Have we been treating depression the wrong way for decades?

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A new analysis of the cause of depression has seemingly upended what we know about this common condition and challenged the use of antidepressants. But it mayalso leavepatients with more questions than answers asthe science evolves.

A systematic umbrella review of 17 studies published in Molecular Psychology on July 20 looked at the decades-old theory that depression is caused by low serotonin, and found there was "no consistent evidence" of "an association between serotonin and depression."

The theory that depression is caused by a chemical imbalance in the brain has been around since the 1960s. But for years, many expertshave doubted this, feeling itoversimplified a complex condition.

"The serotonin theory is very old and has been very popular since the '90s, when the pharmaceutical industry started promoting it," said Dr. Joanna Moncrieff, a psychiatry professor at University College London and lead author of the study.

"But since about 2005, probably a bit before then, there's been sort of rumours that actually the evidence isn't very strong, or it's inconsistent. Some studies are positive, some studies are negative, but no one's really got that evidence together anywhere."

Moncrieff and her team set out to challenge the serotonin theory in a systematic review of available research. They also went a step further in their conclusion by suggesting that antidepressants are ineffective at treating depression and havelargely workedas a placebo.

"Evidence from placebo-controlled trials show that antidepressants are a little bit better than a sugar tablet," she said. "And if that little difference is not to do with rectifying a chemical imbalance, improving low serotonin levels, what is it to do with?"

The research paints a compelling picture that depression isn't caused by low serotonin alone. Manyexperts say this is already widely accepted and that it's also true that antidepressants can be extremely beneficial to some patients even if we don't know exactly why.

So where does this leave patients and physicians, and could the analysis impact the way we treat depression inthe future?

Are antidepressants effective against depression?

Antidepressants are widely believed to affect the behaviour of neurotransmitters, chemical messengers in the brain like serotonin and dopamine, in a way that can alter emotions and mood to help improve the symptoms of depression in some patients.

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People with depression can face a wide range of symptoms, including persistent feelings of sadness and desperation, changes in appetite, sleep deprivation, fatigue, irritability and loss of interest in hobbies and social connections that can impact everyday life.

While it's unclear exactly how antidepressants work at a biological level to alleviate those symptoms, it's clear that they can still be hugely helpful to some patients.

"It's a typical discovery in medicine you find a drug that works, but you don't quite know why," said Dr. Phil Cowen, a professor of psychopharmacology at the University of Oxford.

"[The review] isa debunking exercise and in a way, they're criticizing older studies that were hard to do," he said. "These [older] studies, clearly, were very indirect and they're messy, and I don't think anyone thought that they were that great."

Moncrieff's team found that some depressed patients actually had higher serotonin levels in certain areas of the brain, and in some cases the long-term use of antidepressants could actually lower the amount of serotonin though the findings were "inconsistent."

"I think it makes a huge difference, because how [antidepressants] work actually influences whether they work," she said. "It influences how helpful we think they are."

The findings havecaused a major stir in the media and scientific community, with hundreds of news outlets covering the study quickly landing it in the top five per cent of all research scored by Altmetric, a company that analyzes where published research is shared.

Findings of this perceived magnitude can have a seismic impact on the way we understand and treat a widespread condition like depression, which affects an estimatedone in eight Canadians at some point in their lives.

While the research questions the very nature of what we know about depression, many doctors are hesitant to change the way we treat it.

Antidepressants can be 'lifesaver' for some

Dr. David Juurlink, head of clinical pharmacology at Sunnybrook Health Sciences Centre in Toronto, said he's not surprised by the findings, because the chemical imbalance theory for depression is now widely seen as an "obvious oversimplification" for a complex condition.

"Although I think doctors prescribe serotonin-enhancing antidepressants far too often, in part because of this oversimplification, it's important to acknowledge that they really do improve the well-being of some patients," he said in an email.

"How exactly they do that isn't as clear-cut as we've been led to believe."

Dr. David Gratzer, a psychiatrist and attending physician at the Centre for Addiction and Mental Health (CAMH) in Toronto, said he wasn't surprised by the findings just that they got as much attention as they did.

"This suggestion that depression is all about serotonin all the time hasn't been accepted by psychiatrists for many years, probably many decades," he said, adding that the researchers are "terribly biased" in their assessment of antidepressants.

"Their paper shows things are much more complicated than serotonin no surprise and then they turn around and say, 'You see, that's another example of the fact that antidepressants don't really work.' One doesn't necessarily give rise to the other."

Gratzer said he still prescribes antidepressants regularly as a treatment option for depression, and has no plans to stop doing so based on the research.

"That's not going to change. These medications work," he said.

"An antidepressant is not necessarily [recommended]in everyone who has depression some people might in fact do better with talking therapy but it is certainly a tool in our tool kit and, to be blunt,it's a lifesaver for some of our patients."

Research calls antidepressants into question

Moncrieff said the research found that another way in which antidepressants may function isby desensitizing the brain to negative emotions associated with depression. In theory, that could also impact other feelings.

She said one of the effects previous studies havereported in patients is "emotional numbing," where they not only don't haveunwanted emotions like depression and anxiety, but positive emotions like joy and happiness.

"There may be some people that feel that that's an effect they want.But I think generally, people aren't going to want to be emotionally numbed, not for long periods, anyway, and so I think it totally changes the sorts of decisions people might make about antidepressants," said Moncrieff.

Chris Davey, the head of the department of psychiatry at the University of Melbourne, said in an email that underminingthe confidence that people with depression have in their treatments can be"very damaging."

"People will stop their medications suddenly, without supervision," he said, "which can cause dramatic deteriorations in their mental health."

Davey said he is concerned that the paper diminished a treatment option that can be incredibly beneficial to some patients, especially when alternatives may not always be available to those at risk of severe depression.

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"This [research] shouldn't make any difference to the treatment of depression. I hope it makes people realize that depression is a very complex condition, and that there are no simple explanations for it," Davey said.

"Everyone should know that improving their diet, exercising moreand paying attention to their sleep can be helpful. Everyone should have access to psychotherapy. And for those people for whom those things don't help, that's when we think about medications."

Gratzer said there are many new areas of research into treatment options for depression that can be beneficial, including novel ways of delivering psychotherapy, emerging medications and discoveries like the use of ketamine.

Ketamine is ageneral anesthetic first approved in Canada in the 1960s formedical or veterinary surgery, as well as apsychedelic party drug sold on the illicit market.It's also increasingly being used as a fast-acting and effective treatment for depressionin low doses, by working torestore synapses in the brain that are destroyed by stress.

There's "an understanding that certain life experiences might be more connected, and so research is very active. Maybe at the end of the day, we'll understand depression isn't one illness," Gratzersaid.

"As is often the case with mental health care, these are early days."