Genetic defect confers risk of major depression, resistance to SSRI drug therapy

A newly discovered genetic defect might represent an important risk factor for major depression, a condition which effects 20 million people in the U.S., according to Duke University Medical Center researchers. The mutation in the gene — whose protein product plays a primary role in synthesizing the brain chemical serotonin — could lead to the first diagnostic test for genetic predisposition to depression, the team said.

“Abnormalities in brain levels of serotonin have been widely suspected as a key contributor to major depression and other neuropsychiatric disorders,” said James B. Duke professor Marc Caron, Ph.D., a researcher in the department of cell biology, the Duke Institute for Genome Sciences and Policy and senior author of the study. “Our findings provide a novel molecular mechanism underlying dysfunction in serotonin neurotransmission in some patients with depression.”

The genetic defect is the first genetic variant of functional consequence in the production of serotonin identified in any psychiatric disorder, the researchers said. Patients with depression who carry the abnormal gene also show resistance to treatment with selective serotonin reuptake inhibitors (SSRIs), a class of drugs that includes paroxetine (PaxilTM), sertraline (ZoloftTM), and fluoxetine (ProzacTM), the team found. In addition to its diagnostic use, the genetic marker might therefore also aid in identifying, in advance, those patients who will likely fail to respond well to SSRI therapy.

The researchers further suggest that this and other variants of the gene might also explain such paradoxical adverse reactions to SSRI treatment as suicidal behavior and SSRI-exacerbated mania and psychosis. The Duke team reported its findings Dec. 9, 2004, in the early online edition of Neuron. The work was supported by the National Institutes of Health, the Human Frontiers Science Program and the Canadian Institute of Health Research.

The brain is a network of billions of cells called neurons. When stimulated, neurons fire, sending a wave of electrical signals from one end to the other. One neuron will trigger an impulse in others by launching bursts of chemical neurotransmitters, including serotonin, that set off an impulse in receiving neurons. Once the original cell has passed its message on, it sops up the chemical it released to dampen that signal and prepare for the next.

If serotonin levels are decreased, communication among neurons stalls. Such decrease may occur in patients with depression and other psychiatric disorders including anxiety, post-traumatic stress disorder and attention deficit hyperactivity disorder. SSRIs counteract the depletion by slowing the re-uptake of serotonin, allowing the body to make the best use of abnormally low levels of the chemical messenger, the researchers explained.

Scientists had long considered the enzyme known as tryptophan hydroxylase (TPH1) to be the sole enzyme governing serotonin synthesis in the nervous system. Last year, however, researchers at another institution found that a second enzyme, tryptophan hydroxylase-2 (TPH2), is present in the brain, while the earlier discovered TPH1 is found primarily in peripheral nerves. Caron’s team reported earlier this year that different variants of that enzyme have a major effect on brain levels of serotonin in mice, suggesting that the human variant of the gene might underlie psychiatric disorders characterized by low levels of the chemical messenger.

To search for variants of TPH2, researchers screened the genomes of 48 individuals included in another Duke study of psychosocial and behavioral risk. Among these samples, the researchers uncovered one novel variant of the gene that generates a mutant TPH2 enzyme. The team then inserted both versions of TPH2 into cell cultures. Cells expressing the mutant TPH2 enzyme produced approximately 80 percent less serotonin than did cells with the more common form of the brain enzyme, they found.

The researchers then searched for the gene in 87 patients with unipolar major depression, 60 patients with bipolar disorder, and 219 control patients not diagnosed with either condition. Of those individuals, more than 10 percent (nine of 87 individuals) of those with major depression carried the abnormal serotonin synthesis gene, compared to one percent (three of 219 individuals) of those in the control group. None of the patients with bipolar disorder were found to have the mutant gene.

Seven of the patients with depression who carried the defective gene also had a family history of mental illness or drug and alcohol abuse, six had exhibited suicidal behavior or had made a suicide attempt and four had generalized anxiety symptoms. Furthermore, all of the patients with the mutant gene were either unresponsive to treatment with SSRIs or only responded to the drugs when prescribed at the highest doses.

The three control patients with the mutant gene, who had not been diagnosed with major depression, did display clinical symptoms, including generalized anxiety, mild depression and a family history of mental illness or drug and alcohol abuse — further suggesting a higher susceptibility for certain neuropsychiatric disorders in the presence of the abnormal gene variant. “The current study identifies a functional genetic variant, which leads to a major decline in the production of serotonin and which may be an important risk factor for major depression,” said Duke researcher Xiaodong Zhang, Ph.D., lead author of the study. “The findings provide a potential molecular mechanism for aberrations in the production of serotonin that underlie depression and other neuropsychiatric disorders.”

“We believe this is a major finding with implications not only for understanding the cause and development of depression, but also its treatment and management,” added R. Ranga Krishnan, chairman of psychiatry at Duke and an investigator on the study. “Depression can seriously impact a person’s functioning, both at work and with their family, and can lead to suicidal thoughts and actions, making more effective diagnosis and treatments a high priority.”

Further large-scale genetic studies are needed to confirm the findings and investigate in detail the connection between the mutant TPH2 and unipolar major depression, the researchers said. The team will also explore the presence of this and other functional mutations in the serotonin enzyme in people with a wide range of other serotonin-related conditions — such as generalized anxiety disorders, suicidal behavior, autism and drug abuse — and in those with adverse reactions to treatment with SSRIs.

Collaborators on the study include Raul Gainetdinov, Jean-Martin Beaulieu, Tatyana Sotnikova, Lauranell Burch, Redford Williams and David Schwartz, all of Duke.