LAS VEGAS – More than 10 years ago, Gerard Sanacora, PhD, MD, came across a study in the medical literature that stopped him in his tracks.
Dr. Gerard Sanacora
For the study, Austrian neurologist Eberhard A. Deisenhammer, MD, and colleagues sought to determine the length of the period between consideration and accomplishment of a suicide attempt (J Clin Psychiatry. 2009;70[1]:19-24). To do so, they interviewed 82 patients who were referred to a psychiatric university hospital after a suicide attempt. Nearly half of the patients (48%) reported that the period between the first current thought of suicide and the actual attempt had lasted 10 minutes or less.
“When you’re talking about treating suicide behavior, there are so many components: the impulsivity component, the resilience component – all these things that can’t be measured with a simple outcome measure,” Dr. Sanacora said at an annual psychopharmacology update held by the Nevada Psychiatric Association. “That’s one of the real challenges. It requires us to take a good look at how we’re treating these patients in general.”
It also underscores the need for new treatments that target suicidal ideation and behavior.
“There is increasing evidence that ketamine and esketamine can produce effects that could be used in the treatment of mood disorder patients with suicidal ideation or behavior,” said Dr. Sanacora, professor of psychiatry at Yale University, New Haven, Conn. “However, there are many challenges to performing the studies that are required to more definitively demonstrate rapid and sustained improvement in suicide risks.”
The global 12-month prevalence of nonfatal suicide attempts is about 0.3% to 0.4%, and the lifetime prevalence is 3%, “which is pretty shocking,” he said. In the United States, there are more than 30 suicide attempts for each suicide death. At the same time, a World Health Organization community survey conducted in 21 countries found that the 12-month prevalence of suicidal ideation was about 2%, and that the lifetime prevalence was 9%. “These are large numbers that we’re talking about internationally,” said Dr. Sanacora, who also directs the Yale Depression Research Program. In 2013, suicidal ideation constituted nearly 1% of all adult ED visits in the United States, with conservative costs of $2.2 billion. “Every step along the process takes a large toll on the health care system and society, from the top level of completed suicide to suicidal ideation,” he said.
According to 2016 data from the Centers for Disease Control and Prevention, nearly 10 million people in the United States have seriously considered suicide, about 2.5 million made a plan, about 1 million attempted suicide, and about 40,000 completed suicide. “We have to think about what we’re treating,” Dr. Sanacora said. “Are we treating the suicidal ideation, or are we trying to prevent completed suicides?”
A prior history of attempted suicide is the strongest single predictive factor of a completed suicide. “In fact, the risk of dying by suicide is approximately 100 times than that of the general population within 1 year of an index attempt,” he said. Another major risk factor is having a previous psychiatric hospitalization. In fact, up to 41% of those who completed suicide had been psychiatric inpatients within the previous year, and as many as 9% of suicides occurred within 1 day of discharge from psychiatric inpatient care. Other identified risk factors include marital status, belonging to a sexual minority, occupation, military service, general medical comorbidities, diagnosis of personality disorder, chronic pain, traumatic brain injury, childhood abuse, location of residence, access to firearms, and family history of suicide. Protective factors include having a strong social support network, being a parent, and religiosity. “These are things that typically aren’t part of a treatment, but they can be woven into a treatment plan in some way,” he said.
Other identified risk symptoms include feelings of worthlessness and hopelessness, the combination of depression and anxiety, and psychosis, regardless of the specific diagnosis.
Medical stabilization constitutes the first step in the standard treatment approach to suicidal ideation and behavior. “You want to make sure the person is hospitalized and take care of any injuries that may have been sustained in the suicide attempt,” Dr. Sanacora said. The next step is reducing the immediate risks. “For the most part, that’s making sure the individual is in a safe setting commensurate with the level of risk,” he said. “You want to remove any other risks that could be around them. Then, you want to assure that an appropriate level of follow-up is provided on stepdown to lower levels of care. That year after hospitalization puts you at incredible risk, so we want to make sure we’re not just treating something in the acute phase and then not having longer-term follow-up for it.”
Existing treatments that have some evidence to help with the treatment of suicidal ideation and behavior include the use of antidepressants, lithium, and clozapine, but these agents are far from fast-acting for a patient in crisis. “In addition, a lot of docs are hesitant to give lithium because it has the potential of overdose itself,” Dr. Sanacora said. With clozapine, he continued, “there is some level of confounding by indication because, when you’re giving clozapine, it’s usually a more reliable patient, one who is not at risk of self-harm.”
The STAR*D (Sequenced Treatment Alternatives to Relieve Depression) trial demonstrated that, for the patients who do not respond to the first two levels of treatment with citalopram, their chances of having a remission by getting a third or fourth level of treatment is reduced to below 15% (Am J Psychiatry. 2006;163[1]:28-40).
