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J Psychiatry Neurosci
J Psychiatry Neurosci
jpn
Journal of Psychiatry & Neuroscience : JPN
1180-4882
1488-2434
CMA Impact Inc.

39209460
10.1503/jpn.240072
49-4-E282
Editorial
Perspective on adolescent psychiatric illness and emerging role of microRNAs as biomarkers of risk
Morgunova Alice PhD
Teixeira Maxime MSc
Flores Cecilia PhD
From the Douglas Mental Health University Institute, Montreal, Que. (Morgunova, Flores); the Department of Psychiatry, McGill University, Montreal, Que. (Morgunova, Flores); the Integrated Program in Neuroscience, McGill University, Montreal, Que. (Teixeira); the Department of Neurology and Neurosurgery, McGill University, Montreal, Que. (Flores); the Ludmer Centre for Neuroinformatics & Mental Health, McGill University, Montreal, Que. (Flores)
Correspondence to: C. Flores, Douglas Mental Health University Institute, Perry Pavilion, Room #2111, 6875 LaSalle Blvd, Montreal, Que., H4H 1R3; cecilia.flores@mcgill.ca
Jul-Aug 2024
29 8 2024
49 4 E282E288
© 2024 CMA Impact Inc. or its licensors
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY-NC-ND 4.0) licence, which permits use, distribution and reproduction in any medium, provided that the original publication is properly cited, the use is noncommercial (i.e., research or educational use), and no modifications or adaptations are made. See: https://creativecommons.org/licenses/by-nc-nd/4.0/
National Institute on Drug Abuse at the National Institutes of HealthR01DA037911 Canadian Institutes of Health ResearchFRN:17030 and PJT190045 Natural Sciences and Engineering Research Council of CanadaRG-PIN-2020-04703
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pmcIn this perspective, we highlight the urgent need to study depression in adolescence — a period during which this debilitating disorder often begins to emerge — and propose peripheral molecular indices that may be integrated into clinical routine to elevate understanding of the disorder. Although most research on biomarkers of depression has focused on adults, investigating at-risk adolescents is crucial for uncovering factors at the earliest and most impactful stages of the disease. MicroRNAs, which play a key role in brain development, are promising biological signals, and measurement of these molecules in peripheral fluids could be leveraged to infer systemic post-transcriptional dysregulation. We provide an overview of the complexity of microRNA mechanisms, emphasizing that contextualizing them across biological domains — such as epigenetic modifications, genetic splicing events, or signalling pathways — will enhance understanding of the relevant processes they may be regulating. Circulating microRNAs hold potential as early indicators of adolescent depression; however, collaboration between researchers and clinicians is essential to unravel their role as markers or mediators of risk.

Depression in adolescence and the importance of identifying neurobiological trajectories in young populations

Adolescence is a rite of passage celebrated by various cultures and societies with coming-of-age ceremonies.1,2 These sociocultural ceremonies symbolize the profound transformations occurring at the individual level across physical, social, and cognitive domains, which are triggered by hormonal shifts,3 structural refinement of brain networks,4,5 and maturation of specific neurotransmitter systems.6 Behavioural correlates of these ongoing processes include heightened exploration, formation of identity, and emotional reactivity.7–10 Adolescence is also a period of increased vulnerability to mental health impairments when early symptoms of psychiatric illnesses often begin to emerge. Depression is one of the most prevalent disorders with adolescent onset, with discernible sex differences in both timing and rate.11,12 The driving factors of depression in adolescence are complex. No single domain — environmental exposure, puberty onset, or genetic predisposition — can fully explain the etiology of the disorder or the heterogeneity of symptoms, which can differ across cases, even within the same diagnostic criteria.13

To address the gap in understanding of major depressive disorder (MDD), current research strategies involve preclinical studies in model organisms,14 neuroimaging,15 genome-wide association studies,16 functional genomics,17 and monitoring of pharmacological or psychotherapeutic responses.18,19 Findings from these studies have provided a foundation regarding the neurobiological processes that may be altered in the disease. However, most of these studies have included only adults aged 18 years and older or adult animals. Findings from research based on adult studies or encompassing participants of a broad age range are likely to miss the identification of key neurobiological factors involved in disease etiology. This approach is also unlikely to unravel the cascade of neurodevelopmental alterations that accompany the disease.20

