Could Anti-inflammatory Interventions Earlier in Development Confer Primary Prevention of Psychiatric Disorders?

In the last decade a wealth of compelling evidence has established a link between inflammatory processes and the development of psychiatric disorders. Despite this evidence, psychiatric researchers tend to work in silos with a strong thematic demarcation between the biological and the psychological, which can be attributed in part to the age-old philosophical perspective on mind-body dualism. This essay, which not only embraces but seeks to exploit this link, discusses the possibility of implementing anti-inflammatory strategies earlier in childhood development as a prevention strategy for psychiatric disorders later in life.

A link between inflammatory processes and psychiatric symptoms is evidenced by the increased prevalence of psychiatric symptoms and disorders following administration of peripheral immune challenges, the presence of increased levels of inflammatory markers in individuals suffering from psychiatric disorders, and the increased prevalence of psychiatric disorders in patients with chronic inflammatory conditions and autoimmune disorders.¹ Although the increased levels of immune markers could also partially be a consequence of the behavioral effects of psychiatric disorders leading to unhealthy lifestyle or reduced self-care, support for a causative role of inflammation in the development of these disorders has been provided by longitudinal studies showing low-grade inflammation preceding the onset of depression and psychosis.^2,3 Increased levels of low-grade inflammation appear to be particularly relevant in a subset of psychiatric patients who also present with poor treatment response and worse clinical outcome, leading some to consider anti-inflammatory interventions as treatment options in psychiatry.^4–6 So far, anti-inflammatory therapies have been mainly trialed in either patients with established psychiatric disorders or those not responding to conventional antidepressant or antipsychotic medications—albeit not in the early stages of the disorders.

The potential of targeting low-grade inflammation to prevent development of psychiatric disorders should not be overlooked, particularly in light of recent evidence of increased inflammation present even before subjects meet the full diagnostic criteria for psychiatric disorders.^2,3,7 Although such studies have generally focused on adult populations, increased levels of pro-inflammatory cytokines have also been described in children and adolescents with mental health disorders, such as attention-deficit/hyperactivity disorder and depression, further supporting the potential for anti-inflammatory treatments in childhood.^8,9 Considering that childhood trauma is one of the main risk factors for mental health problems, the presence of increased inflammatory markers (e.g., CRP, TNFα, and IL-6) in adults with a history of childhood trauma would indicate that reducing inflammation may be potentially beneficial in preventing the development of psychiatric disorders following the experience of trauma in childhood.¹⁰ This is also supported by one of our recent systematic reviews suggesting that the copresence of biological risk factors, including increased inflammation, with the experience of childhood trauma increases the risk of future depression in adolescents and young adults.¹¹ Animal models of maternal immune activation further highlight the relevance of a primed immune system at an early/prenatal stage in the development of psychiatric disorders.¹² Targeting this stage of development has not yet had much clinical exploration.

Targeting low-grade inflammation seems to be an obvious goal, but clinical trials using anti-inflammatory treatments in adults with depression, psychosis, or PTSD have yielded mixed results. These studies indicate that, although the benefit is (statistically) significant in some of these conditions, the effect size is often small.⁶ The effect is much larger, however, when specific groups are targeted. Such groups notably include treatment-resistant patients with the presence of a baseline raised inflammation or comorbid inflammatory conditions.⁶ The implication may be that inflammation is a dominant mechanism in the disease process only in some of the patients or that different inflammatory mechanisms play a role within the disorder or patient group. While childhood and adolescence may represent an important age for the prevention of psychiatric disorders, evidence for the efficacy of anti-inflammatory treatments in children and adolescents remains relatively small or nonexistent, largely because of the ethical implications of using novel treatments in this age group. Some ethical considerations include the increased risk of side effects with anti-inflammatory medications and difficulties in acquiring consent. As a consequence, research in novel therapeutics is undertaken mainly in adult populations with a multiyear delay before being translated into pediatric research. Investigations that are either invasive or less tolerable in children—for example, PET scans looking at microglia activation—also make the collection of primary data more difficult and invariably limit the scope and duration of experimentation. These barriers make therapeutic investigation in children and adolescents less popular and can stigmatize this area of research, leading to less funding despite there being a great need.

