Brain Inflammation Found in Autopsy Studies of Teen and Adult Suicides
Suicide and depression have both been linked to elevated levels of inflammatory cytokines in the blood and cerebrospinal fluid. A recent study finds that these inflammatory markers are also elevated in the brains of teens and depressed adults who died from suicide.
In autopsy studies, researcher Ghanshyam N. Pandey measured levels of the inflammatory cytokines interleukin-1beta, interleukin 6, and TNF-alpha in the brains of teen suicide victims, and compared these to the brains of teens who died from other causes. Pandey also measured levels of interleukin-1beta, interleukin 6, interleukin 8, interleukin 10, interleukin 13, and TNF-alpha in the prefrontal cortex of depressed adult suicide victims and compared them to levels in adults who died of other causes.
There were abnormalities in the inflammatory markers in the brains of those who died from suicide compared to their matched controls. The suicide victims had higher levels of interleukin-1beta, interleukin 6, and TNF-alpha than the controls. Among the adults, levels of the anti-inflammatory cytokine interleukin 10 were low in the suicide victims while levels of Toll-like receptors (TLR3 and TLR4), which are involved in immune mechanisms, were high.
Brain inflammation has also been observed in positron emission tomography (PET) scans of depressed patients, where signs of microglial activation can be observed. Elevated inflammatory cytokines are also found in the blood of some people with bipolar disorder, depression, and schizophrenia.
Pandey presented this research at the 2016 meeting of the Society of Biological Psychiatry.
Very Low Doses of Opioid Buprenorphine May Reduce Suicidal Ideation
There is no perfect treatment to reduce the risk of suicide in someone who is considering it. Antidepressants can reduce suicidal ideation, but they take several weeks to start working. Intravenous ketamine is used at higher doses as an anesthetic, but in low doses works quickly to reduce suicidal thoughts. However, it requires repeated infusions to keep working. Researchers led by Yoram Yovell are exploring another option: ultra-low doses of the opioid buprenorphine.
In a study published in the American Journal of Psychiatry in 2015, Yovell and colleagues compared low-dose buprenorphine to placebo in 62 patients with no history of substance abuse who had been contemplating suicide for a week or more. Many had attempted suicide before, and more than half met the criteria for borderline personality disorder.
Buprenorphine was administered under the tongue, in doses of 0.1 mg once or twice a day. The researchers used these low doses to minimize the side effects of a drug that could potentially be addictive. Those randomized to receive buprenorphine saw greater reductions in suicidal ideation compared to those who received placebo, both after two weeks and after four weeks.
Use of antidepressants did not affect the likelihood that patients would respond to buprenorphine. The researchers suggest that buprenorphine specifically treats suicidal thoughts, rather than improving depression in general.
Patients with borderline personality disorder, who are often unresponsive to medication, also saw improvement in suicidal ideation after taking buprenorphine, suggesting that the opioid treated a particular symptom of their disorder—sensitivity to feelings of separation from the people with whom they are close.
Patients did not experience withdrawal when they discontinued buprenorphine. Side effects included fatigue, nausea, dry mouth, and constipation. Patients who started out taking 0.2 mg per day were much more likely to drop out than those who started at 0.1 mg per day.
There is another reason the researchers used very low doses. A potential benefit to ultra-low–dose buprenorphine is that even a week’s supply of the drug would not produce a dangerous overdose, so patients could potentially be prescribed a week’s worth of medication to take at home instead of in an inpatient setting.
Buprenorphine is not recommended for patients with a history of substance abuse. The study only explored short-term use of the drug, and replication studies are needed to clarify its effects.
Childhood Maltreatment Associated with Suicide Attempts
A history of childhood maltreatment increases the risk that a person will attempt suicide. Different types of maltreatment, such as physical abuse, emotional abuse, sexual abuse, and neglect, often overlap. In a 2015 study in the Journal of Clinical Psychiatry, researcher Nicolas Hoertel and colleagues used data from an epidemiological survey of 34,653 Americans to clarify the mechanism by which maltreatment is linked to suicide risk.
Hoertel and colleagues found that childhood maltreatment in general was associated with an increased risk of attempting suicide and an earlier age at first suicide attempt. The analysis controlled for demographic characteristics and psychiatric diagnoses. Most of the risk came from effects that were shared across all the types of maltreatment. However, sexual abuse directly conferred an additional risk of suicide attempt.
