The paradox of how antidepressants are tested –

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Trigger warning: This article contains multiple references to suicide
One afternoon in April 2018 I answered my rarely-used home telephone to a barrage of questions. On a crackly landline, a researcher from the University of Exeter, UK, ran through a standard interview to check my suitability for a clinical trial. She was part of a team seeking to test the effectiveness of ketamine – an anaesthetic drug which is being repurposed as a new antidepressant. It is the first pharmacological treatment for depression to have emerged in decades. The Exeter scientists were hoping to find out if the drug, when combined with psychological therapy, could prevent alcoholics from relapsing.
The questions were designed to establish if I was alcohol dependent, which wasn’t a surprise, as I’d applied to the trial to deal with problems I had with drinking. But there were two questions that left me feeling raw and outraged.
“Have you ever thought of harming yourself or trying to take your own life?” asked the researcher.
I struggled to work out why she was asking. Everyone has such thoughts sometimes, I had assumed. I really couldn’t understand the significance. But I reluctantly answered “yes”. Then came two follow up questions: “How often did I think that?” and “Did I have plans for suicide?”
I had such thoughts earlier that day and on many days, I said, but without any plans. But as strange and intrusive as this line of questioning felt, what I later discovered about how my answers would be interpreted was both puzzling and upsetting.
Friends who are psychologists, and another who runs clinical trials in the pharmaceutical industry, told me something that surprised me: clinical trials for antidepressant drugs normally rule out patients at risk of suicide. In fact, this is a patient protection central to how researchers test new treatments. It is easy to see why this is important – doctors and researchers do not wish to increase the risk to vulnerable populations by trialling a new drug on them. It is the reason why, for example, pregnant women tend not to be included in studies of new drugs or vaccines either.
Yet it also seems a strange criterion to impose for a class of drugs that would be used to treat those perhaps most at risk of making an attempt on their own life.
It also would be no surprise if people who might require antidepressants answered yes to such questions. According to some estimates, roughly 50-66% of those who die by suicide have some sort of mood disorder (although it should be noted that only 2-4% of people treated for depression die by suicide). Could excluding these people from trials bring new problems?
Drug trials typically use questionnaires to help select suitable volunteers to take part (Credit: Getty Images)
Despite their questions, the Exeter researchers did recruit me to take part in their trial, which published its results in January 2022.
But as a science writer who has previously worked in, and now regularly covers the pharmaceutical industry, I wanted to understand why others with potentially suicidal thoughts might be excluded from trials like this. This also raises an important question – could such measures be putting patients at risk if they are later prescribed drugs approved through this process?
It is far from a clear cut issue. Some health authorities recognise that this approach can distort what trials reveal about how effective, or risky, drugs are. Some studies also suggest that these concerns mean that those running trials may be underestimating the risks, perhaps due to conflicts of interest or bias in the way they are recorded. But those running clinical trials also have a well-established ethical duty to safeguard the well-being of patients involved in clinical trials and above all protect their lives.
Now, researchers are starting to question whether excluding this group of patients from trials is the right approach and if there are ways of including them in trials while keeping them safe. As a first step out of the moral maze these policies have created, they are proposing new strategies that might make it possible to include a broader range of people in antidepressant trials.
Instinctively, you might expect antidepressant drugs to be a vital tool to help protect people from suicidal feelings. But concern about them started in 1990. Then, reports emerged that the widely prescribed drug class known as selective serotonin reuptake inhibitors (SSRIs) increased suicide attempts among some people taking them. SSRI drugs include paroxetine, sold under the brand names Paxil and Seroxat among others, and fluoxetine, which is most commonly sold under the brand name Prozac. 
Evidence that these widely used antidepressants had a paradoxical effect gradually grew. A documentary on the BBC’s Panorama in 2002 raised the issue into the public consciousness. In 2004, UK scientists highlighted that SSRIs might potentially increase the risk of suicidal behaviour in children and adolescents. Today health authorities warn about the risk of suicidal thoughts and a desire to self-harm, especially when these drugs are used to treat anyone younger than 25.
Eli Lilly, the manufacterer of Prozac, says that fluoxetine is now among the “most studied medicines in history” and that it has submitted decades of safety data to regulatory authorities. “Fluoxetine is approved by the MHRA and FDA for the treatment of pediatric depression and continues to be considered to have a positive benefit risk profile by regulatory authorities, physicians and patients around the world,” a spokesperson for the company told the BBC.
