In Your Head?

A new study provides insight into the molecular characteristics that make a brain susceptible to anxiety and depression and less likely to respond to treatment with antidepressant medication. The research, published in the journal Neuron, may lead to more effective strategies for treating depression, a major health concern throughout the world.

Although brain mechanisms associated with depression and anxiety are not completely clear, recent research has implicated a combination of stressful life events and predisposing biological factors as playing a causal role in depressive disorders. The most popular antidepressant medications, such as the commonly prescribed selective serotonin reuptake inhibitors, increase serotonin levels in the brain.

"Unfortunately, more than half of all depressed patients fail to respond to their first drug treatment," explains senior study author Dr. Rene Hen, from Columbia University. "The reasons for this treatment resistance remain enigmatic. Elucidating the exact nature of both the factors predisposing to depression and the mechanisms underlying treatment resistance remains an important and unmet need."

Previous studies in humans have suggested that regulation of serotonin receptors may be linked with depression and the response to antidepressants. The serotonin-1A (5-HT1A) receptors are found in the serotonin neurons themselves (autoreceptors), where they inhibit serotonin release, and in target areas that receive serotonergic innervation (heteroreceptors). The autoreceptors are critical for setting the "serotonergic tone" in the brain. Interestingly, a recently identified genetic alteration in humans that may regulate 5-HT1A autoreceptor levels has been linked with susceptibility to depression and a decreased response to drug treatment.

Dr. Hen and colleagues developed a novel system with which they could specifically manipulate autoreceptors without altering heteroreceptors. Mice that had higher levels of autoreceptors exhibited a blunted physiological response to acute stress, increased behavioral despair, and no behavioral response to treatment with antidepressants. Interestingly, when 5-HT1A autoreceptor levels were reduced prior to antidepressant therapy, mice that did not initially respond to therapy were converted to therapy responders.

"Taken together, our results establish a causal relationship between 5-HT1A autoreceptor levels, resilience under stress, and response to antidepressants," concludes Dr. Hen. "We predict that treatments aimed at increasing serotonergic tone prior to beginning SSRI administration might prove to be efficacious and possibly faster-acting antidepressant therapies, particularly for individuals with higher autoreceptor levels."