Therapygenetics


by Carl Sherman

March 21, 2013

Psychiatric ills like anxiety and depression can be treated effectively with medication, psychotherapy, or a combination, but no single approach works for everyone, and tailoring treatment to the individual often means an arduous process of trial and error.

For several decades, research exploring links between genetic variation and medication response—pharmacogenetics—has been sufficiently intense to warrant its own journal. But only in the last few years has a similar approach been applied to psychotherapy. Some call it therapygenetics.

This is a very young science, and while investigators are optimistic, they emphasize that practical results are still far off. “I’d predict that at some point we may be able to genotype someone, and say ‘there’s an X probability you’ll respond to this therapy,’” says Christopher Beevers, director of the Mood Disorders Laboratory at University of Texas, Austin.    

“But I think right now everyone realizes we’re just scratching the surface. We’re getting glimpses” of what’s possible.

To extinguish fear

Most of the work thus far has been “hypothesis driven”—investigations of specific polymorphisms within specific genes, based on research suggesting their involvement in brain processes implicated in the etiology and treatment of psychiatric disorders.

Two of the most exciting recent papers have focused on the gene that regulates brain-derived neurotrophic factor (BDNF).

Earlier research had established BDNF as a key player in fear extinction—the “unlearning” of associations between a stimulus (e.g. a place, situation, or image) and the fear response. Extinction learning appears to be the active principle of exposure therapy, used for “fear disorders” like phobias, obsessive-compulsive disorder (OCD), and post-traumatic stress disorder (PTSD):  with repeated, harmless exposure to the feared object, anxiety diminishes.

Animal and human studies have explored the Val66Met polymorphism in the BDNF gene (one variant codes for the amino acid valine in the resulting protein, the other for methionine): those with the “Met” allele release less BDNF, and their extinction learning is impaired. Might Met carriers also respond less well to exposure therapy?

In a study published in the January 2013 issue of Biological Psychiatry, 55 people with PTSD underwent 8 weeks of exposure-based cognitive behavior therapy (CBT)—the most effective psychotherapy for the disorder, but one that fails in up to half of patients.

In the study, those with two BDNF Val genes improved significantly more than those with one or more Met gene: a 62 percent vs 40 percent reduction in symptoms.

The other study, in the July 2012 European Psychiatry, included 98 patients with rather severe obsessive-compulsive disorder (OCD) who received CBT after failing to respond adequately to medication alone. Among the 65 who had both Val alleles, 60 percent improved enough to be considered “responders,” significantly more than the 36 percent of the 32 who carried at least one Met allele.   

 The difference was most marked in patients whose obsessions and compulsions focused on cleaning and contamination (rather than e.g. checking, symmetry, or hoarding)—the group, according to study author Miguel Fullana, who typically benefit most from exposure therapy.

“Ours was the first study, to my knowledge, to look at genotype and the response to CBT for OCD,” says Fullana, of the Autonomous University of Barcelona. “It had its limitations: Our patients were also receiving drugs, so what we really found was that genotype influenced response to combined therapy. But this may make it easier to generalize to real-world practice.”

Kerry Ressler, associate professor of psychiatry and behavioral sciences at Emory University, and a member of the Dana Alliance for Brain Initiatives, called the studies “totally consistent” with basic science research. “In both cases, the Val66Met polymorphism associated with less BDNF and extinction function was associated with a more refractory response to psychotherapy relying on the process of extinction.”

The gene-therapy interaction

Another paper, in the March 2012 Molecular Psychiatry,  considered a gene involved in the serotonin neurotransmitter system. Variation in the promoter region of the serotonin receptor, 5HTTLPR, has been linked to depression and anxiety: People with the “short” allele appear more likely to develop psychiatric problems when they are under high stress.

In a study of 389 children given CBT for diverse anxiety disorders, those with two copies of the short allele were significantly more likely to have recovered six month later than those with two long alleles or one of each (78.4 percent vs 58.4 percent).

Thalia Eley, Reader in developmental behavioural genetics at the Institute of Psychiatry, Kings College London, and first author of the paper, regards her findings primarily as “a clear demonstration of the concept of gene-environment interaction." 

“I see the genetic influence on anxiety and depression as [such an interaction], but testing this is quite difficult because important stressful events come about with little warning and are specific to the individual. The beauty of the study to me as a scientist is that we knew the timing of the experience [the structured manipulations of psychotherapy], which wasn’t stressful but positive.”

That the 5HTTLPR allele associated with vulnerability to stress is linked to a positive response to CBT is not surprising, in her view—it suggests that people with the more “susceptible” version of the gene “in a good environment will do better, in a bad environment, will do worse. There’s a strong likelihood the marker genuinely influences brain processing, making it more responsive to any kind of environmental influence.”

While Eley “totally believes in the potential for clinical applications” of research like hers [it was she who coined the term “therapygenetics,” in this paper], “at the moment, the test of gene-environmental interaction is the driving force, because the other is too far away.”

 The back-and-forth between basic research into causes of illness and clinical research into interventions is a forceful dynamic in this field, she says, “Each drives forward on its own, but also influences the other.”

    Ressler sees their synergy as a potential source of therapeutic innovation. “We feel that biomarkers at the level of genetics and epigenetics will be a powerful way to understand the pathophysiology of these disorders… and as we better understand the molecular pathways underlying neuroplasticity in therapy, it may point toward new treatments.”

Many pathways, many genes

Like others in the field, Ressler takes a long view of clinical applications: Current research is essentially “a portent of things to come. While findings in these papers aren’t ready for prime time in the clinic, they give us a good idea of what may be coming down the pipeline.

 “Any set of medical genetics, certainly psychiatric genetics, won’t be one polymorphism, or one story. As we better understand pathways in learning and memory and neuroplasticity, we may be able to develop a cohort of genes… each with a small effect size… that will together predict treatment outcome with a lot more specificity and sensitivity.”   

Given the complexity of these pathways (researchers are investigating the genetics of dopamine, glutamate, and various neuropeptide and hormone systems, among others), practical therapygenetics will ultimately be “a bioinformatics challenge,” says Christopher Beevers: “taking many polymorphisms within many genes, and integrating them into a single index.”

One such technique, already in use, is the “cumulative genetic score,” which   would analyze an array of genes that might predict response to treatment,   identifying which alleles apparently produce a better or worse outcome and tabulating the number of “risk alleles” one possesses.

“It’s a bit of a primitive approach,” says Beevers,  “because it gives equal weight to all alleles while some clearly have more influence than others. But it’s a step in the right direction. People are working on techniques to do something similar in a more sophisticated way.”