Scientists in Italy have pinpointed an important gene that could be used to predict the chances of success of electric shock treatment, especially for those with major depressive disorder and bipolar disorder that are resistant to other treatments.

Psychotherapy and lifestyle changes works for some people, drugs work for others, and for those less fortunate, nothing seems to work to treat their depression. For these treatment resistant individuals, one of the most effective treatments is electroconvulsive therapy, also known as electroshock treatment.

Despite demonstrating relatively high effectiveness in treating various mental disorders in multiple studies, sticking electrodes to someone’s head and electrocuting their brain is clearly controversial to say the least, especially seeing as it can come with serious side effects including both short-term and long-term memory loss, prolonged seizures and stroke. Knowing in advance from analyzing someone’s genes if electroconvulsive therapy will work or not is a definite, risk-avoiding and cost-effective plus.

In fact, researchers are approaching a consensus that it is each individual’s unique neurobiology, formed from genetic pot luck and a lifetime of gene-environment interactions shaping the networks in our brains and neuronal gene expression, that ultimately decides which type of treatment will work.

This is simply because some treatments affect certain brain regions and cellular processes differently than other treatments do. It’s a very complex key (i.e. a treatment’s unique neurobiological effects) meets a vastly complex lock (i.e. a person’s unique neurobiology) scenario.

For example one study published in JAMA psychiatry reports that patients with major depression that have low activity in a brain region called the anterior insula before treatment will respond better to cognitive behavioural therapy (CBT) than those with high activity in this brain region before treatment, who respond better to the antidepressant Lexapro.

The latest electroconvulsive therapy research concerns genetic biomarkers for responsiveness to electroshock treatment for people with major depressive disorder and bipolar disorder, who have already been deemed resistant to treatment.

As is done routinely in Ireland, Britain, northern Europe and North America, a series of electric shocks were given three times per week, for 2-3 weeks. Out of the 100 patients in the study, 69% had reduced depression symptoms and were considered responsive to treatment with electroconvulsive therapy, while the remaining 31% where considered non-responsive.

The STAR*D study

The hunt for genes predictive of electroconvulsive therapy success was guided by results from the largest and longest study ever conducted to evaluate depression treatment, the NIMH-funded Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. The researchers in the present study focussed on Glutamate Receptor Ionotropic Kainate 4 (GRIK4) gene variants (i.e. single DNA nucleotide mutations) as they were found to be associated with being non-responsive to antidepressant therapy.

The glutamate system and its components, like GRIK4, are a large part of the neurobiology and treatment of major depressive disorder, which is characterized by brain region-specific imbalances and dysfunctional metabolism of the neurotransmitters glutamate and GABA (gamma-amino-butyric acid).

There were statistically significant results found for two GRIK4 gene variants, with particular mutations being predictive of electroconvulsive therapy success or failure. For the first gene variant (rs11218030), simply the presence of one G allele, irrespective of the second allele, presented five times the risk of non-response to electroconvulsive therapy compared to AA homozygotes. For the second gene variant (rs1954787) the opposite was true, GG homozygous patients had double the risk of non-response than compared with having at least one A allele.

Moreover, the researchers had shown in previous research that the G allele carriers of rs11218030 GG homozygotes of rs1954787 have a higher risk of developing a psychotic symptomatology during a depressive episode, which in itself is the strongest negative predictive factor regarding treatment success.

The GRIK4 gene is particularly relevant to response to electroconvulsive therapy for depression as it encodes a protein found in specific brain areas like the hippocampus that makes it critical for rapid excitatory neurotransmission, learning and memory, complex cognitive behaviours, mood and personality, and can negatively impact neuroplasticity, i.e. the death of neurons from overactivaton of glutamate receptors and signalling pathways.

Interestingly, electroconvulsive therapy in humans and animal models has been shown to result in the normalization of glutamate deficits and GABAergic neurotransmission, particularly in the hippocampus as well as other brain areas.

It therefore looks like electroconvulsive therapy works through these neurochemical changes to renurture neuroplasticity and produce the neuronal remodelling required to overcome depression. Importantly, as the results suggest, variants of glutamate signalling genes, like the GRIK4 gene, either hinder or facilitate these neurochemical changes, where facilitation promotes neuroplastic recovery from depression and perhaps other mental illnesses.

Treating patients resistant to electroconvulsive therapy

So what about the 31 treatment resistant individuals in the study that were also resistant to electroconvulsive therapy. How do we treat them?

Another study reported that for the three severely treatment resistant patients included in the research, all responded well to a novel therapeutic regimen combining electroconvulsive therapy with injections of the drug ketamine. This is very interesting, as ketamine mainly acts through binding to NMDA (N-methyl-D-aspartate) receptors, which results in an increase in glutamate neurotransmission in GABAergic interneurons.

Combined, the two aforementioned studies suggest that by altering glutamate signalling pathways in the brain of treatment-resistant depressed patients using specialised drugs, this can create a window of opportunity for electroconvulsive therapy treatment to exert its effects in normalizing glutamate deficits and neurotransmitter imbalances, and stimulating neurogenesis.

Finding a genetic biomarker for electroconvulsive therapy response in the glutamate signalling system, adds to the slowly growing library that includes two dopamine-related genes and a serotonin-related gene.

By furthering this research, there may come a day in the not too distant future where specialized algorithms will consider genetic, clinical and other biological data in accurately predicting treatment response and prescribe the best treatment regimen from specific to the individual, and their unique presentation of depression or any other mental illness.

References

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