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Why is it so hard to find an antidepressant that works?

Upset / depressed woman

QUESTION: My sister suffers from depression and she has been prescribed several different antidepressant medications. While she feels marginally improved, her doctor is about to start her on a new drug to see if she can do better. Why is it so hard for some patients to find the “right” antidepressant?

ANSWER: Only about one-third of depressed individuals experience what’s called “sustained remission” within a few weeks or months after starting an antidepressant medication.  The lucky one-third has no depressive symptoms and stays that way for an extended period of time.

The majority of patients, however, must try several different drugs before finding one that produces the best results. Some of them may feel improvement on a particular drug, but are unable to continue with the treatment because they can’t tolerate the drug’s side effects. As a result, they switch to another medication. And they may change again if the next drug doesn’t work.  They might end up taking a combination of different drugs to get the desired effect.  And, unfortunately, a third of patients don’t receive any meaningful benefit from antidepressant medications.

The reason why it’s so hard to match a patient with the right drug arises from the fact that depression isn’t just one ailment.

“It is many, many different disorders,” says Dr. Ayal Schaffer, a psychiatrist and head of Mood and Anxiety Disorders at Sunnybrook Health Sciences Centre.

“There could be two people who have nothing in common in terms of their experiences or their symptoms,” yet both patients would get the same diagnosis of depression, says Dr. Schaffer who is also an Associate Professor in the Department of Psychiatry at the University of Toronto.

One patient, he explains, could be very sad, sleeping all the time, guilt-ridden and feeling suicidal. The other may be very irritable, agitated and restless, not sleeping well and feeling very anxious about the future.

Furthermore, the underlying causes of their mental health problems could be very different.

Doctors must use their clinical judgment – and a bit of guesswork – when they are prescribing an antidepressant to a patient for the first time.

There are almost 40 different antidepressant drugs that act on one or more neurotransmitters – serotonin, norepinephrine and dopamine – which are the chemical-messenger systems in the brain.

Dr. Schaffer says patients are less likely to respond rapidly to treatment if they are also afflicted with other mental health problems, such as being prone to substance or alcohol abuse.

“Those sorts of things are negative prognosticators and suggest that an antidepressant, on its own, may not be enough and you probably need to do other things to address these other factors,” he says.

The longer patients go without getting proper treatment can also hamper their recovery. “If someone has been depressed for years, many things will have changed in their lives,” he notes. “Their view of themselves has changed, their self-esteem has been affected.”  Prolonged depression also takes a toll on personal relationships, as well as work or school life.

Given the complexity of this disorder, maybe we shouldn’t be surprised that many patients fail to respond to the first course of treatment.

Even so, doctors and researchers think they will eventually be able to minimize the trial-and-error in drug selection.

Using high-tech brain imaging, blood tests, and reams of data from clinical trials, they are searching for patterns that will help predict which drugs are most likely to benefit individual patients.

Numerous studies are now underway.

“This [area of research] represents a promising development, made possible by sophisticated neuro-imaging and more economic ways to look at genome-wide associations,” says Dr. Sidney Kennedy, a professor of psychiatry at the University of Toronto and lead of the Canadian Biomarker Integration Network for Depression program.

His multi-centre study – dubbed CAN-BIND – is sponsored by the Ontario Brain Institute with additional funding coming from the Canadian Institutes for Health Research.

Essentially, Dr. Kennedy and his co-researchers hope to classify the different subtypes of major depression and identify the “biomarkers” associated with each one of them. This information should help doctors make a relatively fast and accurate diagnosis as well as guide treatment selection.

Previous research using MRI imaging, already suggests that there are distinct structural and functional differences in the brains of depressed patients compared with healthy people. Genetic studies might also help pinpoint patients who are prone to develop depression and the treatments that are most likely to help lift them out of a debilitating mental state.

In the first in a series of studies, the team has been examining the response of 200 people to treatment with a commonly prescribed selective-serotonin reuptake inhibitor (SSRI). For those who don’t respond after eight weeks, the team has been observing what happens when the treatment is modified.

Dr. Kennedy says the researchers will need to collect information on thousands of patients before they can draw definitive conclusions.  Fortunately, “there are a number of other groups in the United States and Europe who are doing similar work,” he adds.  “This could allow a pooling of data.”

What’s more, Dr. Kennedy’s team has obtained blood samples from patients who participated in other large clinical trials associated with a new antidepressant drug.  “The pharmaceutical company provided several thousand blood samples – at no cost and with no strings attached,” he says. The samples have been analyzed in several laboratories linked to the CAN-BIND program to identify clues about why some people responded to treatment and others did not.  The group will present preliminary findings this week (June 11, 2015) at the annual meeting of the Canadian College of Neuropsychopharmacology in Ottawa.

Of course, those findings will need to be confirmed by other studies. It will take some time before all this promising research leads to changes in the way patients are diagnosed and treated.  What are patients supposed to do in the meantime?

Dr. Schaffer suggests that it’s important to manage patient expectations. If the bar is too high, it may set them up for failure.

“People who have debilitating severe depression may take a while to fully respond to treatment,” he says.

Still, Dr. Schaffer points out that 60 per cent of depressed people will get at least some positive response when they begin taking an antidepressant.

“If a patient has just gone through years of depression and feels 30 per cent better [after starting an antidepressant], I would say that’s wonderful – and now how are we going to build on that?”

With more energy, the patients might be able to do things that will aid their own recovery and give them a sense of accomplishment.

“Once people start to do more, it has a very positive effect on their mood and on their self-esteem,” he adds. Regular exercise and better nutrition can contribute to their sense of wellbeing. “It’s not just about what the medication can do.”

Psychotherapy might also benefit some patients, although limited public funding for this type of treatment can be an additional obstacle to recovery.

Dr. Schaffer readily acknowledges that it can be difficult to take the first steps on the path to improved mental health. “Depression is cruel because it affects people’s ability to do the things they need to do to get out of their depression,” he says.

“For many people, depression is a life-long condition. That doesn’t mean they are depressed for their whole life, but that they are vulnerable to experience depression and may have some symptoms of depression if they are not in a full state of remission.”

He adds that maintaining a sense of hope is critically important.

“It is a long, frustrating road and I see my patients struggle through that process. We would love to know immediately what is going to be the right treatment. But, ultimately, the only choice they have is to keep going,” says Dr. Schaffer.

“Eventually, most people do get better. They just have to keep trying and trust that, at the end of the day, there is going to be benefit from the treatments.”


About the author

Paul Taylor

Paul Taylor retired from his role as Sunnybrook's Patient Navigation Advisor in 2020. From 2013 to 2020, he wrote a regular column in which he provided advice and answered questions from patients and their families. Follow Paul on Twitter @epaultaylor