For a long time it’s been believed that the cause of schizophrenia lies in the interplay between genetic and environmental factors, complimented by imbalances in dopamine transmission. But a study conducted by researchers at the MRC Clinical Sciences Centre in London showed that another factor may also be in play – the brain’s inflammatory system.
Schizophrenia affects one in 100 people in the UK and its manifestation is marked by psychotic episodes during which the patient’s perception of reality is severely impaired by hallucinations (most commonly auditory), delusions and incoherent thinking. These symptoms alternate with states of social isolation and depression.
The causes of this severe disorder are still uncertain but inflammatory processes have already been implicated in it. Patients with schizophrenia and those with high risk of developing the disorder exhibit high levels of cytokines – small, inflammatory proteins associated with reduced grey matter volume. In fact, during early adulthood a sudden loss of cortical grey matter is observed in schizophrenic patients. This process is termed ‘neuronal pruning’ and is a natural way of removing unwanted synaptic connections in the brain due to learning and synaptic plasticity. Although ‘pruning’ is a natural process everyone undergoes, the rates of loss for schizophrenic patients have been shown to be twice as big.
The brain’s primary immune cells – microglia – are highly involved in this process. Microglia act as the main form of defence against infection and injury in the CNS and as such they engulf and neutralise pathogens by phagocytosis. In much the same way, they remove unwanted synaptic connections in the developing brain.
Earlier studies have suggested that microglia may be responsible for making inappropriate connections between cells during pruning, which later on in life lead to experiencing symptoms of schizophrenia.
In order to test this proposition, Peter Bloomfield and his team examined 14 patients diagnosed with schizophrenia, 14 people who had been identified as being at “ultra-high risk” of developing the disorder (but hadn’t yet experienced a psychotic episode) as well as 28 healthy, age-matched controls for comparison.
They injected all of their participants with the radioactive tracer molecule [11C]PBR28, which binds selectively to a transporter protein synthesised by microglia cells when they’re active. Then using PET scans they visualised the distribution and amount of protein expressed, in order to determine the extent of microglial activation.
Their findings revealed that the activity levels of microglia cells are much higher in the brains of schizophrenic patients. Interestingly, that activity correlates with the severity of symptoms, with people in the high risk group also exhibiting elevated levels of the tracer protein. One participant in the at-risk group, who showed the highest level of microglial activity went on to have their first psychotic episode soon after.
This study is the first one to confirm that there is an association between a hyperactive immune system and greater severity of symptoms. The fact that people at risk also show high levels of microglia activation strongly suggests that inflammatory responses may contribute to the disease’s development. This has many potential benefits and could contribute to the early diagnosis of schizophrenia and its prevention.
“Our findings are particularly exciting because it was previously unknown whether these cells become active before or after onset of the disease” says Peter Bloomfield, lead author of the study. He adds: “Now we have shown this early involvement, mechanisms of the disease and new medications can hopefully be uncovered.”
The use of anti-inflammatory drugs to block or reduce microglial activation is an exciting prospect and clinical trials are already underway for minocycline – an antibiotic that also has anti-inflammatory effects. Such potential new treatments would be life-changing for people who are currently taking anti-psychotics. Although effective to some extent, antipsychotic treatments also have many side effects including weight gain, tachycardia and impotence. If anti-inflammatory drugs can be shown to work in schizophrenia, they would provide a safer alternative and improve the lifestyle of the many people affected by the disorder.