Posted by Phillipa on January 19, 2010, at 19:07:07
Seems a new study has found that an excess of Serotonin receptor sites may be reason SSRI's dont work for many and thus TRD. Please experts explain the technical stuff and the possible meds to take to revers as claimed in article. Phillipa
From Medscape Medical News
Surplus of Serotonin Receptors May Explain Failure of Antidepressants in Some Patients
Janis C. Kelly
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Review data January 18, 2010 Individuals with treatment-resistant depression tend to have the G/G genotype associated with higher levels of 5-HT1A autoreceptors, and turning off some of those autoreceptors might turn on response to selective serotonin reuptake inhibitors (SSRIs), according to researchers at Columbia University Medical Center in New York City.Previous genetic and imaging research has suggested a link between high 1A receptor levels in the raphe neurons and antidepressant treatment failure. However, the current study, conducted in mice, is the first to show directly that increasing 1A receptor levels in raphe neurons reduces antidepressant response and, conversely, that reducing 1A receptor levels in raphe neurons can restore drug effectiveness.
The research team, led by René Hen, PhD, professor of pharmacology in the Departments of Psychiatry and Neuroscience at Columbia University and a researcher the New York State Psychiatric Institute, discovered that too many serotonin receptors of the 1A type on the raphe neurons sets up a negative feedback loop that reduces serotonin production.
"The more antidepressants try to increase serotonin production, the less serotonin the neurons actually produce, and behavior in mice does not change," Dr. Hen told Medscape Psychiatry.
The study was published online January 14 in Neuron.
Causal Relation
Dr. Hen and colleagues measured the effect of antidepressant medications using a common behavioral test that measures the boldness of mice retrieving food from bright, open areas. Mice on antidepressants usually become more daring, but the drugs had no such effect on mice with surplus serotonin receptors.
"Our study is the first to establish a causal relation between 5-HT1A autoreceptor levels and stress response, depression, and response to antidepressants in an animal model," said Dr. Hen.
"Autoreceptors are located on serotonin neurons, where they control serotonin levels, while heteroreceptors are located in other brain areas, where they mediate the effects of serotonin. Our research suggests that even subtle changes in a specific serotonin receptor (the 5-HT1A autoreceptor) are sufficient to make an individual vulnerable to depression and unresponsive to SSRIs," he added.
Using new genetic engineering techniques, Dr. Hen created a knock-out mouse that can be programmed to produce high or low levels of serotonin receptors of the 1A type only in the raphe neuron. The levels present in the mice mimicked those found in humans with treatment-resistant depression.
"By simply tweaking the number of receptors down, we were able to transform a nonresponder into a responder. The biggest surprise was that a small decrease in 5-HT1A autoreceptor levels was sufficient to change serotonin levels and to convert a nonresponder into a responder (to SSRIs)," said Dr. Hen.
The researchers suspect that a similar strategy of reducing the number of 1A autoreceptors or blocking their activity might help treatment-resistant patients. .
"Adrenergic drugs may be useful, or drugs that target the intracellular signaling cascades activated by 5-HT1A autoreceptors," he said.
The next step is to confirm that surplus serotonin autoreceptors play the same role in humans as in mice.
"To generalize our findings to humans, we need first to investigate whether individuals with high 5-HT1A autoreceptor levels are less responsive to SSRIs in clinical trials," Dr. Hen said.
"The next question is what mechanisms are triggered by these changes in serotonin levels in other parts of the brain to produce an antidepressant response."
Plausible Hypothesis
Commenting on the findings, Paul R. Albert, PhD, professor, senior scientist, and CIHR/Novartis Michael Smith Chair in Neurosciences at the Ottawa Hospital Research Institute, in Ontario, said the data are convincing. Dr. Albert, who was not involved in the study, was one of the first investigators to report an association between 5-HT1A receptors, gene repression, and depression in humans.
These data show that selective knock-down of 5-HT1A autoreceptors in adult mice by only 30% is sufficient to produce an "antidepressant-like" phenotype for at least some established behavioral assays. Interestingly, there was no effect on anxiety-like phenotypes.
"These studies provide important evidence for the model that 5-HT1A autoreceptors exert negative feedback inhibition on 5-HT neuronal firing, and that decreasing 5-HT1A receptors by only 30% is sufficient to enhance 5-HT neuron firing and 5-HT release in response to the SSRI fluoxetine; this correlated with a reduced latency in the behavioral actions of fluoxetine," Dr. Albert told Medscape Psychiatry.
He noted that the matching time courses of increased 5-HT release and behavioral actions of fluoxetine in mice low in 5-HT1A strongly suggests that the autoreceptor restrains SSRI responsiveness, and that blocking or reducing its expression enhances the response.
However, Dr. Albert also noted that 5-HT neurons can be regulated by other systems, such as dopamine and noradrenaline, and that compounds targeting these systems could act synergistically with reduced 5-HT1A autoreceptors to mediate antidepressant response.
Dr. Albert said that these new data match very well with the expected changes from the C(1019) resilience, compared with the G(1019) risk 5-HT1A promoter alleles, that are associated with major depression and were reported by his group in 2008 (Neuropharmacology. 2008;55:977-985).
"The G allele is expected to increase 5-HT1A autoreceptor expression, and the G/G genotype is associated with higher levels of 5-HT1A autoreceptors in depressed subjects. We, and others, have also associated the G/G genotype with reduced response to SSRI treatment, or vice versa, although this association needs further replication," Dr. Albert said.
This study was supported in part by NIMH, NARSAD, and AstraZeneca. Dr. Hen reports receiving compensation as a consultant for Braincells, Inc and from AstraZeneca in relation to the generation of novel antidepressants.
Neuron. Published online January 14, 2010.
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