Kondo’s main goal is to test the anti-suicidal ability of uridine. If the data are encouraging, they could set the stage for a larger multi-site study. He also hopes to identify, through neuroimaging, brain chemistry changes that occur when participants experience a reduction in suicidal thoughts while taking uridine.
"There been an increase in evidence that GABA and glutamine may be where the action is, where the rubber hits the road, so to speak, when you're talking about the neurobiology of suicidal behavior."
Kondo, also an associate professor at the University of Utah, stresses that uridine is still considered 'investigational.”
'That means it’s not ready for prime time,” he says. 'As with any drug in the early stages of development, no conclusions can be drawn right now.”
'We’re just playing a small role in this problem,” he adds. 'Suicide is a big problem not just for Veterans, but for everyone.”
According to Kondo, uridine has never been studied for suicidal ideation in a non-VA setting. He’s now leading a separate trial to see if the compound reduces signs of depression in adolescents with bipolar disorder, a mental condition marked by alternating periods of sadness and elation. Bipolar disorder is one of the most common psychiatric illnesses linked to suicide.
The non-randomized pilot phase of the trial tied uridine to a drop in depressive symptoms in the seven adolescents who consumed the drug for six weeks. However, Kondo and his team cautioned that uridine should not enter clinical practice as a treatment for depressed adolescents with bipolar disorder until randomized controlled trials have been done to confirm its effectiveness.
'Rapid onset of action may be a distinguishing feature of uridine,” the researchers wrote. 'Open-label studies are an initial step in testing a novel intervention, but these findings should be considered preliminary.”
Kondo is testing uridine at the same time VA scientists are researching two other drugs that are believed to possess anti-suicidal properties: ketamine and lithium (see sidebar). Ketamine has long been used as an anesthetic but has emerged in recent years as a possible antidepressant. Lithium has FDA approval for treating bipolar disorder, which could lead to suicidal thoughts.
Suicide prevention is VA’s highest clinical priority. An average of 20 Veterans a day are killing themselves, a rate that has been holding steady in recent years. Studies have found that former service members, both men and women, are more likely than non-Veterans to commit suicide.
Research has also shown that about a quarter of Veteran suicides occur within seven days of the person’s final VA visit, and that half occur within 30 days of their last appointment.
Those statistics, Kondo says, provide a 'window of opportunity” for an oral and rapid-acting treatment with mild side effects, such as uridine, to be an effective clinical tool for VA researchers. If uridine proves effective, he notes, its status as a natural compound in breast milk means it could be prescribed by primary care, emergency department, and women’s health professionals.
For the uridine trial, scientists are recruiting 90 Veterans who have suicidal ideation as defined by a diagnostic interview and two scales that help measure those at risk for suicide: the Beck Scale for Suicidal Ideation and the Columbia-Suicide Severity Rating Scale. The researchers will combine the scores from all three assessments to figure out if someone is eligible for the study. Eligibility is based on whether suicidal ideation has had a negative impact on one’s social life, family life, spiritual life, and recreation and hobbies.
The American Psychiatric Association and the World Health Organization have no official diagnosis for suicidal ideation. That’s partly because suicidal thoughts and attempts and completed suicides are not unique to any one diagnosis. Instead, patients with a wide range of disorders can be at-risk for suicide, according to Kondo. Some experts have argued that suicidal behavior should be recognized as a separate and independent diagnosis.
Notwithstanding his study, Kondo notes that people who have had suicidal thoughts or who have tried to kill themselves are typically excluded from clinical trials on psychiatric drugs because they are considered 'high-risk.”
'That’s because most large-scale clinical trials in psychiatry are sponsored by pharmaceutical companies, with the goal of obtaining FDA approval for a new prescription drug,” he says. 'It costs more than $1 billion to bring a new psychotropic drug to market. If your new medication gets associated with suicidal thoughts, self-harm, psychiatric hospitalizations, or even participant deaths, then your company stands to lose its investment of more than $1 billion. The recurrent failure of new drugs is the reason many of the largest pharmaceutical companies, such as GlaxoSmithKline and Pfizer, have closed or dramatically reduced their psychiatric research and development divisions.”
Hypothesis: Uridine will `rapidly reduce’ suicidal thoughts
In Kondo’s randomized, double-blind trial, half of the participants will take uridine twice a day for a month and the other half will take a placebo pill twice a day for the same period.
The primary outcome measurement—whether uridine is superior to placebo in its impact on suicidal thoughts and behavior—will be based on interviews with both groups: one at baseline, four on a weekly basis during the month-long period, and one at follow-up. The researchers believe in the end uridine will 'rapidly reduce” suicidal thoughts in Veterans.
Kondo and his team will monitor for possible adverse reactions to uridine through pre- and- post-treatment lab testing. The tests will include a urinalysis, a measurement of blood count, and an examination of kidney and liver function. The researchers will also record Veteran accounts of uridine’s most common side effects: vomiting, diarrhea, and nose bleeds.