An important issue in implementing anti-inflammatory treatments as a primary prevention strategy concerns the side-effect profiles of these medications, which include gastrointestinal effects, fatigue, headaches, and dizziness. Considering also what we have learned from the above-mentioned clinical trials, a potential step toward the use of anti-inflammatory medications for prevention strategies would be to identify individuals who would be more likely to benefit from these treatments in spite of their potential side effects. Such individuals would need to exhibit not only low-grade inflammation but also other risk factors, such as childhood trauma. Our systematic review showed that increased inflammation is associated with subsequent onset of adolescent depression mainly in the context of experience of childhood trauma; we suggest that combining low-grade inflammation with other nonbiological risk factors (such as exposure to childhood trauma) may further improve our ability to identify individuals more likely to benefit from anti-inflammatory interventions at an early stage.¹¹ Some recent advances specifically for the adolescent population include the development of composite risk score—based on multiple sociodemographic factors—able to predict development of depression in adolescence.^13,14 In the context of anti-inflammatory interventions, we suggest that it is important not only to select subjects with an increased risk because of clinical/sociodemographic/environmental factors, but also to take into account the presence of low-grade inflammation, which would be the main target of the intervention.¹¹ One potential issue with targeting high-risk individuals is linked to the possibility that they may be less likely to engage with life-style interventions due to their inherent characteristics, such as higher impulsivity.¹⁵ This problem could potentially be overcome, however, by conducting participatory research and co-developing the treatment strategies with high-risk individuals/adolescents to improve acceptability and feasibility of interventions in this population.

In terms of pharmacological interventions, some well-tolerated anti-inflammatory treatments have been trialed in adolescents. N-acetylcysteine, a derivative of the essential amino acid cysteine, has been found to be effective in small-scale, randomized trials treating various psychiatric disorders.¹⁶ Although no large-scale trials have been performed to date in children and adolescents, this topic is of interest because of the drug’s relatively good safety and tolerability profile. Minocycline, a putative microglial inhibitor, is also a safe and well-tolerated pharmacological intervention that has shown some positive effects in adults with depression but has yet to be much explored in the treatment or prevention of psychiatric disorders.⁶ Ultimately, the use of such pharmacological interventions boils down to a risk-benefit balance; their use could potentially be warranted for particularly high-risk demographics.

Especially pertinent in the context of children and adolescents is the possibility of exploring the anti-inflammatory effects of nonpharmacological interventions, which boast a substantially lower risk profile. See Figure 1. Alternative treatments such as dietary supplements, dietary changes, mindfulness, exercise, and weight loss have all shown varying degrees of anti-inflammatory effect. One such example is supplementation with omega-3, which has been shown to have multiple anti-inflammatory effects in the brain.¹⁷ Adjuvant omega-3 supplementation appears to be most promising in recent randomized, controlled trials that include pediatric populations.^8,17 Other potential dietary supplements include folic acid, vitamin D, and probiotics, which have all been suggested to hold anti-inflammatory properties.¹⁷ Studies on probiotics in pediatric populations are relatively limited; more research is needed to understand their potential in prevention and treatment strategies for psychiatric disorders.¹⁸ Exercise in the form of high-intensity interval training, which leads to improved mental health outcomes in people with severe mental illness, has interestingly been associated with reduced inflammatory markers.¹⁹ Studies also indicate that talking therapies, such as cognitive-behavioral therapy, and mindfulness activities, such as self-guided meditation, can produce a low but significant reduction in low-grade inflammatory markers in subjects with attention-deficit/hyperactivity disorder, posttraumatic stress disorder, and depression.²⁰ Conducting trials on such alternative treatments could be challenging because of multiple confounding effects and difficulty in blinding. However, the close to absolute safety of such interventions makes pursuing large and robust blinded, randomized studies an attractive prospect. Given that primary prevention needs to be easily accessible, uncomplicated, and relatively inexpensive, there is certainly a social and economic justification for researching these types of strategies.

Figure 1: Addressing inflammation to tackle mental illness. This figure describes how childhood trauma, presence of inflammatory disorders, or recurrent infections can lead to chronic inflammatory states that can cause central inflammation in the form of raised inflammatory markers and increased microglial activation, which in turn can contribute to the development of mental illness. We could take better steps toward reducing development of mental illness by addressing the role of inflammation more directly—by promoting engagement with primary prevention strategies that yield a reduction in said inflammation, such as dietary changes, exercise, and psychotherapy/mindfulness. HIIT, high-intensity interval training.

With the increased expansion of research in psychoneuroimmunology and improved knowledge of the interaction of biopsychosocial risk factors, we will reach a better understanding of how systemic and central low-grade inflammation relate to disease processes in major psychiatric conditions. Rather than waiting for psychopathology to floridly manifest itself, we would be able to deliver early-intervention options, including anti-inflammatory treatments, to patients in high-risk categories. The success of such efforts will hopefully lead to a greater focus on primary prevention, something that is currently difficult to practice in mental health. Furthermore, integrating psychological and biological approaches when developing prevention strategies for mental health will steer the discourse away from the mind-body dichotomy, support a holistic yet individualized approach, and promote destigmatization of mental illness.