Picture this: A world where 4-5% of young people are grappling with full-blown depression and a further 9-16% tiptoe along the threshold. Sadly, this is our current reality (Thapar et al., 2012; Bertha and Balàzs, 2013) and the repercussions are equally undeniable and disturbing; from academic downfall and social withdrawal to a tragic increase in suicide risk (Malhi and Mann, 2018; Oliva et al., 2023).
Psychotherapeutic and pharmacological interventions, including selective serotonin reuptake inhibitors (SSRI) antidepressants, only effective for some, potentially leave up to 60% of adolescent patients unresponsive (Cuijpers et al., 2021; read more about treatment-resistant depressions in this blog by Talbot, 2023). The unresolved and heterogeneous aetiology of depression, coupled with treatments that fail to address specific biological mechanisms, demands a paradigm shift.
In the last few years, researchers have discovered strong associations and possible causal relations between immune disturbances and depression. This pathway is yet to be fully understood, but it may help pave the way for alternative treatment strategies targeting the immune system (Hasselmann, 2014). Cellular immune phenotypes of depression may also prove beneficial as a gateway towards precision medicine (Corsi-Zuelli, 2023).
Vöckel et al. (2024) performed a systematic review and meta-analysis focusing on anti-inflammatory agents and their antidepressant effects in young people. This is the first effort to synthesise the current evidence in underage patients. So, gather around fellow mental health enthusiasts, as we discover a treatment option that might just redefine our approach to (youth) depression and help improve the quality of life and wellbeing of our young people.
Current psychotherapeutic and pharmacological interventions are not working effectively enough for young people with depression and a paradigm shift is needed.
Methods
The authors screened PubMed, Web of Science, and PsycInfo for all types of clinical trials, transcending randomised controlled trials (RCTs) exclusivity, that have investigated anti-inflammatory drugs in young people with depressive symptoms, independent of psychiatric or somatic conditions. All interventions with an anti-inflammatory mechanism of action were included, regardless of treatment duration or modality.
A language restriction (English or German) and the absence of an Embase search due to accessibility constraints are noted. Furthermore, no quality assessment of the included trials was performed. In an exploratory approach, however, only the double-blinded RCTs were analysed.
Studies were combined into an overall effect size (Standardised Mean Difference) using a three-level meta-analysis model. Side effects were narratively approached because of the high heterogeneity of the assessment scales.
Results
Overall, 22 studies met the inclusion criteria, of which 3 were not included in the meta-analysis due to insufficient information provided in the paper. The trials included a total of 1,366 subjects with a mean age of 14.1 years. Most trials investigated omega-3 polyunsaturated fatty acids (PUFAs; read more about PUFAs and their role depression in this blog by Crick, 2023), but other agents (aspirin, rosuvastatin, doxycycline and lyceum barbarum polysacharride) were also reported.
- In the pooled analysis, agents with anti-inflammatory properties showed a significant effect on the severity of depressive symptoms in youth (SMD -0.298, 95%CI -0.524 to -0.071, p=0.01).
- Those treated with an anti-inflammatory agent, showed an improvement in their reported depressive symptom severity.
The sub-analysis of omega-3 fatty acids (N=1,167) also found a significant effect (SMD -0.283, 95%CI -0.551 to -0.015, p=0.037); those treated with an omega 3 PUFA showed an improvement in reported depressive symptom severity.
Seven studies showed some or a high risk of bias – as indicated by Eggers test for publication bias and a visual inspection of the funnel plots. Additionally, the broad search strategy, although inclusive, led to a large amount of heterogeneity (or differences) between studies.
The participants in each study also differed in:
- Diagnosis – participants had varying psychiatric and somatic disorders.
- Treatment duration – ranged from 2 weeks to 1 year.
- Symptom severity score measurement – self-rated and/or clinician-rated scales.
Regarding side-effects, one study on omega-3 fatty acids found a significantly higher frequency of muscle cramps, while another reported more nausea. Moreover, participants that received a high-dose of omega-3 fatty acids more frequently reported headache, abdominal pain and vomiting. However, most studies showed no significant differences in side effects when compared to placebo.
Young people treated with anti-inflammatory agents saw an overall improvement in the severity of depressive symptoms experienced.
Conclusions
The review concludes that anti-inflammatory agents, though yielding a small effect, are a promising treatment option for alleviating the burden of youth depression.
However, the authors do not provide clinical guidance on the administration of anti-inflammatory agents in young people with depression. The nuances in the relationship between inflammation and (specific) depressive symptoms are still very much unexplored in the adolescent population. If anything, the heterogeneity, and scarcity of available trials are a call to explore these preliminary findings further to ultimately transform the results into tailored, impactful treatments.
Further immunopsychiatry research and clinical trials focusing on the adolescent population is needed if we are to work towards implementing these results into clinical practice.
Strengths and limitations
Strengths
To the best of my knowledge, this is the first attempt to summarise current evidence on anti-inflammatory treatments for youth depression. An inclusive broad search strategy was used, justified by the scarcity of available evidence. The authors used a three-level meta-analysis model, including both youth and clinician ratings, to provide a more comprehensive and accurate representation of the change in depressive symptom severity. The risk of bias was assessed for all included trials, and potential moderators of treatment outcomes were analysed and presented in the Supplementary Material. Overall, the comprehensive search strategy and rigorous statistical methods form a reliable and valuable effort in this first attempt to review the current evidence.