In an earlier study of 648 outpatients with bipolar disorder by this editor Robert Post and colleagues (led by Gabriele Leverich), 34% had a history of suicide attempts, and these participants had a higher incidence of traumatic stressors in childhood and more stresses at illness onset than those without a history of suicide attempts. A history of sexual abuse in childhood was also linked to an increased risk of a serious suicide attempt in the earlier study, which appeared in the Journal of Clinical Psychiatry in 2003.
Link Between Childhood Trauma and Difficult Course of Bipolar Disorder Clarified
A collaboration between Norwegian and French researchers led by Bruno Etain has clarified the pathway by which childhood trauma is linked to worse outcomes among people with bipolar disorder. The researchers, who presented their work in a poster at the 2015 meeting of the Society of Biological Psychiatry, replicated earlier findings by this editor (Robert Post) that patients who experienced trauma as a child had a more adverse course of bipolar disorder. Etain and colleagues found a link between childhood trauma and an earlier age of onset of bipolar disorder, rapid cycling, suicide attempts, and cannabis misuse.
The researchers identified more than 550 patients with bipolar disorder, who answered questionnaires about their history of bipolar disorder and childhood trauma. Their DNA was also analyzed, and the researchers found that the effect of childhood trauma on age of onset was mediated by the presence of common genetic variants in proteins related to stress (the serotonin transporter) and immune function (Toll-like receptors). They also found that the traits of mood lability (or moodiness) and impulsivity mediated the effects of trauma on clinical outcomes.
The lasting epigenetic effects of child maltreatment and adversity noted in the above abstract are consistent with a large literature showing more epigenetic effects in these individuals than in controls. While genetics are important, the impact of the environment is also substantial.
Ketamine Temporarily Reduces Suicidal Thoughts
Intravenous ketamine can bring about rapid improvement in depressive symptoms among people with treatment-resistant depression. Because of its rapid effects, which can appear after only two hours, ketamine is being investigated as a treatment for people with suicidal thoughts.
At the 2015 meeting of the Society of Biological Psychiatry, Laili Soleimani and colleagues presented a poster about their recent double blind, randomized, controlled pilot study of ketamine inpatients and outpatients who scored highly on a measure of suicidal ideation. The 24 participants were randomized to receive either a single intravenous infusion of ketamine (0.5mg/kg) or a single infusion of midazolam (0.045 mg/kg), which shares ketamine’s anxiety-reducing effects but does not have antidepressant effects. They reported suicidal thoughts at 24 hours post-infusion, 48 hours, 72 hours, and 7 days. At 48 hours, those who received ketamine reported significantly reduced suicidal ideation compared to those who received midazolam, but this effect was no longer significant at the 72-hour mark.
The findings show that ketamine can briefly reduce suicidal ideation, and that the treatment is safe and tolerable for patients. This pilot study paves the way for further study of ketamine to reduce suicidal thinking in people who are at high risk for suicidal behavior.
Ketamine Improves Sleep and Reduces Suicidal Thoughts in Certain Patients
Intravenous ketamine is known for its fast-acting antidepressant effects, which can appear within two hours of an infusion. Researchers are now investigating its use for the reduction of suicidal thoughts. In a study presented in a poster at the 2015 meeting of the Society of Biological Psychiatry, Jennifer L. Vande Voort and colleagues compared the sleep of patients whose suicidal thoughts decreased after a single ketamine infusion (0.5 mg/kg over 40 minutes) to those whose suicidal thoughts remained.
Study participants whose suicidal thoughts diminished after one infusion of ketamine had better sleep quality the following night, with fewer disruptions in sleep than among those who did not have an anti-suicidal response to ketamine. The participants who responded well to ketamine had sleep quality similar to that of healthy controls.
Vande Voort and colleagues hope that these new findings about ketamine’s effect on sleep may provide clues to the biological mechanism behind ketamine’s effect on suicidal ideation.
Trace Amounts of Lithium in Drinking Water Associated with Lower Suicide Rates in Men
Studies in Japan, Austria, and Texas have reported that trace amounts of lithium in drinking water are associated with lower suicide rates. A new study seeks to clarify these findings by removing any statistical factors other than lithium levels that could produce these results.
The study, published in the Journal of Clinical Psychiatry, collected 434 lithium samples in drinking water over three years, and compared these with suicide rates in the population of 274 municipalities of Kyushi Island in Japan.
The researchers, led by Nobuyoshi Ishii, then controlled for size of population, proportion of elderly people, proportion of one-person households, proportion of people with a college education or more, proportion of people engaging in primary industry, overall unemployment rates, annual marriage rates, annual mean temperature, and annual savings in per person in Japan’s popular postal bank. In places with slightly higher trace levels of lithium in drinking water, there was a lower rate of suicides in men. Suicide rates for women and overall were not significantly associated with lithium levels.
