What to know about depression and serotonin levels

What is the “serotonin hypothesis”?

The serotonin hypothesis is a version of the “monoamine hypothesis of depression.” Basically, monoamines are a group of chemicals that act as neurotransmitters in the brain. They include serotonin, dopamine, and norepinephrine. Way back in the 1950s, psychiatrists theorised that these chemicals were important for mood regulation, after discovering that some drugs seemed to be effective in treating depression by increasing the levels of monoamines in the brain. On the other hand, drugs which lowered monoamine levels often made some people more depressed.

This was a lightbulb moment where scientists thought they had finally discovered a biological explanation for depression. But this didn’t last for long. As Robert J Boland and Kelly Truong summarised in Psychology Today: “Most antidepressants take weeks to work even though they increase brain monoamine levels only a few hours after ingestion. Furthermore, even though there was an occasional positive finding, studies looking at how levels of monoamines in the brain correlate with symptoms of depression were inconclusive.”

As far back as 1965, Harvard psychiatrist Joseph Schildkraut was casting doubt on the serotonin hypothesis. Like Moncrieff he concluded that it was not possible to confirm or to reject the hypothesis.

Why did this theory persist?

Despite the fact that there has always been doubt cast on the theory that monoamine levels are key to treating depression, nearly all drug treatments for depression target one or more of them. And Serotonin is usually one of those.

Something Moncrieff highlighted in her study is that serotonin theory became an easy way to explain to patients what might be causing depression, describing it as a “chemical imbalance” – even if that might not have applied to everyone. “This biological explanation was perceived less stigmatising for most patients, who tended to blame themselves for something outside their control,” write Boland and Truong.

Is this study a game-changer?

The short answer is: not really. Since the monoamine theory emerged, thousands of scientists have questioned it and also added to knowledge about depression and its treatment. Most modern theories take an “integrative” approach, which basically means that a combination of chemical and social factors can cause depression. The “perfect storm” could include genetics, stress, a traumatic event and, yes, serotonin levels too. Every person is different.

In the simplest possible terms: for some patients, antidepressants are not necessary. But for others, they can be life-changing. Just as before, there is no evidence to suggest that they work for everyone who has depression.

Context is important too. In 2018, the largest ever meta analysis in psychiatry published in medical journal The Lancet found that, based on a large swath of evidence, that antidepressants proved effective. It also found some antidepressants could be more effective than others for some people.

What are mental health advocates saying about the study?

Stephen Buckley, Head of Information at mental health charity Mind, told Woo: “The specific action of SSRIs on the symptoms of depression has never been clear; equally it’s not well understood why SSRIs can alleviate the symptoms of depression in some people, but not in others.”

“There is very little credible evidence to support the idea that depression is itself caused by some imbalance in brain chemistry. Childhood experiences, difficult life events or other physical or mental health problems are all potential causes of depression. It’s vital that doctors treat the ‘whole person’ when supporting someone with depression and offer a range of appropriate treatments.”

Micha Frazer-Carroll, author of an upcoming book Mad World: the politics of mental health, highlights that Moncrieff’s study is not only about “antidepressants” but different models of depression treatment. “For decades, there has been a powerful, widespread public conception that depression is 'caused by a chemical imbalance in the brain' – specifically, a lack of serotonin,” she tells Woo.

“This study, which echoes previous research, doesn't find evidence that this is the case. Many doctors and psychiatrists have said that they knew this – but this information has not been adequately communicated to the general public, and lots of psychiatrists have perpetuated this.”

Frazer-Carroll thinks antidepressants can be lifesaving, but aren’t a one-stop fix for everyone, particularly when societal factors, such as stress, come into play. “We should be striving for a world that creates less distress and a world in which people can give informed consent to the drugs they take, which means understanding what is known about them and what is not”.

Dr Michael Bloomfield, a consultant psychiatrist and principal clinical research fellow at University College London, told the Guardian: “Many of us know that taking paracetamol can be helpful for headaches, and I don’t think anyone believes that headaches are caused by not enough paracetamol in the brain. The same logic applies to depression and medicines used to treat depression. There is consistent evidence that antidepressant medicines can be helpful in the treatment of depression and can be life-saving.”

Dr Mark Horowitz, PhD in biopsychology at Kings College London and an honorary clinical research fellow at UCL, however, highlighted the ‘straw man argument’ that gets bandied around, equating how we think about the prescribing of antidepressants for depression with how we think of paracetamol, its use, and effects.

“People are not told that paracetamol fixes the underlying cause of a headache, or that they should keep taking them each day and if they stop them the headache will come back and it is irresponsible to stop them,” he tweeted. “Most of the population has been told that they have a chemical imbalance in depression that is treated by antidepressants.” He believes it is “disingenuous” then to deny what patients are told about chemical imbalances in GP offices across the country.

The issue, then, is not whether antidepressants actually work (as many responses to the study have focused on), but how they are being sold to people. We know that they take a while to work, and as many as two-thirds of people with depression aren't helped by the first antidepressant they try. Up to a third don't respond to several attempts at treatment.

The moral panic around antidepressants

People who take antidepressants have long described a stigma against them. And since Moncrieff’s study was published, it has been seized upon by some as evidence that “antidepressants don’t work”, or are part of some sort of profit-driving plot for pharmaceutical companies. In the US, Rolling Stone reported that networks like Fox News and prominent pro-Trump figures such as Marjorie Taylor Greene have used the study to whip up a moral panic about the use of antidepressants.

James Harris, Associate Director for Campaigns and Communications at Rethink Mental Illness, tells Woo that, when reacting to this study, we shouldn’t lose sight of the fact that antidepressants can make a big difference to some people.

“The reaction to this study reminds us why we need more research to better understand the causes of poor mental health, and to improve the range of options available to help people who are struggling. Social media lit up in response to the headlines from this study, but it wasn’t all negative. Lots of people told us the important role that antidepressants play in helping them to stay well, often alongside other support such as talking therapies, keeping physically active and self-care,” he says.

Harris thinks that, although we’ve come a long way in shifting people’s attitudes to mental health, medication is one part of the conversation where there is still a lot of stigma. “This is worrying and we need to keep challenging this, because it can put people off accessing the support they need. What we need to say loud and clear, is that if you’re taking antidepressants and are doubting if they’re the right option for you, it’s essential that you don’t just stop taking them or reduce your dose without speaking to your doctor first.”

For more resources for seeking information around antidepressants and depression, visit Mind