Research — 13 August 2015

Mental disorders have been notoriously difficult to treat, and those treatments have long been accompanied by pretty severe side effects. So it’s been no surprise that non-compliance with a doctor’s prescription has been a persistent problem in mental illness over the decades.

One barrier to success in combating mental illness is that we have yet to arrive at an understanding of how these diseases are caused, and how they progress. This knowledge gap has resulted in serious consequences. Two British scientists, Joanne Doherty and Michael Owen of Cardiff University, wrote recently:

Despite considerable advances in neuroscience, there have been few if any notable advances in pharmacotherapy, and as a consequence of this and the perceived challenges in the field, many pharmaceutical companies are discontinuing research in neuroscience and psychiatry.

Another problem, as discussed in a recent Genetic Literacy Project article, has been the lack of perspective on the human mind and where the mind may exist in the nervous system. Our consciousness, emotions, moods and other such functions also have called out for some more context, especially when things go wrong.

Both of these concerns may be getting a little help from genetics.

The largest study ever conducted of the genetics of mental disease found 108 independent genetic loci appeared to contribute some risk of schizophrenia. This marked a good start, but other studies have discovered genes that overlap between certain mental disorders, indicating that either symptoms of the separate disorders overlap, or that the disorders themselves need to be redefined, to more closely follow the genetics underlying each disease.

Symptom overlap in mental disorders has been known to psychiatrists for some time on a clinical basis. For example, patients have been diagnosed with both schizophrenia and bipolar disorder. But psychiatric treatments of these disorders have not overlapped, leading the psychiatric profession to establish a hierarchy of diagnoses. For at least a century, patients with symptoms of multiple disorders were diagnosed with the highest “ranked” disorder—so, in the case of schizophrenia and bipolar disorder in the same person, that person was diagnosed with only schizophrenia, and treated accordingly. Bipolar was ignored.

While this practice may have helped boost the failure rate of psychiatric treatments, the acknowledgement of its limitations may yet lead to better definitions of mental disorders, this time based on genetics and biological mechanisms.

Where does one disease end and another begin?

In 2013, the first of many studies identified five major mental illnesses that could be traced to the same gene variations. Schizophrenia, bipolar disorder, depression, attention deficit hyperactivity disorder (ADHD) and autism all share variations on four chromosomes. Genome wide association studies (GWAS) were able to determine that these genetic variations explained between 17 – 28 percent of the risk of getting any of these illnesses. On the other hand, twin studies showed 81 percent heritability in schizophrenia. Clearly, a lot more is going on biologically than we know about.

Since, studies have shown single nucleotide polymorphisms that each contained some effect on the risk of mental disorder. Scientists have also found alleles that were over-represented in schizophrenia were also over-represented in bipolar disorder, and ADHD, but not in autism. Other studies have found copy number variations, a rare variant, may increase the risk of certain disorders, but in other cases may help protect against these disorders. Still more work has found that genes involved in synaptic transmission, specific nerve cell receptor channels, the ability of synapses to “rebound” and change, signal transduction and nerve cell structure were altered in cases of mental illness.

When size matters

The strength of a genome wide study depends on the number of samples it works with, however. The bigger the study, the theory goes, the more rare but important variants it will pick up. Along these lines several large consortia have been set up to combine data and develop larger research projects. These include the U.S. National Institute of Mental Health’s Research Domain Criteria, establish to find new ways of “classifying mental disorders based on behavioral dimensions and neurobiological measures.”

Another, similar group is the Psychiatric Genomics Consortium, now based at the University of North Carolina, has amassed genetic research on autism, attention-deficit hyperactivity disorder, bipolar disorder, major depressive disorder, schizophrenia, anorexia nervosa, drug use disorders, Obsessive Compulsive Disorder/Tourette’s, and post-traumatic stress disorders (PTSD).

When it doesn’t

The concept has not escaped criticism, however. While some researchers and practitioners have hailed a “profound transformation” in the understanding of mental illness thanks to advances in genetics, others warn that the road to psychiatric miracles has dug deep ruts. In an editorial in Dialogues in Clinical Neuroscience, Harvard Medical School psychiatrist Lynn DeLisi asked for caution when applying genetics to psychiatric diseases.

One example came from the schizophrenia study with 108 loci. DeLisi observed that creating a risk scoring method based on those loci produced too many false-positive and false-negative relationships to be clinically useful. She also warned that GWAS studies, while large enough to find variants, in a sense “washed out” the connection between an individual variant and an individual with a specific mental disorder (or combination of disorders).

Nonetheless, the study of genes in the brain and in mental illness may be comparable to the state of cancer biology, just as advances in genetics were being made. As that disease has slowly progressed from one that classified tumors based on location to one that classified them based on genetics, so too may mental illness change its diagnostic and treatment basis. But we’ll have to identify the right genes first.

This article first appeared on ‘Genetic Literacy Project’ on 12 August 2015.

 

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