the individuals we aim to support. This involves a variety of perspectives, from inquiring about the social media platforms teenagers use to understanding their relationship with physical activity. We have also investigated whether the proportion of Brazilian teenagers with depression is similar to the proportion reported in wealthier countries and explored the set of symptoms adolescents present and how they define "depression."
This knowledge is essential to define relevant research topics and to understand which initiatives will have positive results, for whom, and in which context, both in terms of prevention and promotion of mental health.
Risk Factors: Is it possible to identify individuals at higher risk of depression in adolescence?
The ability to prevent any disease is linked to knowledge about the risk factors for that condition, often a combination of aspects that operate simultaneously to increase vulnerability. For example, in cardiovascular disease, a mix of biological variables (such as gender) and behavioral variables (such as smoking) is considered in the assessment of a person's risk of developing heart disease. By considering the contribution of each variable, it is possible to generate a "score" that informs whether the person's risk is higher or lower, allowing the use of prevention strategies. In other words, it is not only a matter of having or not having risk, but also of the size of that risk.
In the case of depression, knowledge has advanced in relation to some risk factors, of which having family members with depression is one of the best studied. However, it is also known that one factor in isolation is not enough to trigger depression; it takes a combination of factors, and we still need to understand how family history or other aspects interact with each other. Little is also known about which important risk factors for depression are linked specifically to adolescence, a phase of life that involves intense physical, psychological and social changes.
To understand these aspects, Prodia partnered with one of the largest and most important epidemiological studies ever conducted in Brazil: the Pelotas Birth Cohort of 1993. This study, performed by researchers from the Center for Epidemiological Research and the Graduate Program in Epidemiology at the Federal University of Pelotas, is tracking various aspects of the health of all individuals born between January 1st and December 31st, 1993, residing in the urban area of Pelotas, a city in southern Brazil. Using data from this study, Prodia researchers gathered sociodemographic variables that showed evidence of association with depression. These variables were specifically related to adolescence and easy to measure, such as relationships with family and friends, school problems, and drug use. This is important because obtaining information on some commonly used risk factors can be challenging. For instance, if we think again about "family history," people often do not know if any family member has had depression. Similarly, other studies exploring genetic risk scores (known as polygenic risk scores) are technically complex, and their results are still inconclusive or difficult to use in clinical practice.
Prodia then combined these sociodemographic variables into a score whose purpose was to detect the individual's level of risk for depression. This score was named "Identifying Depression Early in Adolescence (IDEA) Risk Score," or IDEA-RS, as it is being studied within the context of the International IDEA Consortium, of which Prodia is a member. Consequently, the IDEA-RS was tested with young people from different countries to determine if it could be used globally with adolescents or if it varied across different cultures. Additionally, Prodia conducted a study with Brazilian adolescents selected based on their classification in this score. One group was classified as low risk for depression, another as high risk for depression, and a third group with current depression at the time of selection was formed. These adolescents were followed over a period of 3 years to observe how aspects of their trajectory could reflect a change in their depression risk status.
Preliminary results from all these observations indicate that the IDEA-RS created by Prodia is sensitive in classifying the risk of depression and can help in the development of prevention strategies. This work to determine the risk status for depression in adolescents was also explored in association with various other measures (e.g., biological, neuroimaging, and qualitative measures).
CLINICAL PRESENTATION
Sometimes, understanding depression can be difficult — many people still wonder if depression is really a disease, or how it manifests in affected individuals.
Part of this difficulty arises from the multifactorial and heterogeneous nature of depression: depression is expressed differently in different people, with varying levels of severity and a differential course over time. In fact, clinicians and researchers currently believe that it is not enough to simply diagnose a person as "having depression" or "not having depression" — for prevention, monitoring, and treatment, we need to understand contextual aspects (for example, where the person lives or studies, their relationship with parents or caregivers, the type of home they live in), individual aspects (such as sex, age, personality traits, life history), the set of symptoms the person presents, and which of these symptoms are most deleterious in each specific case.