'I’m going on the assumption that something present in human breast milk, in other words something newborn infants consume on their first day of life, won’t be harmful to adult Veterans,” Kondo says. 'But we have to test that theory.”
In the neuroimaging phase of the study, the scientists will perform brain scans at baseline and at one week after drug treatment begins. They’ll use a form of MRI called spectroscopy, which can measure substances in the brain. They’ll gauge the concentration of chemicals that may trigger suicidal ideation. The scans, which will not use radiation, will be performed on a 3-Tesla magnetic resonance imaging (MRI) scanner that is FDA-approved for clinical use. The 3-Tesla can produce higher-resolution images than traditional MRI.
Scientists to focus on two chemicals in brain
Each scan will measure the level of about 20 brain chemicals. The main focus will be on whether uridine is linked to greater increases in GABA and glutamine, compared with placebo. The scans will zero in on the anterior cingulate cortex, a brain region believed to be linked to cognitive and emotional processing.
'There been an increase in evidence that GABA and glutamine may be where the action is, where the rubber hits the road, so to speak, when you’re talking about the neurobiology of suicidal behavior,’ Kondo says. 'In the past, scientists focused on neurotransmitters like serotonin and dopamine. But recent work has focused on GABA, glutamine, and glutamate. The increased focus on these three neurotransmitters and the glutamatergic system, in general, is largely because this is the system that ketamine targets.”
The researchers will cross-check the neuroimaging results with the suicidal ideation questionnaires completed by the Veterans. They hope this approach will provide clues to what’s happening in the brain when someone has suicidal thoughts, as well as what brain chemistry changes occur when uridine helps to reduce those feelings. For instance, Kondo and his colleagues hope to learn if there’s a change in the glutamine and GABA as the uridine appears to curtail suicidal ideation.
'By pairing the imaging with the placebo-controlled study,” he says, 'we have an opportunity to see if we’re able to alter glutamine and GABA in the brain with uridine, and if there’s a correlation between that and whether Veterans in the study are experiencing a relief from their suicidal symptoms.”
The trial can be scientifically informative even if the uridine is ultimately ineffective in subduing suicidal thoughts, according to Kondo.
'Studies don’t always turn out the way you hypothesize,” he says. 'If the uridine dramatically and statistically alters the GABA and glutamine, and there are no changes with placebo, but the uridine doesn’t really help with the clinical symptoms of interest, which are suicidal thoughts and impulses, then we can disregard GABA and glutamine as treatment targets for patients with suicidal ideation.
'But even in that case,” he adds, 'if there are other disorders in psychiatry and neurology where glutamine and GABA are relevant and need to be increased, then right away uridine would present itself as a potential treatment. That could be for seizures, narcolepsy, insomnia, or another disorder. This approach is called experimental medicine. It’s thought to be the next step in the evolution of clinical trials and medication development.”
Measuring uridine against other anti-suicidal drugs
In the medical community, the natural compound uridine is no household word when it comes to possible anti-suicidal medications. The drug has also been met with strong skepticism from psychiatrists who are studying ketamine and related medications for their anti-suicidal potential.
So says Dr. Douglas Kondo, a psychiatrist at the Salt Lake City VA who is leading a randomized trial on uridine for suicidal ideation.
At the same time, Kondo believes uridine offers advantages over ketamine and lithium, another drug VA researchers are examining for its ability to subdue suicidal thoughts. Uridine shares important brain mechanisms with ketamine and lithium, meaning those three substances can possibly alter the same brain chemicals that are believed to reduce suicidal thoughts and actions, he says.
'The pharmaceutical industry is betting hundreds of millions and probably billions of dollars on ketamine,” Kondo says. 'With that much money and so many careers at stake, it makes sense that no one is prepared to believe that a natural product like uridine can produce similar effects. But the preclinical evidence is clear that ketamine increases uridine in the blood and the brain. And ketamine poses significant risks for Veterans if they have a history of PTSD, traumatic brain injury [TBI], psychosis, or substance use.”
Ketamine, which is administered intravenously, is an established anesthetic for surgery and diagnostic procedures. Research has shown that use of the drug for depression can produce rapid short-term effects, although the U.S. Food and Drug Administration (FDA) has not yet approved ketamine to treat depression.
But ketamine is abused recreationally, hence its nickname 'Special K,” and is a common date rape drug. It’s derived from phencyclidine, which is known as PCP or 'angel dust,” and can cause psychotic effects like hallucinations. It can also lead to drowsiness, increased heart rate, elevated blood pressure, delirium, and confusion.
Plus, Kondo says, anesthesiologists may have concerns about administering ketamine to patients with PTSD, TBI, or combat experience because of the possibility of emergence delirium. That reaction occurs immediately after one emerges from general anesthesia and is marked by agitation, confusion, and violent behavior.