Limitations
However, despite these strengths, the inclusion of studies solely in English or German may introduce a linguistic bias, and no Embase search was performed, potentially overlooking relevant studies indexed exclusively in Embase. Furthermore, the pooled sample size was small, and, apart from the omega-3 fatty acids, other anti-inflammatory agents were only investigated in individual studies, precluding meta-analysis of these agents.
Additionally, no attempt was made to explore the effect of anti-inflammatory agents on specific depressive symptom domains. However, some recent studies suggest a potentially more pronounced reduction in specific symptom domains, such as immunometabolic symptoms (e.g. leaden paralysis, energy loss, somatic symptoms) (Miller et al., 2017; Lamers et al., 2020)
The authors suggest that subgroup differentiation may be associated with improved treatment effect sizes. Recent studies indeed propose that only a select group, perhaps characterised by aberrant inflammatory markers or the above-mentioned specific symptom profiles, might be more receptive to anti-inflammatory agents (Miller et al., 2012; Colasanto et al., 2020).
The small effect sizes, potential bias, limited available evidence, and the heterogeneous samples contribute to a lack of confidence in firm conclusions. Nevertheless, the review highlights once again the importance of understanding the unique biotypes of depression, also in youth, and the potential to unlock more personalised and effective treatment modalities.
This is an important first attempt at summarising current evidence on anti-inflammatory treatments for youth depression. However, the small effect sizes, potential bias, limited available evidence, and the heterogeneous samples mean firm conclusions cannot yet be drawn.
Implications for practice
While the study reveals a promising reduction in depressive symptom severity with anti-inflammatory interventions, translating these findings into practice requires careful consideration.
First, the small effect sizes align with recent insights into immune-mediated depressions; we need to explore which specific groups of young people respond better to anti-inflammatory treatments and how the symptoms they experience relate to inflammation. Identifying youth with aberrant inflammatory markers or specific symptom profiles could enhance treatment effectiveness.
Secondly, the study’s limitations, including heterogeneity in study populations and variations in treatment agents, highlight the need for additional research. Conducting clinical trials with anti-inflammatory drugs is already challenging in adults, let alone in minors. Hence, it’s logical that most trials focused on omega-3 fatty acids supplements. However, for effective translation into clinical practice, investigating specific biological mechanisms, conducting stratified clinical trials enriched with adolescents exhibiting abnormal inflammatory blood markers, and using potent anti-inflammatory agents at an effective dosage is needed to enhance our understanding of anti-inflammatory treatments in youth depression.
As a researcher studying the effects of anti-inflammatory medications in adults in such a stratified clinical trial, I see first-hand how personalised approaches to mental health can make a big difference. Some participants, while initially feeling overwhelmed by feelings of despair, experience a newfound hope when they learn about the role the immune system can play in depression. I strongly believe these findings present new possibilities, including better treatment options for young people dealing with depression.
There is still a lot of work to do, but this review represents a step towards better, more personalised treatments aimed at improving the mental health of our young people. The inflammatory pathway and its associated biological depressive subtype, holds the potential to reshape the therapeutic landscape into a more tailored, effective treatment approach for depression in young individuals.
Identification of subgroups of young people for whom anti-inflammatory therapeutics may be beneficial is the next vital step in our work towards more effective and personalised treatments for depression.
Statement of interests
Similar work: Céline is currently conducting a clinical trial with anti-inflammatory medication on a sample of adults with depression.
Grant funding: Seal of Excellence PhD fellowship from the University of Antwerp.
Links
Primary paper
Vöckel J, Markser A. et al (2024) Pharmacological anti-inflammatory treatment in children and adolescents with depressive symptoms: A systematic-review and meta-analysis. Eur Neuropsychopharmacol. 2024 78:16-29. [PubMed abstract]
Other references
Thapar A, Collishaw S et al (2012) Depression in adolescence (PDF). Lancet. 2012 379(9820):1056-1067
Bertha EA, Balázs J (2013) Subthreshold depression in adolescence: a systematic review. Eur Child Adolesc Psychiatry. 2013 22(10):589-603. [PubMed abstract]
Malhi GS, Mann JJ (2018) Depression. Lancet. 2018 392(10161):2299-2312. [PubMed abstract]
Cuijpers P, Oud M et al (2021) Psychologic Treatment of Depression Compared With Pharmacotherapy and Combined Treatment in Primary Care: A Network Meta-Analysis (PDF). Ann Fam Med. 2021 19(3):262-270
Talbot A. The experience of treatment-resistant depression: we need to rethink treatment for people who do not respond to antidepressants. The Mental Elf, 11 Dec 2023.
Hassellmann H. Anti-inflammatory drugs for depression: new review points to benefits, but more research needed. The Mental Elf, 28 Nov 2014.
Corsi-Zuelli F. Cellular immune phenotypes of depression: a gateway to precision medicine. The Mental Elf, 29 Jun 2023.
Crick D. Does what you eat affect how you feel? The Mental Elf, 8 Jun 2023.
Miller AH, Haroon E et al (2017). Therapeutic Implications of Brain-Immune Interactions: Treatment in Translation (PDF). Neuropsychopharmacology. 2017 42(1):334-359
Lamers F, Milaneschi Y et al (2020). Depression profilers and immuno-metabolic dysregulation: Longitudinal results from the NESDA study (PDF). Brain Behav Immun. 2020 88:174-183
Miller GE, Cole SW (2012). Clustering of depression and inflammation in adolescents previously exposed to childhood adversity (PDF). Biol Psychiatry. 2012 72(1):34-40.
Colasanto M, Madigan S et al (2020). Depression and inflammation among children and adolescents: A meta-analysis (PDF). J Affect Disord. 2020 277:940-948.
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