This has many important implications. including for the diagnosis of depression. Generally, the diagnosis of depression is based on operational criteria that are based on the presence or absence of certain symptoms. The number of symptoms is an important indicator of severity, but the scores usually add up the symptoms assigning equal importance to all the items — for example, fatigue, a more generic symptom, carries the same weight as anhedonia (lack of pleasure). We know, however that different symptoms can indicate different degrees of severity — and, more than that, that the experience of each person with depression is unique.
In fact, our group has shown that there are clusters of symptoms that determine a different individual response to depression treatments using medication psychotherapies. In other words, we observed that treatment was more effective in adolescents with a symptom cluster that included depressed mood, difficulty enjoying activities, social withdrawal, sleep problems, excessive fatigue, school difficulties, and irritability, and less effective in adolescents with a different symptom cluster. Recognizing the differences in clinical presentation is, therefore, essential in choosing the best treatment for each adolescent, as well as for advancing prevention strategies and depression research.
QUALITATIVE RESEARCH
Understanding depression as a result of the interaction among diverse elements involves studying the disorder from the perspective of various disciplines, such as psychiatry, psychology, neuroimaging, and chronobiology, among many others. It also involves expanding the possibilities of these disciplines with different methods of collecting and cross-referencing information.
One of these methods is the qualitative approach, which can be used to contextualize phenomena and highlight the perceptions and experiences of the participants. This can be achieved through interviews, focus groups, or participant observation. The qualitative approach can be particularly important in the case of depression since aspects of everyday life — for example, relationships with parents, peers, socioeconomic situation, and other cultural factors — can help us understand when, by whom, and how depression is experienced during adolescence. This approach is also productive for adolescents because it allows them to express their opinions or viewpoints. As most research is developed by adults for adults, asking adolescents what they would like help with and how they think it should be done is very relevant. And, in general, the qualitative approach is the best way to achieve this.
Prodia's experience with qualitative research has yielded relevant results that could not have been achieved with other methods. For example, in one study, we investigated the perception of a group of adolescents from southern Brazil regarding depression. Through interviews, we found that social isolation is a central characteristic of depression for these adolescents. Additionally, considering that the participation of adolescents in our research could reveal a diagnosis of depression, we sought to understand the impact of receiving such a diagnosis. For some adolescents, it was difficult to understand the feelings of that moment as part of an illness or to express the difficulty of sharing the information with others. All these points could have implications, such as hesitancy to seek help, disbelief in treatment, or self-stigma about their condition.
Another interesting application of the qualitative approach is the opportunity to ask participants for their opinions on research tools or methods. In one study, the methodological approach was used to gather the opinions of different groups about an app that predicts the risk of depression (a risk calculator). In another project, adolescents tested a mobile app that would be used for data collection and made several relevant suggestions. As a result, the app was adjusted according to the suggestions before being used in the research.
DIGITAL PHENOTYPING
Beyond the search for biological and neurobiological characteristics that can aid in the early identification of depression, the rapid advancement of digital technologies is particularly useful for mental health. With data collected from digital devices (such as smartphones or activity monitors), we can create what is called a "digital phenotype": a set of digital variables that could identify the risk or presence of depression.
Currently, smartphones represent a fairly accessible tool for collecting data and monitoring daily events in real-time and location-specific settings. These data include information about sleep, movement, geographic location, interactions with people and places, geographic routes recorded via GPS, mobility patterns through accelerometers, and audio data captured by microphones, among others. These data can be collected passively, relying mainly on the individual's regular use of devices, greatly expanding the possibilities for data capture.
At Prodia, we are using digital phenotyping to understand changes in mental health over three years in a group of adolescents. This study also involved gathering information using a chatbot based on WhatsApp (IDEABot). In this case, the adolescents had to actively engage and respond to a mental health monitoring questionnaire or other questions. They could also send audio messages through the app whenever they wished. One of the significant advantages of this data collection method is that responses are given in the participant's environment, often at moments close to good or challenging situations that may influence mental health. In contrast, in clinical and research settings, patients often need to provide information about past periods (e.g., the last few weeks) and rely on memory, which may influence the information they share.
