12 Dec 2018

Scientists probe links between anti-depressant drugs and epilepsy onset

A/Prof Nigel Jones in the lab
Series about National Health and Medical Research Council (NHMRC) Project Grant recipients in Central Clinical School (CCS) starting in 2019

Associate Professor Nigel Jones has been awarded two NHMRC grants for projects investigating:
antidepressants in epilepsy and brain waves in schizophrenia.

by Anne Crawford

A Monash University researcher has been funded more than $1million over four years to investigate the possibility that anti-depressant drugs contribute to the onset of epilepsy in people with traumatic brain injury (TBI).

The potentially controversial research is being conducted by A/Prof Nigel Jones from the Department of Neuroscience.

A/Prof Jones said the research was prompted by emerging and compelling clinical and experimental evidence that raised concerns that the treatment of mood disorders with antidepressants could promote the development of epilepsy following head injury. Between 20-25 % of patients will develop epilepsy after TBI. Many of these patients also suffer from psychiatric problems, and require treatment with antidepressants.

Data he has derived from experiments in rat models of acquired epilepsy have indicated that treatment with commonly used selective serotonin reuptake inhibitor (SSRI) antidepressants accelerated epilepsy development, led to more severe epilepsy, and increased the risk of developing epilepsy following head injury.

A/Prof Jones said his studies into this were originally prompted by clinical observations made a decade or so ago by psychiatrists noticing a steady flow of epilepsy patients being referred to them. It is now recognised that while many patients with epilepsy also suffer from psychiatric problems, the reverse is also true; if you have a psychiatric disorder you’re more at risk of developing epilepsy, he said.

A/Prof Jones has been untangling cause and effect ever since and came across an unexpected finding. While testing the effects of stress on the onset of epilepsy in animal models he found that animals treated with anti-depressants to reduce the stress were actually more vulnerable to developing epilepsy.

“There was something about the drugs that was promoting the vulnerability to epilepsy,” he said.

A/Prof Jones and colleagues then tested SSRI antidepressants and found that no matter what type of epilepsy the effects were consistent; the drugs were inducing the susceptibility to the disease.

A $1.02million NHMRC grant has enabled A/Prof Jones, as Chief Investigator - A (CIA), to continue experiments into this area to probe the mechanisms involved. CIB is Dr Asla Pitkänen from the University of Eastern Finland.

The first set of experiments will explore whether other classes of antidepressants have the same effect as the SSRIs. These include noradrenaline reuptake inhibitors and some drugs that target the dopamine system.

“From a scientific perspective, this will tell us that if these other types of drugs also induce the same vulnerability, the mechanism by which it occurs is a property common to all modern depressants. So we can draw conclusions about which neurotransmitter systems were being induced or more broadly what else might be triggered and be related to the mechanism,” he said.

“However, if the effect is exclusively caused by SSRI antidepressants and not the other classes then again we can narrow down the exact mechanism of how this is happening and target our investigation to look at serotonin.”

The findings could potentially inform clinicians about what might be suitable anti-depressants to prescribe to a patient who might be at risk of developing epilepsy, such as epilepsy following traumatic brain injury.

A second series of experiments, using transgenic mice and pharmaceutical agents, attempts to understand exactly how SSRIs work while a third, larger experiment in Finland will divide animals with TBI into those treated with antidepressants and those that are not and see which, and how many, of them develop epilepsy. The researchers will then look for any associated cellular markers to understand the biological mechanisms driving these effects.

Brain wave research attracts a second grant

Schizophrenia is a complex psychiatric syndrome that is disabling and distressing for sufferers, and costly for families and society. Despite decades of research, its underlying causes are still unclear.

A/Prof Jones has been funded $642,000 by the NHMRC to investigate a potential cause: aberrations in high-frequency brain waves called ‘gamma’ neural oscillations. These brain waves coordinate brain activity and underlie many cognitive processes that are disrupted in schizophrenia.

Although schizophrenia typically includes a variety of symptoms including hallucinations, and social withdrawal, cognitive symptoms are the first to emerge and are considered core features of the disease. They are also thought to be the best predictor of long-term disability and functional outcome.

A/Prof Jones and researchers in his lab in the Department of Neuroscience will probe the role of aberrant gamma oscillations driven by NMDA receptor hypofunction hypothesising that it this a key mechanism underlying the cognitive symptoms of schizophrenia. NMDA (N-methyl-D-aspartate) receptors are proteins that control electrical impulses in the brain.

“There’s some pretty strong evidence that in humans and animals, brain waves are very important in higher order cognitive processes like working memory and attention,” he said. “We have a lot of evidence that we’re trying to strengthen. The primary goal of the project is to determine whether the cognitive deficits that are caused by NMDA receptor antagonists are doing so by changing gamma oscillations.”

The researchers aim to characterise the functional role of gamma oscillations occurring during cognitive behaviour using some advanced technology; small ipads allocated to each mouse or rat which the animals press while undergoing tests for working memory and attention for a reward (a strawberry milkshake). The tests are based on those used in human psychological tests making them translationally relevant to humans too.

A/Prof Jones said the project benefited from the innovative technology being used. “These tests were coupled with measuring electro-physiology, which is the real strength of the application.”

The investigators will then test the ability of a variety of different drugs that interact with the NMDA receptor complex to see if they can improve the deficient gamma oscillations that are caused by the NMDA receptor antagonists and improve the cognitive profile.

“If we are able to succeed in that, this could promote the development of new classes of anti-psychotic drugs which would be used clinically to treat patients with schizophrenia, in particular those who have cognitive problems.”

A/Prof Jones said both NHMRC grants were testament to the years of hard work his teams had conducted. “It’s a team effort,” he said. “My two teams have worked consistently and hard in a very focussed manner,” he said.

“This funding will allow us to expand and add new scientists to the team and make cutting-edge discoveries.”

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