Complicating matters further, however, a study in 2014 said that these warnings had decreased antidepressant use and in turn increased suicide rates. Other researchers dispute that finding though, including one working for the US Food and Drug Administration (FDA)
Scientists understandably wanted to avoid a similar situation which might put vulnerable people at risk.
For their work, researchers running clinical trials needed methods to assess suicide risks before and after people start taking drugs. To help them do this, they developed several questionnaires that rank a person’s risk on slightly different scales.
The questions I answered came from the Columbia Suicide Severity Rating Scale (C-SSRS), explains University of Exeter psychopharmacologist Celia Morgan, who led the trial I was on. Every clinical trial conducted in the UK goes to the country’s Medicines and Healthcare products Regulatory Agency (MHRA) for approval. Likewise in the US every trial for a new drug treatment goes to the FDA. When Morgan’s team submitted their trial protocol, the MHRA asked them to include the C-SSRS, which is commonly used in trials worldwide.
But suicide risk scales are not used to assess people joining every medical trial, says Hugh Davies, a research ethics advisor at the UK’s Health Research Authority. “Where you feel that there is an association with suicidal risk, you have to look at that and say, ‘Will joining this research increase that? What is the benefit? How do we assess that?’,” he says. “You might want to do suicide scores. Look to see the actual risk, quantify that, and you then make a judgement. Above this risk, we’ll exclude them. Below that risk, we’ll accept them.”
A similar situation exists for trials regulated by the Food and Drug Administration in the US and the European Medicines Agency in Europe.
In practice that means that trials for drugs that affect the brain assess participants using suicide risk scales as standard practice. Some antidepressant trials that assess people in this way but don’t exclude them are now starting to happen again but remain exceptionally rare.
Still, given that so many trials do exclude people based on suicide risk, does this approach really protect trial participants?
“The risk of suicide in trials has gone down,” says Arif Khan, medical director at the Northwest Clinical Research Center in Bellevue, Washington. According to him, screening out patients at risk of suicide is, perhaps unsurprisingly, leading to lower rates of suicide in clinical trials.
In 2018, a study by Khan and his colleagues found that suicides fell from 644 per 100,000 patients to just 26 per 100,000. Suicide attempts also fell sharply, even among people given inactive placebos instead of antidepressant drugs. This comes amid a 36% decrease in suicide rates globally in the 20 years since 2000, but a 46% increase in the US. While they couldn’t rule out other trial design changes causing the effect, Khan and his colleagues say it could be thanks to tools like the C-SSRS questionnaire.
“These findings may reflect enhanced screening procedures and effective exclusion of suicidal patients,” they write.
Not everyone agrees that trials are getting safer, though.
SSRI drugs are among the most commonly widely prescribed antidepressants in the world (Credit: Joe Raedle/Getty Images)
Suggestions that the risk of suicide in trials has fallen are “utterly unreliable” says Michael Hengartner, senior lecturer and researcher at the Zurich University of Applied Sciences. One reason is that suicides and suicide attempts are still happening, but companies running trials are not recording them properly, he argues. Hengartner bases this argument on evidence that includes a 2014 study comparing results published in scientific journals with detailed data in an online database. More than half of suicide cases in the database weren’t reported in journal papers when they were published. Hengartner says there are even accusations of suicide attempts being recorded instead as “emotional lability (constant emotional change) or worsening depression instead”.
In response, Khan notes that trial data is audited by FDA staff. “If these reports are unreliable, then what is reliable?” he asks.  
An FDA spokesperson says that it encourages “compliance with the legal requirements” for registering trials and submitting results. “When these requirements are not met, the FDA has the authority to take enforcement action,” they say. The FDA takes its role in enforcing the registration and result submission requirements “extremely seriously”. Meanwhile, an MHRA spokesperson says that while the organisation doesn’t comment on specific studies, they likewise highlight the standards that trials must follow, and a related obligation to publish results.
