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There are currently no good treatments for people thinking about ending their lives.

The World Health Organization recently estimated that, worldwide, one person ends their own life every 40 seconds. Suicide is a leading cause of death, especially among young people, and the Covid-19 pandemic has prompted fears that cases of suicide could take a sharp rise.

Suicidality comes on a spectrum ranging from thoughts or ideation to attempt and completion.

Suicidal thoughts, despite being an incredibly high-risk factor for suicide attempts, have been largely overlooked by clinical research until quite recently.

Dr Elizabeth Ballard is director of psychology and behaviour research and director of predoctoral training at the US National Institute of Mental Health’s (NIMH) Experimental Therapeutics and Pathophysiology Branch. As a clinical psychologist, she has extensive clinical experience working with suicidal individuals and spearheaded research on the neurobiology of suicide.

As she wrote in a recent paper, the majority of clinical trials on suicide risk focus on suicide attempts, and as such, “new clinical trials that use suicidal thoughts as the primary outcome require a number of slight modifications to their clinical trial design”.

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In recent years, psychedelics have re-emerged as promising treatment options for many areas of depression-related illness for their ability to have almost instantaneous effects, while widely used antidepressants can take week or months to bring any benefit.

The FDA’s landmark approval of Johnson & Johnson’s ketamine-derived nasal spray Spravato for depression in March 2019 may have helped open the floodgates for other drugs commonly used recreationally but with significant therapeutic potential.

In the paper, Ballard et al wrote that “the rapid onset of these new interventions permits an experimental therapeutics approach to suicide research, in which psychological and neurobiological markers are embedded into clinical trials to better understand the underlying pathophysiology of suicidal thoughts”.

In their review, the authors discuss these methodologies using recent research looking into ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, which has been associated with rapid effects on suicidal thoughts.

Clinical Trials Arena spoke to Ballard to discuss the neurobiology of suicide, the challenges and key considerations of conducting trials for suicidal ideation and to find out how the literature from ketamine trials have helped provide a blueprint for researchers evaluating rapid-acting treatments for suicidal thoughts.


Kezia Parkins: What do we know about the neurobiology of suicidal thoughts or ideation?

EB: We know that suicidal thoughts are often associated with later suicidal behaviour and are a very important risk factor. Certainly, it’s going to elevate your risk overall for a suicide attempt, or even death. However, there are people who are suicidal for years who have suicidal thoughts, and never actually make an attempt so it’s tricky to piece apart who is suicidal in a chronic state and who’s suicidal and about to actually act on those thoughts. Suicidal thoughts are associated with depression, hopelessness, anxiety, feeling like a burden and social disconnection. There’s a wide range of those thoughts so a lot of our work right now is really trying to piece that together and identify specific brain circuits.

KP: Do you think suicidal thoughts are separate from depression, or caused by it?

EB: I personally think that suicidal thoughts are related to but distinct from depression. It’s an open question. I’m sure you could ask a number of researchers and they might say slightly different things. The findings related to ketamine are really interesting, in that we do see this potential separation of an antidepressant response and an anti-suicidal response – some people can have a depression response to ketamine, but not necessarily a suicide ideation (SI) response and vice versa. Overall, I think they’re linked. Suicide is associated with almost all psychiatric diagnoses but I think of it more as its own entity and try to study it as such – something more akin to anhedonia [the inability to feel pleasure], or other symptoms that we know occur across diagnoses but might have their own particular signature.

KP: Why is there a need for more trials focusing on SI as a primary outcome?

EB: Firstly, we just need better treatments for suicide in general because it’s a leading cause of death. People are very concerned about potential rising suicide rates as related to the pandemic but in the US, suicide rates have risen in the last 15 years, which is very concerning.

Because of a number of factors, there’s a lot of reluctance and difficulties associated with doing suicide clinical trials, in terms of getting through ethical review boards and worries around the ethics of enrolling suicidal individuals into trials.

The power is an issue, especially if you are thinking about powering to suicide death or attempts because it’s such a low base rate phenomenon, you would need thousands of individuals to have effects on death, but even on risk of attempt.

Suicidal ideation is much more common and is not such a low base rate binary outcome so it is an appealing potential proxy for suicide risk. I think it’s a really exciting area to get involved with, but at the same time, these trials are even newer than trials powered to look at suicide attempts, so there’s still a lot that we need to understand. Therefore we need to make sure that we’re really thinking carefully through the clinical trial design as they’re so new.

KP: What are the key challenges in conducting trials for suicidal thoughts?

