Modern anti-depressants, for which Americans spent more than $5.6 billion last year, have been a huge boon, partly because they have few disastrous side effects, even in overdose.
With older, “tricyclic” anti-depressants like Elavil, for instance, “a 10-day supply could kill you,” says Dr. Michael Jenike, associate chief of psychiatry at Massachusetts General Hospital. The newer drugs, called SSRIs, or selective serotonin reuptake inhibitors, are rarely fatal.
The leading SSRIs — Prozac, Zoloft and Paxil — also sidestep a hazard of older anti-depressants: MAO inhibitors like Nardil and Parnate can cause a fatal rise in blood pressure when taken with red wine, aged cheese and other foods.
But for all their magic against both depression and anxiety, the SSRIs do have drawbacks. Like the older drugs, they can take weeks to kick in. They can also cause sexual dysfunction (lack of orgasm) and, initially, agitation. (A fourth SSRI, Luvox, which combats depression but is approved for obessessive compulsive disorder, may be somewhat less likely to cause sexual dysfunction.)
Worse yet, the SSRIs don’t work for nearly a third of the people who try them.
This is frustrating for the 18 million Americans who are depressed and 23 million more who are anxious, but it’s strong motivation for drug companies racing to find better drugs.
And they are, including new classes of anti-depressants designed to act through entirely different pathways in the brain — drugs that block a brain chemical called substance P and others that block CRH, corticotropin releasing hormone.
Spurring this effort is an explosion of basic knowledge about the brain, some of which will be presented this week in Washington by the Dana Alliance for Brain Initiatives, a nonprofit organization involving more than 185 neuroscientists.
“For four decades, we have been increasingly perfecting anti-depressant drugs,” says Dr. Steven Hyman, director of the National Institute of Mental Health. “Now, for the first time. . .we are beginning to see the possibility of real alternatives.”
Much of the excitement comes from the growing recognition that an almond-sized brain structure called the amygdala plays a central role in the processing of fear and almost certainly in depression and chronic anxiety as well.
The amygdala is rich in receptors for substance P, a brain chemical originally thought to transmit pain signals but now believed to be more important for depression and anxiety. The amygdala is also rich in receptors for CRH, the stress hormone.
At the same time that drug makers are scrambling to find drugs to block CRH and substance P, they are scurrying to improve the current SSRIs, which combat depression and anxiety by increasing levels of a brain chemical called serotonin in the synapse, or space, between nerve cells.
Scientists have never proven that depression is caused by a deficiency of serotonin, but they have found low serotonin levels in studies of people who are aggressive or suicidal, says Dr. Peter Whybrow, director of the neuropsychiatric institute at UCLA. Increasing serotonin, he adds, is a “fulcrum where one can intervene,” but there may be even deeper root causes of depression yet to be found.
In recent years, scientists have discovered that there are at least 15 subtypes of serotonin receptors on brain cells, as well as subtypes for two other neurotranmitters, norepinephrine and dopamine, that are also involved in depression.
This is crucial information: It means scientists should be able to tailor a drug so it acts on some receptors and not others, keeping anti-depressant activity high while minimizing side effects like time lag to efficacy and sexual dysfunction.
Here’s how it works: An electrical signal travels down one brain cell, telling it to release serotonin into the synapse. The serotonin lands on “post-synaptic” receptors across the synapse in the next cell, triggering new signals in that cell.
Serotonin then floats back toward the first, or presynaptic, cell, which sucks some of it in through a “re-uptake pump” to be recycled for further use. It is this re-uptake system that the current SSRI drugs block.
But brain cells also have “autoreceptors” that interact with serotonin in another way — by telling the cell when there’s enough serotonin in the synapse that no more needs to be made, in essence, a negative feedback loop.
Scientists now think that one reason it takes so long for SSRIs to kick in is that it takes weeks for the cell to learn to “ignore” this feedback and start making more serotonin, says Dr. Scott Ewing, director of the depression and anxiety service at McLean Hospital in Belmont. By tinkering with drugs aimed at these autoreceptors, he says, it should be possible to make drugs that work faster, though none are available yet.
