Mental disorders arise from a wide variety of causes, and recently researchers have been increasingly interested in the role of the immune system in causing neurological disorders such as depression and schizophrenia. This field of research, historically known as psychoneuroimmunology, is now referred to as immunopsychiatry, reflecting the understanding that it is not your moodiness that means you will get flu, but the fact that your flu may lead to disruptions in affect and cognition.
Whilst there are many unanswered questions regarding the exact role of the immune system in mental disorders, recent epidemiological and immunological evidence has increased confidence in the importance of this role. Doctor Khandakar and colleagues have elaborately reviewed existing evidence in an article published in this month’s edition of The Lancet Psychiatry. Here they also discuss the mechanisms by which immune responses may contribute to conditions such as schizophrenia, and the implications this has for further research and treatment possibilities.
According to Dr Khandakar: “the article brings together some disparate elements in immunopsychiatry into the possibility of an overarching approach. This approach might contribute to a better understanding of neuropsychiatric disorders both in terms of disease mechanisms and therapeutics”.
So, what does the review tell us?
Epidemiological studies have long noted the link between schizophrenia childhood infections, both in the prenatal period and later on in childhood. A recent example of this cited in Dr Khandakar’s review are findings from the Avon birth cohort study (ALSPAC), where Dr Khandakar and colleagues demonstrated that increased levels of inflammatory markers at age 9 were associated with an increased risk of first-episode psychosis at age 18. Furthermore, other studies have shown that first-degree relatives of individuals with schizophrenia also experience increased rates of autoimmune conditions and that there is a linear relationship between the number of severe infections and risk of developing schizophrenia in individuals with autoimmune disorders.
Taken together, this epidemiological evidence suggests a common pathway between schizophrenia and autoimmunity, probably involving the inflammatory immune response. This is also supported by genetic studies of schizophrenia, which have found robust associations with immune-related genes.
On a more biological level, the review finds that evidence for the link with schizophrenia comes from studies of both the innate and adaptive immune system. The former is the body’s first line of defense, which often acts quickly and in a more general way. The adaptive immune system is able to form memories, and responds to specific threats (for instance, this is how most vaccines work).
The findings from the ALSPAC study are concerned with the innate immune system, as the study looks at the production of markers of inflammation called cytokines. The specific inflammatory marker studied (interleukin 6) is also associated with depression, pointing towards a potential ‘common cause’ for both disorders. Studies in mice have shown the brain effects of raised cytokine levels. This could potentially explain a variety of symptoms in schizophrenia, as well as impaired mood, cognition and perception in other disorders.
A second component of the innate immune system is microglia, which are essentially the resident immune cells of the brain. In healthy individuals they’re not particularly active, but they develop a more active phenotype in response to systemic inflammation. This may lead to the increased expression of certain proteins such as TSPO. This has been confirmed by PET-scanning in patients with a recent onset of psychosis, as well as in patients with acute symptomatic exacerbations. Previously activated microglia can respond more strongly to stimuli, and this is a possible partial explanation for the link between childhood infection and development of schizophrenia.
In terms of the adaptive immune system, the evidence is promising, but still very preliminary and difficult to compare or add together. The review article states that this is due to study limitations such as small sample sizes and reporting percentages instead of absolute numbers. The problem with small sample sizes is that it’s hard to show a big effect (even if that effect might be there in reality), and the problem with just reporting percentages is that you don’t know what you’re adding up (20% of 10 or of 150 is very different!). However, the review finds that schizophrenia is frequently associated with the presence of certain antibodies, particularly so-called anti-NMDA receptor antibodies. Whereas this association is technically biologically plausible, much is still unknown. However, the authors call for randomised controlled trials (RCTs) where immunotherapy is tested alongside standard antipsychotics to test the hypothesis that this would improve prognosis.
Where does all this evidence leave us? How can immune reactions lead to schizophrenia? The review provides four possible answers to this question, and they’re not mutually exclusive.
It could be that immune dysregulation plays a role in disturbances of neurotransmitter systems (the way in which your brain sends signals to the rest of your body). This has been found in mice, but findings are yet to be replicated in humans. In this case, causality is likely to be bidirectional. So, the immune system influences neurotransmitters, but these same transmitters also influence the immune system.
Secondly, in other diseases activated microglia have been associated with neural degeneration and it is possible that this plays a role in schizophrenia too.
Thirdly, there is a possible common neurodevelopmental pathway between early life infection and schizophrenia. A Finnish cohort study has shown an additive effect of family history and prenatal infection, so it is plausible that genetics play a mediating role in this.
Finally, intestinal microbiota are suspected to play a role via the so-called brain-gut axis. In mice, manipulation of microbes in the gut has affected cognitive function and behaviour. This might be possible in humans too.
As has become clear, there are still many unknowns in unravelling the causal pathway between immune responses and schizophrenia. Research is promising and coming from a wide variety of fields, but it is also relatively preliminary. Many animal findings are yet to be replicated in humans, and the authors call for integrated clinical research encompassing a variety of immunological, genetic and microbiological biomarkers.
This would potentially have far-reaching treatment implications: there could, for instance, be a role for immunotherapy alongside traditional medication in schizophrenia, and stratification of patients by immune phenotype could make more targeted treatment possible. More integrated research could further highlight a suspected ‘common cause’ between various mental disorders.
The importance of the renewed interest in immunopsychiatry is echoed in the editorial of this month’s edition of The Lancet Psychiatry, where it is stated that: “The road ahead forks: one branch leads to progressively more fragmented disease classifications managed by ever more specialised physicians, the other to holistic care of patients by integrated teams, taking into account their immune, somatic and psychiatric symptoms. For the sake of our patients, we need to follow the path to integrated care.”