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.
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.
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.
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.
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.
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.
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.
Suicide is a serious risk for people with mood disorders. We have noted before that various studies of lithium show that the drug lowers suicide risk in people with mood disorders. A 2013 meta-analysis by Andrea Cipriani et al. in the journal BMJ confirms this finding. The review of 48 randomized controlled trials comparing lithium with placebo or other active drugs in the long-term treatment of mood disorders showed that lithium reduces the risk of suicide and death from any cause.
Lithium was more effective than placebo at reducing number of suicides and deaths from any cause, and more effective than carbamazepine and anticonvulsants in general at reducing deliberate self-harm. The authors wrote that lithium seems to reduce risk of suicide and death by more than 60% compared to placebo.
Lithium may reduce suicide risk by preventing relapse of mood disorders, but it may also have other mechanisms of action, such as decreasing aggression or impulsivity.
One thing to note about these findings is that the reduction in suicide risk also applies to those with unipolar depression, not just those with bipolar disorder. There is a case to be made that lithium treatment could be targeted specifically to reduce suicide risk.
Blüml et al. reported in the Journal of Psychiatric Research in 2013 that among 226 counties in Texas, the ones with higher trace levels of lithium in the public water supply had lower rates of completed suicide in the general population than did the counties with lower lithium levels. The naturally occurring lithium levels in public water supplies in the geographic regions described in this study ranged from 2.8 to 219 ?g/l or 0.00043 to 0.0315 mmol/l (much lower than the levels used to treat bipolar disorder).
This is the fourth positive study describing this effect, including two in Texas, one in Japan, and one in Austria. (One study from part of England failed to show this relationship, though levels measured in that study had a much lower and restricted range, from less than 1 to 21 ?g/l.) The most recent studies have collected more water samples and used more sophisticated statistical analyses to control for socioeconomic and a variety of other demographic effects on suicide.
Editor’s Note: Why higher trace levels of lithium occurring naturally in the water supply should have this anti-suicide effect in the general population is unknown, but it is a fascinating finding. It also gives indirect credence to the clinical findings in patients with unipolar and bipolar disorder that lithium (albeit in the much higher levels achieved with medication) has anti-suicide effects.
Suicide is an unfortunate consequence of bipolar disorder in 10-15% of patients. A study by Manchia et al. examined suicidal behavior in 737 families of bipolar patients, including 4,919 first-degree relatives. Suicidal behavior ran in families and was more prevalent in those with an early age of onset and a shorter duration of illness. The good news: lithium treatment decreased suicide risk independent of its degree of effectiveness in treating bipolar disorder. Those on lithium also had a longer median age of survival (73 versus 65 years).
Editor’s Note: These data are consistent with a variety of other studies and raise the question why lithium is used less frequently in the US than in many European countries and Canada. Given its neuroprotective effects, its prevention of suicide and dementia, and its positive effects on longevity, it is hard to see why lithium is not included in the treatment regimens of more patients (at whatever dosage is well-tolerated), even if it alone is not sufficient for treating their manic and depressive episodes.
Research (by this editor Robert Post and colleagues) shows that bipolar disorder is a more pernicious illness in almost all respects in the US compared to the Netherlands and Germany (International Journal of Neuropsychopharmacology, 2011). Whether bipolar illness would be less severe in the US if it were more often treated with lithium is an unanswered question. The field cannot provide an answer with systematic prospective controlled data, as most study designs would be unethical (i.e. would deny useful treatment to suffering patients), although one large randomized comparative study called BALANCE did show the superiority of lithium over valproate. However, individual patients in consultation with their physician could evaluate the evidence and request that lithium be considered in their treatment regimen.
If a patient has some clinical predictors of a likely good response to lithium, the decision to include lithium should be a slam-dunk. Some of these include: a positive family history of mood disorder, especially bipolar disorder; a classic course with distinct episodes and clear periods of wellness; manic episodes that are euphoric as opposed to dysphoric (i.e. anxious/irritable); lack of an anxiety disorder or substance abuse comorbidity; the absence of mood-incongruent delusions; and a sequence of episodes of mania followed by a depression and then a well interval (MDI) rather than the sequence of DMI.