Highlights of Research
• How we began to understand the link between immune response and mental illness
• High levels of inflammation and the links with Depression and Mental Illness
• New anti-inflammatory therapies & how to access them
A Nobel Prize winning discovery
A curious discovery made in an Austrian asylum 136 years ago is making an impact today in shaping our understanding of depression and mental illness. The finding, made by the Austrian neuro-psychiatrist Julius Wagner-Jauregg, was so groundbreaking it earned Wagner-Jauregg a Nobel Prize.
The story started in the winter of 1883, at the First Psychiatry Clinic of the Asylum of Lower Austria. Wagner-Jauregg was first starting his psychiatry position at the clinic and was tasked to look after a wide variety of mentally ill patients. He came across a woman with psychotic delusions who also suffered from a high fever induced by acute bacterial skin infection. As the fever subsided, the patient became coherent and was cured of her psychosis. This perplexing discovery stuck with Wagner-Jauregg, and he began his decades-long quest to replicate that observation. [1,2]
During the late 19th century, syphilis was still a dangerous health threat in Europe. Neurosyphilis (or general paresis of the insane, GPI), marked by grand delusions, paralysis, and dementia, was the manifestation of the tertiary stage of syphilis.  For many patients, death was a welcomed escape from the horrible disease. Ironically, GPI would also be the disease that propelled Wagner-Jauregg to international fame.
Since his encounter with the woman in the Austrian Asylum, he had been experimenting with different types of infection to induce fever but to no avail. It was until the end of World War I that Wagner-Jauregg had the serendipitous opportunity to inject a malaria-infected blood sample from a soldier into several patients with GPI. The malarial inoculations were proven to be successful. This treatment, known as malariotherapy thereafter, was then widely used around the world.
In 1927, Wagner-Jauregg was awarded the Nobel Prize for his contribution in developing malariotherapy.
The missing link between fever and the remission of mental illness
Wagner-Jauregg’s work with malariotherapy had not only made him the first psychiatrist to be awarded a Nobel Prize, but it also broke the “therapeutic nihilism” surrounding psychosis, which he believed to have a natural cause. However, he admitted that he had no clear understanding of the underlying mechanism that made malariotherapy worked in his Nobel Lecture. 
Nonetheless, his work had produced an important nuance in understanding GPI – that there was a specific, organic root rather than universal, non-specific cause. In other words, induced fever was a targeted therapy for an illness caused by an anomaly or anomalies in the brain. In his concluding remarks during the Nobel Lecture, he said: “…… malaria besides a non-specific action against the syphilitic infection, also exerts a specific elective action on the cerebral process of progressive paralysis, including advanced infection of the cerebro-spinal fluid.” 
It was not until the past decade that scientists began to understand the role of inflammation in mental illnesses such as depression. In a recently published study, scientists found as many as 90 genes over-expressed in individuals with major depressive disorders that were associated with the body’s immune response towards infection. 
Additionally, there was some evidence that suggested physiological changes in response to depression. Inflammatory molecules such as interleukin-6 (IL-6), tumour necrosis factor (TNF)-alpha and interleukin 1-beta (IL-1β) could cross the blood-brain barrier to enter the brain and disrupt the functions of neurotransmitters such as serotonin.  It was previously thought that the blood-brain barrier was impenetrable to inflammatory molecules and, therefore, could not significantly influence any functions of the brain.
Such a discovery had shifted the paradigm of our understanding of depression pathogenesis and opened new possibilities for novel treatment avenues.
The interleukin-6 molecule, a prominent pro-inflammatory protein that could unlock a new treatment of depression.
The effect of inflammation on depression was particularly prominent in patients who were given interferon-alpha treatment for cancer. Interferons are a group of naturally-occurring proteins that are secreted by the immune system. Interferon-alpha has been shown to elicit inflammatory responses in the body and was intimately linked to depressive symptoms in patients who received infusions of the medicine.
In the late 1990s, physicians began to realise that anxiety and depressed mood that arose from interferon-alpha treatment could not be entirely attributed to toxicity but could due to a more complex pathophysiological mechanism. It was also postulated that by reducing inflammation through alternations of the immune system, depression symptoms could be alleviated or, at least, reduced. 
Stimulation of the vagus nerve
The cumulative evidence from these studies has strongly supported the hypothesis that reducing inflammation is beneficial for depression. As the production of pro-inflammatory signals is largely controlled by the central nervous system, much attention has been given to the role of the vagus nerve in regulating the inflammatory response.
Simulations of the vagus nerve had shown to reduce pro-inflammatory cytokines such as IL-6, TNF-alpha, high mobility group box 1 (HMGB1) and macrophage migration inhibitory factor (MIF), which were closely linked to the relief of depression symptoms.  Acetylcholine, a major neurotransmitter of the vagus nerve, also demonstrated promising results in suppressing pro-inflammatory cytokines including IL-1β and IL-18. 
It is also important to note that both the invasive (surgical) vagus nerve stimulation and the safer, transcutaneous alternative have shown a similar capability to suppress pro-inflammatory cytokines. Thus, these treatments could provide a viable treatment option to patients especially those who are non-responsive to standard antidepressant treatment due to high levels of inflammation. 
From Wagner-Jauregg’s malariotherapy to today’s vagus nerve stimulation, the medical community has gained substantial insights into the instrumental role of inflammation in depression. These discoveries have helped us to better manage depression and could possibly lead to safer more effective treatments and benefit to those who are not responding to traditional therapy which doesn’t address inflammation.
1 Tsay CJ. Julius Wagner-Jauregg and the legacy of malarial therapy for the treatment of general paresis of the insane. Yale J Biol Med 2013;86:245–54.
2 Wetsman N. Inflammatory illness: Why the next wave of antidepressants may target the immune system. Nat Med2017;23:1009–11. doi:10.1038/nm0917-1009
3 Nobelprize.org. Julius Wagner-Jauregg – Biographical. Nobel Media AB. 2019.https://www.nobelprize.org/prizes/medicine/1927/wagner-jauregg/biographical/ (accessed 3 Mar 2019).
4 NobelPrize.org. Julius Wagner-Jauregg – Nobel Lecture. Nobel Media AB. 2019.https://www.nobelprize.org/prizes/medicine/1927/wagner-
jauregg/lecture/ (accessed 7 Mar 2019).
5 Leday GGR, Vértes PE, Richardson S, et al. Replicable and Coupled Changes in Innate and Adaptive Immune Gene Expression in Two Case-Control Studies of Blood Microarrays in Major Depressive Disorder. Biol Psychiatry 2018;83:70–80. doi:10.1016/j.biopsych.2017.01.021
6 Zhu C-B, Blakely RD, Hewlett WA. The Proinflammatory Cytokines Interleukin-1beta and Tumor Necrosis Factor-Alpha Activate Serotonin Transporters. NeuropsychopharmacologyPublished Online First: 1 February 2006. doi:10.1038/sj.npp.1301029
7 Das UN. Vagus Nerve Stimulation, Depression and Inflammation. Neuropsychopharmacology2007;32:2053–4. doi:10.1038/sj.npp.1301286
8 Borovikova L V., Ivanova S, Zhang M, et al. Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature2000;405:458–62. doi:10.1038/35013070
9 Cattaneo A, Ferrari C, Uher R, et al.Absolute Measurements of Macrophage Migration Inhibitory Factor and Interleukin-1-β mRNA Levels Accurately Predict Treatment Response in Depressed Patients. Int J Neuropsychopharmacol 2016;e. 19 pyw045. doi:10.1093/ijnp/pyw045