Studies focusing on young people can reveal the biological profile of the psychiatric disease during its earliest and most impactful phase.21,22 People who develop MDD in adolescence tend to have a more severe course of the disease, higher rate of recurrence,23 elevated risk of comorbidities with other psychiatric illnesses,24 and increased risk for subsequent depression later in life, compared with those with an older age of onset.25,26 Prioritizing research involving youth is urgent, given that this demographic is particularly sensitive to developing adverse treatment responses.27,28 Moreover, suicide is among the leading causes of death of people aged 15–19 years;29,30 and there have been cases where patients younger than 30 years have requested medical assistance in dying.31,32 Biological psychiatry research focused on high-risk periods is crucial to identify people before or during early stages of the disease and to provide the support they need. Indeed, early intervention (i.e., in adolescence) has been shown to have a greater and more lasting effect than at any other age in terms of quality-of-life improvement, predictions of individualized trajectories, and effectiveness of interventions and preventative programs.12

Revealing mechanisms involved in adolescent depression using epigenetic approaches

Research to date has shown that the strongest predictors of depression onset in adolescents are environmental and lifestyle factors, such as persistent or chronic stressors or substance abuse, particularly among those with predisposing genetic risks.33,34 Environmental factors can modify ongoing or emerging biological processes through epigenetic mechanisms, by eliciting immediate or enduring alterations in gene expression.35–38 Non-coding RNA molecules, including microRNAs, are considered part of this epigenetic response system and are emerging as crucial factors for depression vulnerability.39–41

MicroRNAs are short sequences of RNA that can be transcribed along with their host gene or via an independent promoter.42 They regulate gene expression post-transcriptionally by matching specific sequences in the 3′ untranslated region of target mRNAs, which commonly, but not exclusively, results in inhibition of translation or degradation of specific or multiple mRNAs.43 Their biogenesis takes place within the cell soma. Depending on local or spatial demands, such as during neuronal activity, microRNAs can undergo rapid transformation into their mature functional form in different cellular compartments.44,45 In addition to local modulation,46 microRNAs can be released into peripheral fluids to regulate gene expression at distal sites.47

By modulating gene expression, microRNAs control molecular networks, disruption of which can result in a convergence of biological impairments, particularly in severe or chronic conditions. In MDD, altered gene expression has been observed across several brain regions,48,49 not only at the level of individual genes, but also of entire gene modules.50 Distinguishing between disease-causing mechanisms and those arising because of the disease itself is challenging given many other independent ongoing processes, such as the effects of aging on gene expression.51,52 Monitoring molecules that modulate gene expression, such as microRNAs, during the adolescent developmental period, could aid in distinguishing the initial alterations in MDD from those that result from prolonged illness.

MicroRNAs are involved in core neurodevelopmental processes53,54 and neuroplasticity,55 and their global pattern of expression has been shown to change drastically over the course of brain maturation and aging.56–58 In adolescence, there is a shift in microRNA expression in the prefrontal cortex,59 a brain region that achieves full maturation only in early adulthood, up to the third decade of life in humans.60 Perturbations to microRNA trajectories, particularly during adolescence, can predispose individuals to increased risk for neurodevelopmental disruption. In addition, microRNAs could serve as sensors of altered function at micro- and macro-system levels as they affect developmental processes via the simultaneous regulation of multiple genes in various tissues. Currently, not enough research has involved adolescent populations to reach a consensus of candidate microRNA markers for early onset depression.

Circulating microRNA profiles as biomarkers of disease

MicroRNAs are used as signalling molecules in cell-to-cell communication.61 For this purpose, they can be encapsulated in vesicles or bound to proteins for protection from degradation, allowing them to enter target cells.62,63 The different mechanisms of uptake by recipient cells and subsequent degradation are not fully understood; however, researchers agree on the presence of highly controlled regulation processes.64–66 One feature of microRNAs that makes them valuable as potential peripheral biomarkers is their small size, which renders them resistant to degradation even under nonphysiologic temperatures or pH conditions.67 The half-life of microRNAs ranges from a few hours to days,68–70 thus qualifying them as real-time detectors of biological states. Given that routine organ biopsies are impractical, numerous studies have begun to measure microRNAs in biological fluids such as blood and saliva to monitor disease states,71–73 with notable progress made in microRNAs related to cancer.69