Hengartner has also reinforced the previous evidence that some antidepressants can increase suicide risk. In 2021, he and his colleagues published a review looking at data from 27 observational studies of people prescribed SSRIs and other similar antidepressants, rather than scientific papers of clinical trial results. That helps because suicides are relatively rare – so to reliably estimate any changes in risk, you need to track a lot of people, Hengartner says. His team’s review spanned 1.45 million subjects. It found a link between SSRIs along with other “new generation” antidepressants and increased suicide risk in young people and adults when compared with people who were not taking them. By analysing whether studies or authors were funded by the pharmaceutical industry or not, Hengartner’s team also found evidence of financial conflicts of interest and bias toward publishing positive results. “We see absolutely no evidence of reduced risk of suicide events,” Hengartner stresses.
Suicide remains one of the leading causes of death worldwide. In 2019 more than 700,000 people died by suicide, accounting for one in every 100 deaths. The World Health Organization last year issued new guidance to assist suicide prevention, which included early identification, management and follow up of anyone affected by suicidal thoughts or behaviour.
So, even if screening is working to protect trial participants, it could be introducing other problems. The irony of excluding people at risk of suicide from trials of antidepressants means that potential increases in suicide rates among vulnerable people go undetected. And this could have far greater implications if the drug is then approved for general use.
“We know from many studies that those people included in antidepressant trials barely reflect the actual population using these drugs, because they have very strict inclusion/exclusion criteria,” says Hengartner. Most antidepressant trials also exclude participants taking other drugs or those with substance abuse problems, for example. That helps divide people up into easily compared groups in randomised controlled trials, usually seen as the best way to test new medical treatments. Strict controls on who goes into a trial are supposed to makes sure that researchers see the clearest signs possible that a treatment works.
But that also creates an important weakness in randomised controlled trials. Screening out people based on factors like having other illnesses, substance abuse and suicide risk mean that these trials don’t directly reflect the real world populations who might take them. “You can’t actually extrapolate to the broader population of people,” Hengartner says.  
“By excluding whole populations from research, entire groups of people are denied the potential benefits of research findings and their health may suffer as a result,” says Ana Iltis, director of the Center for Bioethics, Health and Society at Wake Forest University in Winston-Salem, US. In February 2020, Iltis and her colleagues reviewed 64 clinical trials published between 1991-2013. Only one included a participant considered at risk for suicide. “Protection from research risks by excluding people solves one problem but creates new ones,” says Iltis. She believes that health researchers should look for ways to help people with “a broader range of health interests”.
National health authorities say that they want to address these issues. In 2018, the FDA mentioned in guidance that patients with a history of suicidal thoughts or behaviour “need not be systematically excluded” from clinical trials for major depressive disorder. “The agency is working to ensure meaningful representation of underrepresented populations in clinical trials that test new medical products, while ensuring adequate safeguards to protect study participants are in place,” an FDA spokesperson told me.
Other medicine regulators around the world are thinking along similar lines. A spokesperson for the UK’s MHRA agreed that there is no need for systematic exclusion. “Inclusion and exclusion criteria are decided and justified based on the individual benefit-risk assessment of each trial,” they said. “It is important that any clinical development program is representative of the population affected by the indication for which the product is being developed.”
Clinical trials undergo rigorous approval processes before they are permitted to go ahead (Credit: Alamy)
To help researchers running clinical trials include people at risk of suicide, Iltis and her colleagues have recommended a new strategy when setting up studies. “Inclusion requires at least three critical elements,” she explains. “The first is having protocols that are written to include people at risk for suicide and that have appropriate protections built in.”  
Such protections include monitoring participants, working out when they might be brought into hospital and communicating with caregivers and family members. They also involve telling participants where the limits of confidentiality are with regards to suicide and having plans for managing when people disclose suicidal intent and suicide attempts. Finally, protocols should include independent safety monitoring and criteria for withdrawing participants or stopping a study for safety concerns.
The second critical element is having researchers willing to include such persons and who work proactively to do that, Iltis continues. “The third critical element is having individuals who are willing and able to give voluntary informed consent to participate,” she says. 
These steps should help groups running clinical trials overcome barriers related to their legal liability and risks to the trial participants, according to Iltis and her colleagues. One major remaining challenge is that the measures her team suggests would be costly, and there are no financial incentives in place to encourage researchers to adopt them.
As such, Iltis has not heard of anyone adopting her team’s suggested approach. “Change in medicine and biomedical research takes a long time,” she says. “I do not expect to see significant change until the incentives are set up to encourage improvement.”
