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David Baxter PhD

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Have we been treating depression the wrong way for decades?

by Adam Miller, CBC News Second Opinion
August 31, 2022


A recent analysis paints a compelling picture that depression isn't caused by a chemical imbalance in the brain. But experts say this is already widely accepted and it's also true that antidepressants can be extremely beneficial to some patients — even if we don't know exactly why. (Shutterstock / Chanintorn.v)

This is an excerpt from Second Opinion, a weekly analysis of health and medical science news. If you haven't subscribed yet, you can do that by clicking here.

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 may also leave patients with more questions than answers as the 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 experts have doubted this, feeling it oversimplified 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 have largely worked as 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. Many experts 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 in the 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.

Living alone during pandemic can exacerbate anxiety, depression: 2 years ago. Duration 2:02

The ongoing physical distancing precautions because of the COVID-19 pandemic can exacerbate anxiety and depression, especially for people living alone.

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] is a 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 have caused 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 estimated one 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."


A bottle of antidepressants is shown in Miami, Fla. A new analysis suggests depression isn't caused by low serotonin, and that antidepressants are ineffective at treating it. (Joe Raedle/Getty Images)

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 is by 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 have reported in patients is "emotional numbing," where they not only don't have unwanted 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 undermining the 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.

Research shows how exercise helped fight pandemic depression, 7 months ago, duration 2:04

A study conducted by B.C. researchers during the COVID-19 pandemic showed how exercise, especially a combination of yoga and high-intensity exercise, helped fight depression – backing up decades of research on how exercise improves mental health.

"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 more and 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 a general anesthetic first approved in Canada in the 1960s for medical or veterinary surgery, as well as a psychedelic party drug sold on the illicit market. It's also increasingly being used as a fast-acting and effective treatment for depression in low doses, by working to restore 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," Gratzer said.

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


Daniel E.
Another good thing about being on any medication is you need a prescriber -- another person in your support network. That's why I pay a little more to see a psych provider that I like and can reach easily. I don't want the "drive thru" experience.

And though some people do well on a relatively low dose of medication like SSRIs, some people would have done better on a higher dose:

Most patients being prescribed an SSRI to treat their depression never receive the dose that according to recent meta-analyses is most likely to effectively combat their condition [>20 mg citalopram, >10 mg escitalopram, >10 mg fluoxetine, >10 mg paroxetine or >50 mg sertraline]. The lack of consensus regarding effective dosing of SSRIs may have contributed to this state of affairs.

And, of course, few people would suggest that someone taking antipsychotics is mostly experiencing placebo effects. In the case of my husband's bipolar disorder, therapy has not done much for him, but Zyprexa, relatively speaking, was a miracle pill. Me being on a SSRI like Prozac or Zoloft makes me a less irascible, more easy going partner as well. So why the disparity in how people view the effectiveness of SSRIs vs. antipsychotics, especially since "a number of recent studies have demonstrated both the safety and efficacy of antidepressant monotherapy in treating bipolar II depression."
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Daniel E.
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 have largely worked as a placebo.

The same researcher suggests that COVID-19 vaccines are overrated:


Additionally, it should be noted that Moncrieff doesn’t exactly have a reputation for impartiality. She has spent years questioning SSRIs as well as the classification of depression as a mental illness, Rolling Stone reported. At one point, Moncrieff said there could be evidence to support the conspiracy theory that drug companies are purposing hiding information about the side effects of SSRIs.

Black said this incident concerned him because it’s a situation in which people misrepresented science to distort what is known about treatments for psychiatric conditions.

“Many people will be drawn in by the misinformation that the latest study ‘proved that antidepressants don’t work,’ when in fact the study did not show that,” he said. “We have overwhelming evidence that they do work, and the entire paper is an effort by biased professionals who have a history of only portraying medications in a negative light.”
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Daniel E.
From an interview with Thomas Insel, former director of NIMH and author of Healing:

Most of the time when you talk about serious mental illness, that means schizophrenia, bipolar disorder, severe depression, perhaps eating disorders. But most of the time when you talk about treatments, people immediately get into a conversation about medication. Is America overmedicated? Is it undermedicated? Are the medications actually safe and effective? All of that is a conversation we have to have.

I think it's important to realize that medication may be a necessary part, but it's a completely insufficient part of the care of somebody with a serious mental illness. There are psychological supports that are critical. There are family interventions that are really effective in some ways as what you see with medications. There are extraordinarily important forms of rehabilitative care, like housing support and supportive employment [and] education, things that help people to get a life.
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Daniel E.

One way to improve results would be to distinguish between patients with severe depression, for whom SSRIs are most likely to be effective, from patients with less severe depression. But the diagnostic criteria doctors use may not be up to the task.

In 2010, Dr. Jay Amsterdam, then director of a large mood disorder clinic at the University of Pennsylvania's Perelman School of Medicine, used his own questionnaire to measure severity among patients.

For those with "very severe" depression, the results of SSRI medications were "markedly superior" to the placebo. For depressed patients with moderate symptoms, the drugs were no better than placebo.

Daniel E.
Personally, I am back to a low dose of Abilify along with Prozac for OCD/anxiety/depression.

From 2014, regarding augmentation for depression:

"Using Cochrane review methodology, they found 12 relevant randomized controlled trials, and despite some methodological concerns they concluded that augmentation of SSRIs with lithium or an atypical antipsychotic drug is likely to be beneficial in patients with treatment-resistant depression, and that there was no statistically significant difference between the 2 augmentation strategies."

Regarding antipsychotics like Abilify:

"Antidepressants alone may not be enough for adults with major depressive disorder. Aripiprazole (Abilify) can be taken alongside antidepressants to treat symptoms of depression."

"Aripiprazole also acts as a dopamine D2 partial receptor agonist, and has a possible action at adrenergic receptors. Furthermore, aripiprazole may have possible neuroprotective effects."

Daniel E.
Other SSRI alternatives/augmentors include Wellbutrin (bupropion) and Buspar (buspirone).

SNRIs are a close alternative to SSRIs, and so SNRIs not added to a SSRI. This is due to potential interactions like serotonin syndrome.

"The main difference between SSRIs and SNRIs is that SSRIs prevent the reuptake of serotonin and SNRIs prevent the reuptake of serotonin and norepinephrine. Serotonin and norepinephrine are substances that the brain uses to send messages from one nerve cell to another."
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