Results from different studies have put forward several biomarker candidates for clinical depression, irrespective of participants’ age, with only a handful of overlapping candidates. One microRNA that has been found in several studies to play a role in depression is miR-132.74 Studies have found that peripheral levels of miR-132 were associated with altered grey matter and poorer executive function among unmedicated patients with MDD, with miR-132 playing a crucial role in neurogenesis, dendritic morphogenesis, and synaptic plasticity.75 Another common candidate in depression is the miR-34 microRNA family (i.e., miR-34a, miR-34b/c). Altered circulating levels of miR-34 have been observed among patients with depression76 and have been linked to cognitive function77 and antidepressant response.78,79 In addition, studies involving rodents have indicated that miR-34 plays a role in brain development, in synaptic and behavioural plasticity in response to early life stress,80,81 and in dendritic spine remodelling after exposure to chronic stress.82–84

A recent meta-analysis examined microRNAs from peripheral blood that were reported to be differentially expressed among people with psychiatric disorders in 3 or more independent studies.85 It identified several microRNAs that were consistently upregulated in MDD, including miR-124-3p, miR-132-3p, miR-139-5p, miR-182-5p, miR-221-3p, miR-34a-5p, and miR-93-5p, whereas, miR-144-5p and miR-135a-5p were found to be persistently downregulated. The strength of this systematic review was that it provided a rigorous analysis of the most frequently identified differentially expressed microRNAs, but the study overlooked the value of hypothesis-driven studies. For instance, microRNAs that are low in abundance in the periphery but directly measurable in brain tissue may be underrepresented in the literature. In addition, this review reflected other limitations in depression research, including the lack of demographic specificity (e.g., age) and possible diagnostic subtypes.

Studies involving rodents have demonstrated that the expression of certain circulating microRNAs can reflect their expression pattern in the brain. For example, in epilepsy-related research, significant correlations have been found between microRNA expression in the brain and blood of adult mice,86 in this case, microRNAs originating from neurons in the temporal lobe.87 Other studies have reported that manipulating miR-218 in the prefrontal cortex neurons of adult mice induced corresponding changes in whole blood.88 In addition, circulating levels of miR-218 in adolescent mice have been shown to be potential biomarkers of susceptibility of depression-like phenotypes in adulthood.89,90

Although the use of circulating microRNAs in peripheral samples from humans is encouraging, it is not without challenges.74 A major caveat to this approach is the unclear origin of differentially expressed microRNAs in peripheral fluids. To this end, recent methods have been developed to isolate brain-derived microRNAs using protein markers localized to the membrane of vesicles.91 Studies involving adult patients have increasingly used this approach to measure response to antidepressant treatments.92 Circulating microRNAs may therefore be used as noninvasive indicators of brain health and disease. The source of circulating microRNAs and their potential mechanistic role in adolescent MDD likely depend on individual microRNAs. Key research priorities for microRNA studies include establishing their expression trajectory across adolescence and identifying disease-specific microRNA signatures in accessible peripheral fluids.

Establishing longitudinal microRNA data sets in adolescent research

Studies of circulating microRNAs in psychiatric conditions in adolescence could shed light on the molecular processes affected during this neurodevelopmental state. Peripheral microRNAs can be measured using minimally invasive methods, allowing early detection and prospective investigation. MicroRNA research in psychiatry is still in its nascent phase, and a notable lack of studies involved youth.

Through multi-institutional collaborations, our group is beginning to assess peripheral microRNAs in adolescents at risk or with diagnoses of MDD using population-based and clinically diagnosed cohorts.93,94 These cohorts are deeply phenotyped, with clinical, behavioural, and neuroimaging data available for each participant, as well as corresponding multiomics data, often encompassing genomics and metabolomics.95–98 Assessing microRNA expression profiles longitudinally and cross-sectionally creates opportunities to measure and monitor possible interactions between biological processes and phenotypic outcomes. For instance, cross-sectional longitudinal studies of adolescents could combine brain imaging and cognitive measurements with peripheral microRNA profiling, allowing the study of ongoing, normative, neuromaturational processes in different domains. Prospective assessment of microRNA expression could determine whether healthy controls and adolescents with depression have distinct microRNA profiles and whether differentially expressed candidates could predict future symptom severity and are associated with specific trajectories of brain maturation. These types of studies would provide open-access tools for researchers to explore hypothesis-based questions, determine if specific biomarkers of neurodevelopment and disease susceptibility are found across ethnically diverse cohorts, and encourage replication of findings.

