SCIENTISTS IDENTIFY NEW PATHWAY OF ANTIDEPRESSANT ACTION

Scientists at UC San Francisco have discovered a new chemical pathway in the
brain by which the most common antidepressants may alter mood. The research
demonstrates that many popular mood modulators trigger chemical activity along
more than one track at a time. It shows too how a brain chemical, known as a
neurosteroid, might make a prime target for drugs to improve severe mood
swings.

The researchers are publishing their study in the November 9 issue of the
Proceedings of the National Academy of Sciences (PNAS).

Antidepressants such as Prozac, Paxil and Zoloft are thought to relieve
depression by increasing the availability of one of the body’s natural
mood-enhancing chemicals, the neurotransmitter serotonin. But the UCSF
experimenters examined the effect of these same antidepressants on an entirely
different chemical pathway—one increasingly thought to play a role in mood
regulation as well. It involves a natural brain compound called a neurosteroid,
only recognized in the last 10 or 15 years.

The scientists discovered that all three of these antidepressants, known as
SSRI’s, not only affect serotonin availability, but also greatly increase the
synthesis of a key neurosteroid—10 to 30-fold. The profound effect, they
found, comes from the SSRI’s ability to greatly boost the action of the final
enzyme involved in the synthesis of the neurosteroid in the brain.
“Each of these three serotonin reuptake inhibitors, or SSRI’s, shows a
dramatic positive effect on the levels of allopregnanolone, a steroid made in
the brain, which most likely modulates mood and plays a role in heightened
anxiety and depression found in severe premenstrual disorders and other
conditions,” said Synthia Mellon, PhD, senior author on the PNAS study and a
professor of reproductive endocrinology at UCSF.

“The study points to the likelihood that SSRI’s control mood by more than the
one pathway that has received most of our attention, and it suggests that the
steroids synthesized in the human brain may play a strong physiological role in
regulating anxiety and depression.”

Lead author on the PNAS paper is Lisa D. Griffin, MD, PhD, assistant professor
of neurology at UCSF.

Studies by other researchers have shown below-normal brain neurosteroid levels
among people with some depressive disorders, and SSRI’s such as Prozac have
been shown to elevate these brain steroid levels and alleviate symptoms of
anxiety and depression among women suffering from a severe premenstrual
disorder, Mellon and Griffin said.

Since the disorder occurs during a specific phase of the menstrual cycle,
researchers have deduced that it is affected by levels of ovarian hormones such
as progesterone. Subsequent studies, in rats, showed that Prozac does increase
levels of the neurosteroid allopregnanolone, a derivative of progesterone, they
said.

As a result of these and related studies, the brain’s allopregnanolone has
become a focus of interest in the continuing search for the body’s natural mood
modulators and what regulates them. The study reported by Mellon and Griffin
clarifies the specific way SSRI’s lead to increased neurosteroid levels.

Interest in allopregnanolone has also been spurred by the fact that it is
synthesized in the brain, unlike most of the body’s potent steroids which are
made in the sex glands. The term “neurosteroids” was coined to reflect the
rather unexpected fact that the brain is the site of the steroid’s synthesis.

While it is widely assumed that SSRI’s relieve depression through their effect
on the neurotransmitter serotonin, their effect on the neurosteroid
allopregnanolone follows a different route: the so-called GABA pathway. In this
pathway, the steroid boosts mood-enhancing neurotransmitter receptors by
increasing how many and how long certain openings in the neuron’s membranes
—called GABA ion channels—remain open. (The anti-anxiety medication valium
works by stimulating this GABA pathway.)

To study the effects of the antidepressants on allopregnanolone, Griffin,
Mellon and their laboratory colleagues cloned from both rat and human tissues
the DNA (cDNA) of the intermediate enzymes known to be the key players in
synthesizing the neurosteroid.
They subjected both the rat and human enzymes to the antidepressants in
solution. They tested the three SSRI’s and a tricyclic antidepressant known as
imipramine.
The scientists found that each of the three SSRI’s greatly increased the
affinity of both the rat and human enzyme 3-alpha HSD for the steroid
precursor, resulting in surges of allopregnanolone synthesis. The tricyclic
antidepressant showed no such effect.
Mellon says the research strengthens the likelihood that the enzymes that
synthesize neurosteroids can make prime targets for mood-regulating drugs.

“We’re interested in finding compounds that may directly affect these enzymes
in the brain, and thus regulate mood disorders with minimal side effects,” she
said.

The research was supported by the National Institutes of Health and the
National Alliance for Research on Schizophrenia and Depression.