Abnormal Levels of Cytokines Found in Brains of Suicide Victims
Cytokines are chemical messengers that send signals between immune cells and between the immune system and the central nervous system. Their levels in blood are considered a measure of inflammation, which has been implicated in depression and stress. A new study by Ghanshyam Pandey and colleagues reported increased levels of cytokines in the brains of people who committed suicide. In the prefrontal cortices of people who died by suicide, there were significantly elevated levels of the inflammatory cytokines IL-1 beta, IL-6 and TNF-alpha compared to the brains of normal controls. There were also lower levels of protein expression of the cytokine receptors IL-1R1, IL-1R2 and IL-1R antagonist (IL1RA) in the suicide brains compared to controls.
The researchers concluded that abnormalities in proinflammatory cytokines and their receptors are associated with the pathophysiology of depression and suicide. This research provides direct confirmation of the indirect measures of inflammation observed in the blood of depressed patients compared to controls.
High Risk of Suicide Attempts in Bipolar Disorder with Substance Abuse
At the 2014 meeting of the International College of Neuropsychopharmacology, researcher Rieva et al. reported that 60% of bipolar patients with comorbid alcohol abuse have attempted suicide, and 48% of bipolar patients with cocaine abuse have attempted suicide. Thus, both of these comorbidities deserve specific attention and treatment. Unfortunately there are currently no Federal Drug Administration–approved drugs for bipolar patients with these comorbidities. The most promising treatments, based on data in patients with primary addictions, are the nutritional supplement N-acetylcysteine and topiramate, which have both performed better than placebo in studies of alcohol and cocaine abuse disorders.
FDA Warning About Antidepressants Followed by Drop in Use, and Increase in Suicide Attempts
A decade ago the Federal Drug Administration (FDA) released several warnings that children, adolescents (ages 10–17), and young adults (ages 18-29) taking antidepressants were at increased risk for suicidal ideation and behavior. A recent study found that following these warnings, antidepressant use among adolescents, young adults, and adults dropped, and psychotropic drug poisonings (a validated measure of suicide attempts) increased among adolescents and young adults. Numbers of completed suicides did not change for any age group.
The decision to place the warnings on antidepressant packaging was somewhat controversial because it was based on studies that were not necessarily designed to measure suicide risk. The relationship between depression, medication, and suicide is complicated. Medication can improve mood, but patients may seek out medication because of pre-existing suicidal thoughts, and the medication may not reduce these in young people.
The reduction in antidepressant use that occurred after the warnings was accompanied by a drop in depression diagnoses in children and adults. Studies have suggested that the decreases in antidepressant were not accompanied by increases in other treatments, such as psychotherapy or atypical antipsychotics, among young people. Increased monitoring of patients was called for in the FDA’s box warning, but did not take place.
The study of the aftermath of the FDA warnings, published by Christine Y. Lu et al. in a 2014 article in the journal BMJ, used data from 11 insurance networks throughout the US. The researchers used an interrupted time series study design, which is used to show whether a policy causes an abrupt change in the expected slope of study outcomes. Data covered the pre-warning period (first quarter of 2000 to third quarter of 2003), the warning “phase-in” period (last quarter of 2003 to last quarter of 2004) and the post-warning period (first quarter of 2005 to last quarter of 2010). The study cohorts included around 1.1 million adolescents, 1.4 million young adults, and 5 millions adults per quarter.
Among adolescents, the previously upward trend in antidepressant use declined by 31.0% in the second year after the warnings, and psychotropic drug poisonings increased by 21.7% (a figure that was statistically significant for males). Poisonings by any drug increased by 13.9% in the second year after the warnings. After 2008, the downward trend in antidepressant use reversed, indicating that either the initial effects of the warning had worn off or that modifications to the warnings in May 2007, which encouraged patients and doctors to consider the risk of antidepressants alongside the risk of leaving mood disorders untreated, led to increased use.
Among young adults, the upward trend in antidepressant use declined by 24.3% in the second year after the warnings, and psychotropic drug poisonings increased by 33.7%, a statistically significant change for both male and female patients.
Among adults, to whom the warnings were not directed, antidepressant use decreased by 14.5% in the second year after the warnings.
The study by Yu et al. is the first to show that suicide attempts actually increased after the FDA warnings. The authors suggest that the increase in suicide attempts might be a consequence of undertreating mood disorders, since antidepressant use dropped simultaneously. The warnings and related media attention may have led to these unintended consequences, since media reports can sometimes be oversimplified.