Two recent studies have profiled circulating microRNAs in extracellular vesicles isolated from young people of ethnically distinct backgrounds. A study involving participants (aged 13–18 yr) from a discovery and a validation cohort of a Chinese population identified elevated levels of serum microRNAs among untreated adolescents with MDD compared with psychiatrically healthy controls, with some associations partially mediated by early-life adversity, such as trauma.99 The Brazilian High-Risk Cohort Study of adolescents with depression (aged 10–21 yr) — who could also have comorbid attention-deficit/hyperactivity disorder and anxiety — found that several microRNAs were downregulated among those with depression compared with those without a psychiatric diagnosis. In addition, the target genes of these microRNAs were previously linked to MDD.100 A longitudinal aspect is lacking in the studies to date and no microRNAs that could be monitored over different time points have been determined.

Possible approaches to understanding the biological implications of identified biomarkers

Our interest in microRNAs as markers of risk in adolescent depression is rooted in our mechanistic studies involving mice.88,89,101–103 Although clinical studies serve to identify altered targets relevant to human pathologies, the use of rodent models enables the interrogation of the specific mechanisms in which microRNAs are involved.

To assess microRNA expression in peripheral fluids of humans, we developed a minimally invasive method to perform microRNA sequencing from blood samples derived from adolescents, using dried blood spots as a source of circulating microRNAs. This method entails a prick to the finger for the collection of only a few drops of blood, thus facilitating incorporation of genetic testing into longitudinal and cross-sectional psychiatric studies. This blood-sampling method promotes equity in biological psychiatry by enabling collection of samples across a wide range of demographic groups.

Building large data sets that incorporate information across biological domains requires the use of sophisticated models to understand the potential function of epigenetic markers and their relationship to psychiatric outcomes. Integrating genotype and neuroimaging measures54 with information regarding tissue expression of genes (e.g., GTEx, www.gtexportal.org)104 and microRNAs (e.g., TissueAtlas, https://ccb-web.cs.uni-saarland.de/tissueatlas2)105 is necessary to provide insights into the possible tissues and biological pathways that may be affected by dysregulated microRNAs.

Genetic variations arising from polymorphisms in the microRNA seed region or the specific sequence of their target genes can alter microRNA–mRNA base pairing. This mechanism may be responsible for distinct biological functions and, in some cases, contribute to disease risk. In addition, post-transcriptional processes such as alternative splicing of genes can alter microRNA-related processes. For example, the splicing of the HTR1A (serotonin 1A) gene can remove an intron section containing the sequence of miR-135,106 a microRNA previously linked to depression.107–110 Most studies on peripheral microRNAs have focused solely on their canonical forms. However, simultaneous quantification of microRNAs in their various forms (i.e., isomiRs) is needed to better understand if and how these variants can affect base pairing and influence disease mechanisms.111

Conclusion

MicroRNA profiling in adolescents offers great promise in addressing the urgent need to identify young people who are at risk for developing psychiatric illness and to begin to understand the underlying psychopathology at the molecular level. MicroRNA biomarkers could provide insights into individual differences in vulnerability and into mechanisms involved in resilience. Effective communication and collaboration between clinicians and preclinical scientists are empowering this research (Figure 1). Such interdisciplinary efforts can bridge the gap between laboratory findings and clinical applications, ensuring that discoveries in microRNA profiling translate into tangible benefits for patients.

Figure 1 Research framework for advancing understanding and treatment of adolescent psychiatric illness using microRNAs. Basic research focuses on developing new methodologies, expanding data sets, and exploring cellular processes and gene variants. These findings can then be integrated into clinical research to inform longitudinal studies, personalize treatments, and advance the field through the collaboration of basic and clinical approaches.

The views expressed in this editorial are those of the author(s) and do not necessarily reflect the position of the Canadian Medical Association or its subsidiaries, the journal’s editorial board or the Canadian College of Neuropsychopharmacology.

Competing interests: None declared.

Funding: The work and authors were supported by the National Institute on Drug Abuse at the National Institutes of Health (no. R01DA037911 to Cecilia Flores), the Canadian Institutes of Health Research (no. FRN:17030 and PJT190045 to Cecilia Flores), and the Natural Sciences and Engineering Research Council of Canada (RG-PIN-2020-04703 to Cecilia Flores). Alice Morgunova was supported by a postdoctoral fellowship from the McGill-Douglas Max Planck Institute of Psychiatry International Collaborative Initiative in Adversity and Mental Health, an international partnership funded by the Canada First Research Excellence Fund, awarded to McGill University for Healthy Brains for Healthy Lives Initiative.
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