Link between ALS, Schizophrenia May Spur New Paths of Research

By Tiffany Parnell
Friday, September 1, 2017
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Amyotrophic lateral sclerosis and schizophrenia share genetic origins, according to recent research published in Nature Communications. That finding has the potential to change how neurological and psychiatric diseases are studied and furthers hopes of curing both conditions.

Although scientists have made strides in understanding ALS, a cure remains elusive. One goal of current ALS research efforts is to uncover the genes responsible for the disease’s development, paving the way for effective, targeted therapies.

The Schizophrenia-ALS Connection

The international team of researchers involved in the Nature Communications study had reason to believe ALS and schizophrenia may be biologically related.

“In 2013, we investigated what other diseases are observed in the families of ALS patients, and we found that psychosis was significantly more frequent than expected in first- and second-degree relatives of ALS patients,” says Russell McLaughlin, the study’s lead author and Assistant Professor in Genome Analysis at Trinity College in Dublin. “This was despite no clear co-occurrence of the two diseases in individual patients. This suggested to us that some of the genetic risk factors between the two diseases may be the same, with other factors — genetic, environmental or other — determining which trajectory a patient ultimately takes: ALS, schizophrenia or both.”

To test this hypothesis, the team examined data from a recently published genome-wide association study (GWAS) for ALS and data from the Psychiatric Genomics Consortium’s 2013 GWAS for schizophrenia.

“The study confirmed the biologic overlap between ALS and schizophrenia,” says Orla Hardiman, BSc, MD, FRCPI, FAAN, FTCD, MRIA, Professor of Neurology at Trinity College and the study’s senior author and lead investigator. “We identified a 14 percent overlap in at-risk genes. ... So, the interpretation is that some forms of ALS and some neuropsychiatric conditions share a common biological basis. What could this be? We propose that it may relate to synaptic integrity — important in both conditions — and the integrity of brain networks; there is strong evidence of disruption in both conditions.”

“Recognizing and documenting the presence of ‘atypical features’ can sometimes allow us to recognize the limitations of the [disease] categorization process, and the systematic evaluation of what might appear to be unusual clinical observations — e.g., higher rates of schizophrenia in family members of those with ALS — can lead to new and exciting ways of subcategorizing patients based on pathobiology rather than clinical presentation.”
— Orla Hardiman, BSc, MD, FRCPI, FAAN, FTCD, MRIA, Professor of Neurology at Trinity College in Dublin

From Lab to Bedside

While it’s too soon to determine what clinical implications this research may have, Dr. McLaughlin is hopeful the results will inspire further inquiry.

“We have observed a broad signal from genetic analyses of both diseases but do not yet have an indication of whether this can be exploited in patient treatment,” he says. “However, this should definitely be an avenue of research that is aggressively pursued in molecular cell biology and pharmaceutical research.”

In addition, case-control studies have suggested potential overlaps between ALS and bipolar disorder, autism and depression. While the current research failed to confirm findings observed in the case-control studies, Dr. McLaughlin believes future studies with larger patient pools could yield more definitive conclusions.

Regardless of whether subsequent research confirms such links, the genetic correlation between ALS and schizophrenia is enough to validate the fact that the disciplines of neurology and psychiatry should be studied together, according to Dr. McLaughlin.

“Our solid, empirical evidence that a neurological disease — ALS — and a psychiatric disease — schizophrenia — have some common origins somewhat nullifies the distinction between neurology and psychiatry, and I hope that this obsolescence might open up avenues in research that will help researchers and clinicians find new ways to treat these diseases,” he says. “As both ALS and schizophrenia are highly disabling conditions, we hope that the fresh ideas that our research injects into the field of brain disorders will engender real progress and ultimately lead to cures for both diseases.”

A Closer Look at an Incurable Condition

There are no effective pharmacologic remedies for ALS. Since the disease was discovered nearly 150 years ago, the FDA has approved only two medications to treat it, which underscores the critical importance of patient-focused drug development.

The first drug, riluzole, received approval more than 20 years ago, and it has little effect on survival. Typically, taking the drug consistently extends a patient’s life by only two to three months, according to Calaneet Balas, MS, MBA, Executive Vice President, Strategy, at the Washington, D.C.-based The ALS Association.

The second drug, edaravone, received FDA approval in May 2017. In the clinical trial on which approval was based, people who took edaravone experienced fewer declines in daily functioning than those who received a placebo during the same time period. Whether or not the drug, which is designed to delay disease progression and is administered intravenously, will improve survival rates is currently unknown.

To complicate matters further, there is no identifiable biomarker for ALS. This makes it difficult for physicians to diagnose the condition in early stages or to test therapies’ effectiveness. In the absence of biomarker data and curative pharmacologic agents, management strategies for ALS are primarily palliative.

“We’re really trying to make people comfortable and make sure that they have the technology that they need to communicate and eat, ...” Balas says. “That certainly helps promote the longevity of their life, as well as the quality of their life, but that’s really how ALS is managed now.”