EB: The go-to, especially for psychotherapy trials, is to take somebody after one suicide attempt, and then see if you can prevent re-attempts because the best predictor of future behaviour is past behaviour. That is a way to isolate people who you think are at high risk to engage in a particular behaviour within a certain time period.

With these trials, in terms of participant selection and outcome selection, it’s dichotomous.

With ideation, however, there are lots of gradations. You can be passively suicidal and have patients who will say, ‘I want to go to sleep and never wake up.’ You can have people who have suicidal thoughts, with intent – they’re actually going to act on these thoughts. You can have people in-between. As of now, it’s not a psychiatric diagnosis so there are not as many clear guidelines around enrolling a suicidal individual as there would be in a depression trial where you are able to define a major depressive episode, for example.

With the ketamine trials some people have gone after acuity, a certain level of suicidal thoughts or suicidal thoughts with intent or a certain score of severity on one of our rating scales. Other people have gone for chronicity – have they had suicidal thoughts for the last three months? All of this is new, and frankly, I think that there probably are different treatments for chronically suicidal individuals as opposed to acutely suicidal individuals. It would not surprise me at all if we ended up with treatments according to levels of risk. But, because we don’t have that literature, it’s tough to know.

Then there’s the whole issue of monitoring within a trial with somebody who’s potentially suicidal. How do you give somebody a placebo if they are suicidal and you are worried about their risk? Just the fact that you’re doing this intensive monitoring and checking in is potentially affecting suicide risk. We know that social support, and social connection is a very important protective factor for suicide so just doing the required safety monitoring could be improving a lot of these individuals. We can’t say that there’s a direct benefit of participating in research, but having somebody check in daily – that’s a lot of what treatment often is.

Then there’s the issue related to what is the appropriate outcome. In a suicide behaviour trial, it’s dichotomous – did you attempt or not, and usually it’s a 5-10% hit rate. In suicidal ideation, are we going to follow the depression literature and go after 50% reduction in suicidal thoughts? What does that mean clinically? Are we okay with people having a treatment where there is still some level of suicidal thoughts?

KP: Is there a need for new measurements for suicidal ideation?

EB: We do have scales which assess the current traits of suicidal thoughts, but they were not necessarily developed to assess these rapid changes over minutes to hours to days and mostly focus on long-term prediction of who is going to eventually attempt suicide.

There’s been a lot of discussion about how to adjust measurement in this way, but I’m not sure we need new scales, I think we need new standards for how we use the scales we do have. There’s a lot of interesting work being done with digital assessments and ecological momentary assessment smartphone devices that can give us good insight and help assess how suicide risk ebbs and flows over the course of days, so thinking about how to integrate that into clinical trials makes a lot of sense.

KP: How are ketamine studies providing a blueprint for researchers evaluating rapid-acting treatments for suicidal thoughts?

EB: For a long time suicide-focused clinical trials have focused on the outcome of suicide attempts and whether you can prevent repeated suicide attempt and usually that is over the course of three to six months or a year. It’s a longer-term outcome and a dichotomous one.

I think that ketamine has revitalised a lot of research and how we think about both depression and suicide risk in that we could see these rapid changes within minutes to hours to days.

Across the board it’s inspired people to think about other rapid-acting treatments. Ketamine was the first out of the gate, but by no means do I think it’s going to be the only drug that can work on suicidal thoughts that quickly. It really has shown that we can start thinking about other interventions that have rapid effects on suicide like transcranial magnetic stimulation (TMS), electroconvulsive therapy or other compounds or psychotherapies.

KP: Can you speak a bit about the ‘experimental therapeutics model’ for rapid-acting treatments?

EB: It’s a very exciting model. We see people get relief with a lot of interventions, whether pharmacologic or non-pharmacologic, but it’s really important to know how and why. Ketamine is associated with a number of side effects, including dissociative symptoms, and is a drug of abuse so there’s always the question of whether we can harness what gives ketamine its antidepressant effects, and minimise some of the side effects.

An experimental therapeutic model is not just looking at what works and what doesn’t. We incorporate a lot of biological markers throughout the trial to really understand what circuit is involved with the ketamine administration and the anti-suicidal responses. That might include sleep studies before and after administration, neuro-imaging or blood, saliva and urine samples. It’s really intensive work in the clinical trial, and oftentimes, the sample size is really quite small, but it’s really important to establish potential mechanisms of treatment, both to understand how our treatments work, but then also to think about new compounds, especially if you’re trying to minimise side effects.