Medications are a common and often effective treatment for depression, but they are far from perfect. In fact, in some cases meds have proven to be no better than a placebo, and some patients don’t respond to any of the drug options currently available. “We have 50 years of depression research, but drugs have not been effective in stemming the tide of suicide. You are more likely to die of suicide than breast cancer, and in teens the most common cause of death is suicide, not accidents or other medical problems,” adds Dr. John H. Krystal, chair of the department of psychiatry at Yale University School of Medicine and chief of psychiatry at Yale-New Haven Hospital. “Ineffective treatment is a huge clinical challenge, and it has huge societal implications.”

But there are some promising new developments in treating depression with medication. Researchers are finding that combining certain classes of medication increase their effectiveness. New chemical possibilities are being researched and may provide additional options for patients in coming years. Combined with the research into the genetic markers of an individual case, physicians will soon be able to better predict which medicines work best with which patients, reducing the time and cost it takes to find an effective treatment.

All these developments lead Krystal, a member of the American Psychiatric Association’s Council on Research, to declare: “This is an extraordinarily hopeful time for the treatment of depression.”

[Read: Is Depression a Disease?]

New Combinations of Drugs

From the time drugs were first developed to treat depression back in the 1950s to today, they have all worked through similar biochemical actions, Krystal says. The most commonly known and prescribed class of drugs is the selective serotonin reuptake inhibitor, or SSRI. These drugs, which include the brands Prozac, Zoloft, Paxil and Lexapro, regulate the amount of serotonin, a brain chemical called a neurotransmitter that carries signals between neurons and is thought to regulate mood. “They have been helpful for many people, and they are easier to adhere to treatment relative to earlier classes of depression medications,” Krystal says. “But the rate of response to is not as high as we need it to be.” Studies have shown that only 1 in 3 patients respond to SSRIs, in fact, and even for those it can take several weeks before improvement is seen.

About 20 years ago, Dr. Steven E. Hyman, then the director of the National Institute of Mental Health, commissioned the important STAR*D trial, which looked to “add something to goose the SSRI treatments.” This trial found that response rates could be raised from the initial 30 percent to as high as 70 percent if patients either switched SSRIs, combined two SSRIs or added a low-dose second-generation antipsychotic such as aripiprazole, quetiapine and olanzapine plus fluoxetine. “The importance of this trial was these were real-world cases,” says Hyman, now the director of the Stanley Center for Psychiatric Research at Broad Institute of MIT and Harvard.

And a large study conducted by the Department of Veterans Affairs, called VAST-D, recently replicated these findings, showing that adding an antipsychotic was more effective than simply switching to another antidepressant or adding a second antidepressant on top of the first. The increase in effectiveness was modest, Krystal says. “But if you are one of those people who responded, that is very meaningful,” he says. “And a 5 percent change among 10,000 patients in a big health system can equal a lot of people.”

[See: Am I Just Sad — or Actually Depressed?]

New Drug Options

The most exciting new development in drug treatment, however, is with ketamine. This drug, sometimes used recreationally — and unadvisedly — as the street drug Special K, has shown remarkable results in people who don’t respond to other treatments. It is currently administered by infusion and requires close monitoring for a few hours because of its hallucinatory side effects. But once those side effects dissipate, patients report their symptoms improve almost immediately. “Those results are holding up in clinical trials,” Hyman says. “Frankly, it is wonderful, even though it has side effects, to have something that acts rapidly.”

Numerous researchers are working to develop versions of ketamine that can be administered in other ways, including as an oral medication or a nasal mist. Krystal, who shares a patent on a ketamine derivative, is one of them. An early pioneer in this area of research, Krystal and his colleagues noted that available antidepressants all targeted chemical systems like serotonin and dopamine that worked in “primitive” areas of the brain, he says. “Higher centers of the brain use different chemicals, like glutamate and GABA. We thought depression might lie with these chemicals, so we probed that system.” One of the few drugs available for glutamate signaling was ketamine, which was already being studied to treat schizophrenia. They tried it on depression.

“It far exceeded our expectations,” Krystal says. “We have seen, in study after study, instead of waiting two months for a response, we could see a high rate of response in 24 hours.” It may be a few years before any of these ketamine treatments are FDA-approved, but because the drug is already approved for other uses, some psychiatrists are prescribing it for depression anyway.

[Read: Why Your Antidepressants Stopped Working — and What to Do About It.]

What the Future Holds

The future of drug treatment for depression, as with for many other diseases, lies in the genetic code. “Everybody in depression treatment is in need of stratifying patients into more homogeneous groups,” Hyman says. “The industry is looking for a way to know who might respond to which drugs.”

Enter genetics. While there is no single gene that causes depression or any other mental illness, researchers are analyzing large data sets to predict how certain genetic patterns lead to certain types of mental illness, and which medications, if any, are most likely to work. This is the exciting new world of personalized medicine, also known as precision medicine. “All the breakthroughs in cancer and heart disease research are also taking place in psychiatry,” Krystal says. “Some people have the impression that all people with depression are alike, but you really need to know a lot about the patient to appropriately prescribe medication for them. The practice is being transformed in this generation to involve careful diagnosis, matching treatments to subgroups and individuals and understanding brain chemistry and wiring to point to novel treatments.”

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What New Depression Drug Possibilities Exist for People Whose Medications Don’t Work? originally appeared on usnews.com