Dr. Punit Vaidya, a psychiatrist at the Louis Stokes Cleveland VA Medical Center, is currently leading a study to learn if ketamine can help Vets at high risk for suicide. He’s unaware of any literature on uridine and its psychiatric effects. But he says many studies have found that ketamine has 'rapid and robust” anti-depressant effects, and that other research supports ketamine as a promising treatment for suicidal ideation.
Uridine: less time-consuming than ketamine, lithium
Lithium, an oral drug, is one of the oldest and best-known medications in psychiatry. But how the drug achieves its therapeutic effect is not fully understood. The FDA has approved lithium for treating such illnesses as bipolar disorder, a mental condition marked by alternating periods of depression and emotional highs.
Long-term lithium use is likely to cause thyroid and kidney damage, and lithium overdoses can trigger permanent brain damage or even death, according to Kondo. 'Lithium is very lethal in overdose, which is a terrible irony because it gives a suicidal patient the tool to do precisely what you’re trying to prevent,” he says.
Uridine’s most common side effects are nausea, vomiting, and nose bleeds.
Kondo also says uridine would likely be less expensive and time-consuming than ketamine and lithium. He notes that ketamine requires regular trips to an IV infusion clinic for injections, and that lithium calls for frequent lab work to monitor blood levels, as well as kidney and thyroid function.
Ketamine’s anti-suicidal effect may be short-lived, he adds.
'If the problem comes back after 10 days, you’re left with the question of what to do,” Kondo says. 'Can a Veteran receive an IV every 10 days indefinitely? What would the costs of that be if your goal is to treat every Veteran who experiences suicidal ideation? I suppose it would be worth it if you were able to prevent a suicide. But the costs and logistics of setting up IV infusion clinics would be considerable. A lot of our patients at the Salt Lake City VA live far away—even out of state, in some cases—and would not be able to come to the hospital for IV infusion every 10 days.”
Kondo acknowledges that uridine would likely take up to seven days to subdue suicidal thoughts. That compares with a 35-minute to six-hour time frame for ketamine. Lithium takes effect over a longer time frame, up to several weeks.
He notes that 'in theory” suicidal patients would prefer taking ketamine because of the speed with which it acts. But given ketamine’s potential for recreational abuse and the suicidal crisis in the Veteran community, he stresses that all options must be on the table.
'If uridine were to be effective in seven days, granted that’s longer than 35 minutes or six hours for ketamine to take effect,” he says. 'But we’re in a dire situation now, with 20 suicides every day among Veterans and no FDA-approved drug to treat suicidal ideation for most of them—to say nothing of the civilian adults, adolescents, and even children who attempt suicide or die by suicide. Thus, given uridine’s safety profile and the likelihood that primary care, emergency department, and women’s health doctors would feel comfortable prescribing uridine should it prove effective, we think it would be a worthwhile addition to the drugs available to VA prescribers.”
'Ketamine is the new wonder drug that has rekindled hopes for a real breakthrough in psychiatry, at a time when many of the major pharmaceutical companies have virtually given up on research and development efforts in psychiatry,” Kondo says. 'The large pharmaceutical companies are very excited about ketamine’s possibilities.”
VA is also conducting a large trial to test lithium for suicide prevention, based on promising evidence from past research.
'Lithium is a tried-and-true psychotropic drug,” Kondo says. 'It’s also 'proprietary' to psychiatry, in that almost no physician who isn't a psychiatrist prescribes lithium on a regular basis. Furthermore, it’s considered the gold standard drug for bipolar disorder, which has one of the highest rates of suicide attempts and completed suicides. Lithium has a very significant name recognition factor in the field of mental health.”
`We need to study all three of these treatments’
Kondo admits that data from clinical trials that enroll and treat Veterans with uridine will be required to convince the skeptics about the drug.
'That’s how we’re trained as clinicians,” he says. 'We’re supposed to make treatment decisions based on the evidence.”
To date, the FDA has approved only one drug, clozapine (sold as Clozaril), to treat patients with suicidal ideation. The drug is limited to patients with schizophrenia, which is a small percentage of the Veteran population.
'I’m not saying we shouldn’t do research on ketamine and lithium,” Kondo said at a VA-sponsored symposium in July 2018 that highlighted his work on uridine. 'We need to. The experts agree that the future of our field is going to be `precision medicine,’ which means identifying the best treatment for each patient based on her or her history and characteristics.
'Since no drug works for every patient, we need to study all three of these treatments,” he adds. 'It’s a long, arduous process to try to validate a new medication in psychiatry or in any branch of medicine. We need all kinds of research to try to get a handle on suicide and suicidal thoughts. It’s a very big public health problem that shows no signs of slowing down.”