For one, Khan remains firmly in favour of continued exclusion. The medical community, the pharmaceutical industry and regulators do not want to expose people at risk of suicide to clinical trials, he says. “If a company reports a suicide in a trial, what do you think happens to the company?” he asks. He also argues that FDA guidelines minimise the problem of groups being excluded from clinical trials. Trial participants should “reflect the characteristics of clinically relevant populations with regard to age, sex, race, and ethnicity”, its diversity guidelines say.
Also, when drugs are not intended to treat suicidality, a person’s suicide risk is not relevant to a trial, Khan argues. “There is no requirement by any regulatory agency/authority that pharmaceutical companies have to include suicidal patients in clinical trials,” Khan says. Khan also says that committees set up to ensure that medical research is conducted ethically would not let trials proceed that include people at higher risk of suicide. But why is this? And could that change?
Hugh Davies explains that the key rules for experiments on people are set out in the Declaration of Helsinki. “While the primary purpose of medical research is to generate new knowledge, this goal can never take precedence over the rights and interests of individual research subjects,” it states. On that basis, trials should avoid increasing any risks to the people involved, as Khan says.
Yet ethics researchers argue over whether that should always hold true, Davies says. The risk of drugs potentially increasing suicide rates generally might be one case where society’s interests are also a factor, especially if measures like those Iltis’ team suggests mitigate risks to individuals.  
So, prompted by Khan’s assertion, I asked 16 members of the Oxford-based research ethics committee Davies chairs how they balance these considerations when deciding whether to approve a trial. I put to them some questions about whether they would allow people at risk of suicide to participate in trials. I also asked whether they supported strategies like that put forward by Iltis and her colleagues.
Of the eight members who responded, most agreed that questionnaires like C-SSRS were essential in measuring a person’s suicide risk. They would also want to know what stage in the drug development process the trial was, and how much risk of suicide there was.
For example, drugs being tested in humans for the first time should exclude people at risk of suicide. “Certainly if the intended population were to include vulnerable people (those with a medical history of severe depression, psychosis etc) I would expect not only a screening process but a strategy for managing those found to be at risk,” writes Christine Montague-Johnson, a senior paediatric research nurse at the University of Oxford, and one of the committee members. But subject to these conditions, a majority agreed that if a strategy similar to that proposed by Iltis was in place, they would allow a trial seeking to include people at risk of suicide to proceed.
Of course, these are the views of only one ethics committee, based in the UK, responding to hypothetical questions. But it gives some insight into the kind of decisions that the people who approve clinical trials must weigh up before allowing them to go ahead.
And even with greater protection for at risk patients during trials, as Iltis has identified in her strategy, not all research groups will be equipped to deal with the potential consequences.  
“It’s a brave researcher who says ‘I will include these people at risk of suicide in a study where the medication might worsen it’,” says Davies. “They need to come along to the research ethics committee and say, we’re being brave, and make the benefits very evident. Then it needs opinions from all groups with legitimate interest and lengthy debate. It’s a brave committee who signs up to that.”
But the benefits must not be ignored either. Inclusion in trials can help patients like myself who participate, but it can also clarify the risks surrounding antidepressant treatments. This can mean safer drugs for patients more widely.
And at a time when Covid-19 has widely worsened mental health, this could be more important than ever.
As Davies outlines, it will require some bold steps from researchers, regulators and pharmaceutical companies if the way trials are conducted is to change.
“But sometimes I think we need to be brave,” he adds.

If you or anyone you know is affected by the issues raised in this story, the International Association for Suicide Prevention has a list of global agencies that may be able to provide immediate support. You can also contact Befrienders Worldwide.
In the UK and Ireland: The Samaritans are open 24 hours a day. Call 116 123 or email
In the US: If you are in crisis, please call the National Suicide Prevention Lifeline at 1-800-273-TALK (8255) or contact the Crisis Text Line by texting TALK to 741741.
In Australia: Call Lifeline on 13 11 14 or  chat online, nightly seven days a week. 
In Canada: If you are in crisis, call 1-833-456-4566 (4357) or text 45645. For more information about suicide prevention, visit Centre for suicide prevention.
In India: You can call the AASRA on 91-982-046-6726 or visit their website.

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