The Placebo Effect: Not All in Your Head

To get a drug to market, pharmaceutical companies have to show that it works better than a placebo. But sometimes the placebo is just as powerful as the real thing. Just why our bodies respond so strongly to fake medicine has long been a mystery, but researchers are a step closer to solving that riddle, having picked out a particular gene that may be responsible for one type of placebo effect.

The placebo effect works because patients believe they are actually receiving treatment. Expecting treatment is similar to anticipating reward, studies have shown, and reward anticipation triggers the release of the neurotransmitter dopamine in the brain, which can help alleviate symptoms of chronic pain and depression. But what about placebo effects for other conditions?

Tomas Furmark, a psychologist at Uppsala University in Sweden, suspected that a different neurotransmitter plays a role in placebo responses to social anxiety disorder (SAD)--an abnormal fear of being judged by others. Brain imaging studies have shown that the amygdala, an area of the brain that regulates the fear response, is unusually active in patients with SAD. What's more, healthy people with certain variations of two genes that regulate the neurotransmitter serotonin have more active amygdalas.

Based on these results, Furmark and his colleagues--in collaboration with the pharmaceutical company GlaxoSmithKline--ran a placebo-controlled trial with 108 patients who had been previously diagnosed with SAD. The volunteers were randomly assigned to receive either a new serotonin medication or a sugar pill for 8 weeks. At the beginning of the trial, the patients had to prepare and deliver a speech in front of small group of people--an anxiety-triggering event--while the researchers tracked their amygdala activity using positron emission tomography. The technique allows researchers to track blood flow--and thus activity--in different areas of the brain. The study participants had to give a similar speech at the end of the treatment period, so researchers could assess whether their patterns of brain activity had changed.

Even sugar was enough to conquer some cases of SAD. Of the 25 patients who received the placebo, 10 reported reduced anxiety by the end of the study. (Numbers for the treatment group were not released because the trial is ongoing.) Brain scans during the second speech showed their amygdalas were also less active. Genetic analysis revealed that eight people who got relief from the placebo had a particular version of a gene that regulates serotonin production called the tryptophan hydroxylase-2 promoter (TPH2), the researchers report tomorrow in the Journal of Neuroscience. This is one of the same genetic variants linked to heightened amygdala activity in healthy people. TPH2 is the first genetic marker tied to any placebo response, the team reports.

Finding genetic markers for the placebo effect could raise ethical questions about how companies design their clinical trials, Furmark says. For example, "it could be tempting to screen all individuals and ... select only those with [the] nonresponsive phenotype [for the trial]."

Psychiatrist Helen Mayberg of Emory University in Atlanta, Georgia, who has studied the placebo effect in depression, agrees that the findings could have major implications for research design. But first, more research is needed to determine if the genetic markers for placebo relief from SAD can be generalized to other diseases, and what other genes might contribute to the phenomena, she says.

It's one of those sites where you have to scroll to the right and back to the left to keep readding the text. So here's the abstract text.

A Link between Serotonin-Related Gene Polymorphisms, Amygdala Activity, and Placebo-Induced Relief from Social Anxiety

Placebo may yield beneficial effects that are indistinguishable from those of active medication, but the factors underlying proneness to respond to placebo are widely unknown. Here, we used functional neuroimaging to examine neural correlates of anxiety reduction resulting from sustained placebo treatment under randomized double-blind conditions, in patients with social anxiety disorder. Brain activity was assessed during a stressful public speaking task by means of positron emission tomography before and after an 8 week treatment period. Patients were genotyped with respect to the serotonin transporter-linked polymorphic region (5-HTTLPR) and the G-703T polymorphism in the tryptophan hydroxylase-2 (TPH2) gene promoter. Results showed that placebo response was accompanied by reduced stress-related activity in the amygdala, a brain region crucial for emotional processing. However, attenuated amygdala activity was demonstrable only in subjects who were homozygous for the long allele of the 5-HTTLPR or the G variant of the TPH2 G-703T polymorphism, and not in carriers of short or T alleles. Moreover, the TPH2 polymorphism was a significant predictor of clinical placebo response, homozygosity for the G allele being associated with greater improvement in anxiety symptoms. Path analysis supported that the genetic effect on symptomatic improvement with placebo is mediated by its effect on amygdala activity. Hence, our study shows, for the first time, evidence of a link between genetically controlled serotonergic modulation of amygdala activity and placebo-induced anxiety relief.

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