UK researchers are using an MS drug to target the root causes of this devastating psychiatric disorder
A new, exciting and ambitious study, reported last year in The Guardian, aims to make a breakthrough in the treatment of schizophrenia by targeting a component of the immune system. In this 2-year trial, 30 patients will receive monthly infusions of natalizumab, a humanized monoclonal antibody against the cell adhesion molecule α4-integrin which can block the movement of cells of the immune system, including the microglia of the brain. Natalizumab is already used as a treatment for multiple sclerosis. Changes in Translocator Protein (TSPO) expression pre- and post-natalizumab or placebo administration will be assessed by positron emission tomography (PET) using radio-labelled ligands selective for TSPO, a technique widely used in vivo in schizophrenia research.
The idea that neuroinflammation plays a part in the aetiology and pathophysiology of mental disorders such as schizophrenia has gained increasing interest and approval in recent years. The central hypothesis that functional dysregulation (over-activation) of brain-resident microglia may interfere with the normal progression of brain development and maturation appears particularly appealing. In fact, an exciting study by Howes’s group1 using PET brain imaging demonstrated elevated microglial activity in patients with schizophrenia and in individuals with a high risk of developing the disease.
It has been shown that in schizophrenia patients, synaptic pruning, a normal phenomenon in developing and maturing brains, appears to become more aggressive, leading to a loss of vital connection2. This was observed in the frontal cortex and the auditory regions, which could perhaps provide an explanation for patients reporting hearing voices. The frontal cortex indirectly controls levels of dopamine in the brain, the elevated release of which is thought to cause delusions and paranoia common in people with schizophrenic.
Most currently available treatments of schizophrenia are based on drugs developed in the 1950s, and work by blocking dopamine function. While these approaches provide some symptomatic relief, they do not tackle the underlying cause of the disease or prevent damage to the brain. Moreover, current approaches only target the delusions, not the less-known yet extremely disabling symptoms associated with schizophrenia, such as memory, cognitive problems and lack of motivation.
Scientists hope that natalizumab will prevent the over-pruning of synapses by restricting movement of the microglia and could therefore potentially tackle the whole spectrum of symptoms associated with schizophrenia. A successful outcome of this new trial would not only add a new therapeutic approach to schizophrenia treatment, but importantly answer fundamental questions about the significance of the immune system in this disease.
- Peter S. Bloomfield, M.Sc., Sudhakar Selvaraj, M.D., Ph.D., Mattia Veronese, Ph.D, et al: Microglial Activity in People at Ultra High Risk of Psychosis and in Schizophrenia: An [11C]PBR28 PET Brain Imaging Study. Am J Psychiatry 2016: 173:1.
- Aswin Sekar, Allison R. Bialas, Heather de Rivera, et al: Schizophrenia risk from complex variation of complement component 4. Nature 2016: 530, 177–183.
This post originally appeared on Nov. 23, 2017 on the KWS BioTest blog, Expert Insights. KWS is now part of Charles River.