“This suggests that, with our current armamentarium, we are limited,” said Dr. Sanacora, who is also codirector of the Yale New Haven Hospital Interventional Psychiatry Service. In the STAR*D trial, the time to response to citalopram was 6 weeks in 50% of patients. “So, when somebody is going through a crisis and is at imminent risk for suicide, and you tell them, ‘You’ll be 50% better in 6 weeks,’ that’s hard to swallow,” he said.
Recent studies of ketamine and esketamine have demonstrated a rapid onset of effect in patients with major depressive disorder, but whether they alter suicidal ideation and behavior remains unclear. “If you are wanting to improve suicidal ideation and behavior, what outcome measure are you using to do this?” Dr. Sanacora asked. “It may seem simple, but it’s not. To do a clinical trial, you would need large sample sizes to look at behavior as an outcome. In fact, even retrospective studies on this topic don’t have enough events to give you statistical meaning.” This leaves clinicians to consider scales that have been used for examining suicidal ideation and behavior over the years, including the MINI suicidality module, the SAD PERSONS scale, and the Suicide Intent Scale. “However, while they could have some value to be used clinically, these scales really don’t have great value as outcome measures,” Dr. Sanacora said.
There also have been attempts to develop scales that capture changes in suicidal ideation and behavior over time, including the C-SSRS (Columbia-Suicide Severity Rating Scale) and the Sheehan Suicidality Tracking Scale. “The sad thing is, none of these measures have been proven to be very useful clinically,” he said. “They may have some level of sensitivity and specificity, but their actual predictive value is not great. So using these clinically is somewhat difficult.”
In 2018, Dr. Sanacora and his colleagues published results from a systematic review and individual participant data meta-analysis examining the effects of a single dose of ketamine on suicidal ideation (Am J Psychiatry. 2018;175[2]:150-8). The analysis included 167 participants with suicidal ideation at baseline. “Within 24 hours there was a very clear decrease in suicidal ideation in terms of clinician-reported scale,” he said. “Over 50% of patients reported having minimal or no ideation after treatment. That was maintained for 7 days.” Effect sizes were moderate to large at all time points post dose.
In the largest meta-analysis of its kind to date, researchers reviewed 15 independent trials of ketamine for suicide ideation in 572 adults with psychiatric disorders, all with a single dose of drug with varying routes and dosages (Aust N Z J Psychiatry. 2020;54[1]:29-45). The researchers in that study concluded that ketamine “may have a role in acute treatment for suicidality. However, there is clearly a need for clinical measures to ensure persistence of any benefits.”
Esketamine, which was approved in March 2019 for major depressive disorder, also shows promise in patients with suicidal ideation and behavior. In a double-blind, multicenter, proof-of-concept study, researchers randomized 68 participants to receive esketamine (84 mg) or placebo twice weekly for 4 weeks, in addition to comprehensive standard-of-care treatment (Am J Psychiatry. 2018;175[7]:620-30). The primary efficacy endpoint was change in score from baseline to 4 hours after initial dose on the MADRS (Montgomery-Asberg Depression Rating Scale). “There was a nice effect in the antidepressant response, compared with placebo. It hit the primary endpoint at 4 hours. The patients got treated twice a week for 4 weeks. People got better quickly and stayed well moving on.” The researchers also found that the rate of remission at day 25 was 60% in the esketamine group, compared with 42% in the placebo group. “The take-home message is that, even without the esketamine, the remission rate was 42% at day 25. That means if you’re giving people really good care, meaning that you’re seeing them twice a week and they’re inpatient until they’re able to go outpatient, people can do pretty well with that level of care.”
Meanwhile, In a proof-of-concept trial, 18 depressed subjects with acute suicidal ideation who presented to the emergency department and required hospitalization were randomized to either IV ketamine 0.2 mg/kg or to saline placebo (Depress Anxiety. 2019 Nov 16. doi: 10.1002/da.22975). Ninety minutes after infusion, 88% of patients in the ketamine group had achieved remission of suicidal ideation, compared with 33% in the placebo group (P less than .05). No serious adverse events were noted.
“There is a clear need for new treatments targeting suicidal ideation and behavior,” Dr. Sanacora concluded. “Any plan to institute a rapid-acting treatment for individuals with imminent risk of suicidal behavior must be placed in the context of a larger comprehensive treatment plan. Getting somebody to feel better in the short run is great, but you really have to think about the whole treatment plan.”
Dr. Sanacora reported having received grants and research support from numerous pharmaceutical companies. He also holds an ownership interest in Biohaven Pharmaceuticals.