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Laughing all the way ... out of depression

Unyielding depression? Laughing gas might get you through the worst of it

The dentist's office might be the last place you'd look to find a quick cure for an implacable bout of depression. But new research suggests that laughing gas -- the mixture of nitrous oxide and oxygen that eases the pain and anxiety of having dental work -- may help banish treatment-resistant depression in about the time it takes to fill a cavity.

At concentrations used in dentist's offices, and in the latest study, laughing gas can induce euphoria, disorientation and mild sedation. The experience is sought out by some drug abusers, who inhale the propellant in jarred whipped cream for a fleeting high.

But it is actually another legitimate sedative-turned-party-drug, ketamine, that prompted researchers to explore whether nitrous oxide might have a rapid anti-depressant effect.

A growing number of studies in recent years has shown that when it is infused at low levels, ketamine has a rapid and powerful antidepressant effect in patients with severe and unyielding depression. As an anesthetic or party drug, ketamine induces a euphoric "out-of-body" high. But when administered to the suicidally depressed, it is thought to be a promising "rescue" drug that offers relief quickly, filling the four-to-six-week gap needed for many standard antidepressant medications, including Zoloft and Prozac, to take full effect.

Like ketamine, nitrous oxide is an antagonist of the brain's NMDA receptor, a key bit of the cerebral machinery that makes the brain hum. Working together, psychiatrists and anesthesiologists at Washington University in St. Louis, wondered whether nitrous oxide -- a far less addictive drug than ketamine, and one that pharmacologists consider less likely to have unforeseen side effects -- might have the same benefits.

In a small pilot study published Tuesday in the journal Biological Psychiatry, the researchers compared the effects of an hour of inhaled nitrous oxide with an hour of an inhaled placebo on 20 patients whose depression had failed to yield to standard antidepressants. Each subject had a session of laughing gas as well as a placebo, spaced a week apart, and the researchers gauged the patients' depressive symptoms two hours after their session, 24 hours later and a week later.

One day after nitrous oxide treatment, three patients reported that their symptoms had disappeared almost completely, while another seven reported significant improvement. Seven patients reported mild improvement in their symptoms. No patients said their symptoms worsened after treatment with nitrous oxide.

A day after they received the placebo treatment, none of the patients reported their depression was virtually gone, and one patient reported feeling worse the next day. But as is common in antidepressant trials, some placebo effect was evident: five patients reported feeling mild improvement and two reported significant improvement in their symptoms a day after receiving the sham treatment.

Washington University anesthesiologist Dr. Peter Nagele said it's still a mystery why nitrous oxide or ketamine would have such a rapid antidepressant effect, because the molecular mechanics of depression are themselves poorly understood. It's clear that NMDA receptors -- docks throughout the brain at which the neurotransmitter glutamate can anchor -- play a key role in depression. But how ketamine or nitrous oxide change glutamate's action to restore hope and reduce feelings of guilt and worthlessness, said Nagele, "is the million-dollar question."

What is clear is that nitrous oxide is "a much more benign drug" than ketamine, which has clear addictive qualities, said Nagele, and that, if dentists can use it in their offices without anesthetists present, it is relatively simple to administer. That said, the drug is not without side effects: Three depression patients reports nausea and vomiting, two complained of headache, and three reported anxiety or panic attacks after the nitrous dose.

More theoretical safety issues, however, would also need to be addressed if laughing gas were to become a widely used bridge back to mental health. Briefly after receiving nitrous oxide, patients in other studies have shown temporarily altered metabolism of vitamin B12. With prolonged use, that side effect might theoretically cause disturbances of nerve conduction, inhibition of red blood cell production in the bone marrow, or folic acid deficits, an issue for women who might become pregnant.

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