Similarly, better knowledge of receptors has led to drugs like Serzone and Remeron, which have fewer sexual side effects because they block certain post-synaptic serotonin receptors.
A new SSRI, Celexa, approved last fall, avoids still other pitfalls than standard SSRIs by triggering fewer interactions with other drugs.
Researchers are also discovering other ways to help people who don’t respond to standard drugs. For instance, some data suggest that taking a blood pressure drug called pindolol with an SSRI makes the SSRI act sooner by acting on the presynaptic autoreceptors to stop the negative feedback loop.
SSRIs can also be made more effective by taking them with other drugs like lithium (normally used for manic-depression), a synthetic thyroid hormone called T3, an anti-anxiety medication called Buspar or tricyclic anti-depressants, says Ewing.
Sometimes, combining two “atypical” anti-depressants like Wellbutrin, Effexor, Serzone or Remeron, also helps people who have not responded to other drugs.
The bottom line is that “if you’re doing well on your current anti-depressant and can stand the side effects, stay on it,” says Ewing. After all, anything you switch to may bring new side effects. “It’s a mistake to go off a drug you’re responding to.”
But if you’re not responding well, don’t give up. Psychotherapy, the talking treatment, can be very effective, even without medications, for many people. The herbal antidepressant St. John’s Wort seems to help many people, too.
And if you do want to switch to a different prescription anti-depressant, talk to you doctor. If he or she can’t provide an answer, see a psychiatrist or psychopharmacologist. Remember: Depression and anxiety are highly treatable problems.
SIDEBAR
Some of the new anti-depressants in the pipeline
Substance P blockers: In terms of published data, Merck Research Laboratories is the leader. Six months ago, it reported in Science that its drug MK-869, worked as well as Paxil in depressed people. Since then, the company says it has finished an unpublished study with less clear results and is now pursuing an unnamed substance P blocker it feels is more potent.
A number of other companies, including Pfizer Inc. and Eli Lilly & Co. are also working on substance P blockers.
Corticotropin releasing hormone (CRH) blockers: Published data are scanty, but informal reports “look promising,” says Dr. Steven Hyman, director of the National Institute of Mental Health. A 1998 study in Munich showed that mice missing a receptor for CRH exhibited reduced anxiety and stress, suggesting that CRH blockers might be effective in humans.
Improvements to SSRIs, or selective serotonin reuptake inhibitors. Many companies are working on this. Lilly and Sepracor are working on R-fluoxetine, a Prozac variant with fewer side effects. Celexa, already on the market by Forest Laboratories, Inc., causes less agitation than standard SSRIs.
Other serotonin-based drugs. Solvay Pharmaceuticals is working on flesinoxan, which boosts serotonin by increasing the activity of a particular receptor called 5-HT1A.
Norepinephrine reuptake inhibitors. This is a new class of drugs that would boost a different neurotransmitter, norepinephrine. So far, Pharmacia & Upjohn’s drug, reboxetine, appears closest to getting approval for marketing.
RIMAS, or reversible inhibitors of monoamine oxidase. The idea is to tinker with MAO inhibitors so a patient doesn’t have to follow a special diet. A drug called moclobemide is already on the market in Great Britain, Canada and Europe to do this. It’s not clear whether any company will bring it to market in the US.
Glutamate drugs. Some scientists think this important neurotransmitter may play a role in depression, as it does in Alzheimer’s disease and schizophrenia. Lilly is exploring this.
Herbal antidepressants. The leader is St. John’s Wort, already shown to be effective in European studies. McLean Hospital is studying a sustained release form of the drug. There’s another study at 12 centers nationwide. If you want to participate, call 617 855 2862 for the first study, or 919 668 8991 for the second. (On the web, you can find out more about the second study at http://hypericum.rti.org.)