Some Prodia publications in this topic:
PHYSICAL ACTIVITY AND SLEEP
One of the factors that sets adolescents apart from both children and adults is their brain development. While the brain does not increase as much in size during adolescence as it does in childhood, the teenage brain continues to develop, a process that ends beyond the age of 20. Engaging in regular physical activity and getting adequate sleep play significant roles in brain development during this stage of life.
To study aspects of physical activity, Prodia researchers surveyed a group of over 7,000 adolescents about their exercise habits — how many days per week they engaged in physical activity and the intensity of their workouts. The results showed that 84% of the group exercised less than what is considered ideal, and those who exercised less frequently or engaged in less vigorous activity exhibited more symptoms of depression.
Regarding sleep, it is known that adolescents may experience irregular sleep patterns, with insomnia and difficulty maintaining sleep after falling asleep. Along with exposure to artificial light at night, these factors can contribute to episodes of depression. A Prodia study that used a combination of questionnaires and actigraphy (a wristwatch-like device for monitoring daily activities, including sleep) observed that aspects such as insomnia or greater exposure to artificial light were more common in adolescents with depression.
Another important finding was related to changes in the adolescents' biological clock, as they tend to prefer going to bed and waking up later — which may not always be feasible, as the timing of many commitments (e.g., school) remains unchanged. Consequently, on weekends or holidays, adolescents often try to catch up on sleep. The difference between their sleep duration on weekdays and on free days is known as "social jet lag." The Prodia study revealed that the average social jet lag for all participants was about 2 hours; however, adolescents with depression had a significantly higher social jet lag of more than 3 hours.
Understanding these connections between physical activity, sleep patterns, and brain development during adolescence is crucial for promoting mental health and identifying potential risk factors for depression. By pinpointing areas for intervention and support, Prodia's research can contribute to improving the well-being of adolescents and guiding effective strategies for prevention and treatment of depression.
One characteristic of depression (and mental disorders, in general) is that they cannot yet be diagnosed or monitored through laboratory or imaging tests. For instance, a blood test can identify various diseases and also monitor the effectiveness of medications in a patient. In other cases, imaging tests like X-rays or CT scans can detect and track the progression of certain illnesses, such as pneumonia. However, there is a significant global effort by researchers to understand whether any changes in the brain (both in structure and function) or in other biological mechanisms in the body (such as alterations in blood levels of certain substances) could help identify depression as early as possible.
Among the substances in the blood that researchers worldwide believe could aid in identifying depression or the risk of depression in adolescents are the hormone cortisol and certain proteins related to inflammation. However, most existing studies have been conducted with adults. Taking into account the unique aspects of adolescence, especially the numerous physical, mental, and social changes that occur during this phase, what applies to adults may not necessarily apply to adolescents.
Our team of researchers has conducted studies evaluating the relationship between depression and several of these biological mechanisms (cortisol, inflammation, proteins, and immune response). Some preliminary results showed a link between the risk of depression determined by a set of psychosocial factors combined in a risk score (IDEA-RS) developed by our group and the presence of low-grade inflammation six years later. This suggests that this set of psychosocial factors determining the risk of depression is biologically integrated over time. Another study found an association between two inflammatory proteins and specific depression symptoms, indicating that specific analyses related to biological markers can aid in understanding the heterogeneity of depression.
Regarding the structure and functioning of the brain studied through neuroimaging, our group found preliminary evidence of a relationship between brain function measured during the execution of certain tasks in functional magnetic resonance imaging (fMRI) and the risk or diagnosis of depression at the time of the examination. Another study with the same group did not observe any differences in the volume, area, and thickness of brain structures.
Overall, Prodia's ongoing research into the biological mechanisms underlying depression in adolescents aims to bridge the gap in our understanding of this complex mental health condition. By exploring cortisol levels, inflammatory markers, and brain structure and function, we hope to pave the way for improved diagnostic tools and early intervention strategies tailored specifically to adolescents, thus enhancing their well-being and mental health.