Using lithium to reduce suicide risk in bipolar disorder
Why lithium is the best medication option, and how to make it work better.
As the treatment arsenal for bipolar (manic-depressive) disorder has expanded in recent years, some experts have become concerned that lithium — a mainstay of treatment since FDA approval in 1970 and still considered the most effective option for long-term therapy — may be falling out of favor.
Treatment options besides lithium include anticonvulsants with mood-altering properties, notably valproate (Depakene, Depakote), carbamazepine (Epitol, Tegretol), and lamotrigine (Lamictal), as well as antipsychotics and antidepressants. As the options have multiplied, prescribing patterns have shifted, not only for acute manic or depressed phases of bipolar illness, when agents that target specific symptoms may be required in addition to lithium, but also for long-term maintenance therapy intended to prevent recurrences of the illness and to minimize morbidity between episodes.
In the United States, valproate is now being used twice as often as lithium as a treatment for bipolar disorder, especially for long-term maintenance therapy, despite questions about its relative effectiveness. And antidepressants are being used more often than any other medications to treat patients with bipolar disorder. As more new drugs become available, the trend in treating bipolar disorder is toward increasingly complex regimens, involving untested combinations of a variety of drugs.
This trend concerns leading experts on bipolar disorder, such as Dr. Ross Baldessarini, a professor of psychiatry and neuroscience at Harvard Medical School and director of the psychopharmacology program and the International Consortium for Bipolar Disorders Research at McLean Hospital. Reducing risk of suicide is a major public health challenge, and suicide rates in patients with bipolar disorder are among the highest of any diagnostic group. "Long-term use of lithium is the only treatment we have that is proven to reduce risk of suicides and life-threatening attempts," Dr. Baldessarini says.
Understanding lithium's benefits
According to international statistics, about three in 1,000 people with bipolar disorder die by suicide each year — a rate that is 20 times higher than the rate in the general population. About one in 100 make life-threatening attempts.
Lithium reduces the risk of suicide and of attempted suicide for patients with bipolar disorder, although it does not reduce the risk to the level in the general population. Studies have found that people with bipolar disorder taking lithium were significantly less likely to commit suicide than others not treated with lithium, or given other treatments, but their suicide rate was still nearly 10 times higher than that of the general population.
Mood stabilization.Why lithium reduces the risk of suicide in people with bipolar disorder is not entirely clear, but it is likely that the drug's mood-stabilizing properties contribute. Lithium is rare in that it has proven effective, long-term, against recurrences of both mania and bipolar depression, and it is also effective in treating patients with acute mania. Maintenance therapy with lithium can reduce risk of recurrence of both mania and bipolar depression, and is effective in about two-thirds of patients. Although some doctors and patients have turned away from lithium over the years, a study determined that overall effectiveness of lithium has remained similar since it was first put into widespread clinical use in the United States in 1970.
In contrast, the use of antidepressants for bipolar disorder is much more controversial. There is no evidence that their use reduces risk of suicide in this population, says Dr. Baldessarini. Researchers are still trying to establish which patients might benefit from using antidepressants, and how significant a risk the drugs pose of triggering mania or mixed agitated-dysphoric states, or inducing rapid mood fluctuations between mania and depression, especially when antidepressant treatment is continued long-term.
Reducing lethality.Lithium may also lower suicide rates in people with bipolar disorder by reducing the potential lethality of suicide attempts. About 20 or 30 people in the general population attempt suicide for every one person who dies. But among people with mood disorders, there is one death per approximately five or six attempts — indicating that the suicidal acts are somehow more lethal among patients with bipolar disorder or major depression. Lithium treatment decreases the ratio of suicides to attempts in people with bipolar disorder by about twofold — effectively reducing the lethality of suicide attempts.
Although it's not clear why lithium has this effect, Dr. Baldessarini and others believe that the drug counters irritability, anger, and impulsivity that contribute to the lethality of suicide attempts. Antidepressant treatment is less likely to affect aggression and impulsivity, although it does appear to improve suicidal ideation in depressed adults.
Clinical monitoring.To be used safely, lithium treatment requires regular clinical monitoring, including visits to a qualified clinician and blood tests. Although it's hard to document, it is possible that this ongoing clinical contact itself reduces risk of suicide because clinicians are more apt to notice changes in a patient's mood or the development of suicidal ideation, and intervene before a patient commits suicide.
Overcoming lithium's challenges
Key medical challenges in lithium maintenance therapy include toxicity and side effects. But by working together, doctors and patients can usually avoid or overcome them.
Toxicity.Lithium has a narrow therapeutic window, which means it can become toxic if blood levels increase much above the therapeutic range (between 0.6 and 1.2 millimoles per liter, or mmol/L). Blood levels only two to three times greater can cause medical problems, and somewhat higher levels may be deadly. Long-term lithium treatment also carries low but significant risks of damaging the kidneys and suppressing normal functioning of the thyroid gland. For all these reasons, regular clinical monitoring is required for its safe use.
To avoid toxicity, lithium is started at relatively low doses and increased gradually. Blood levels are monitored more regularly during the first months of therapy. Clinicians usually order lithium blood tests every few days at first, then weekly, monthly, and, assuming all goes well, quarterly or even semiannually once a reliable individualized dose is established. The American Psychiatric Association (APA) recommends that doctors perform baseline tests of kidney, heart, and thyroid function on any patient over age 40. The APA also recommends testing kidney function every two to three months for the first six months of lithium treatment, and then following up with kidney and thyroid function tests at least annually or semiannually afterward, unless more frequent testing is indicated medically.
Adverse effects.Patients find the most bothersome side effects of lithium are weight gain, cognitive impairment, clumsiness, and tremors. Although the cognitive impairment is generally considered mild by doctors, it can be frustrating to patients, especially those with professional or creative jobs. As many as 65% of patients taking lithium develop tremors.
Some of these side effects might be lessened if the lithium dose is reduced during long-term treatment. "Many American psychiatrists tend to be heavy handed when it comes to dosing, using drugs aggressively," Dr. Baldessarini explains. Because he collaborates frequently with colleagues in other countries, he's noticed differences in dosing practices overseas. "In the United States, doctors tend to aim for therapeutic levels of 0.8 to 1.0 mmol/L of lithium. That may be fine for treating acute mania, but is often excessive for maintenance, and can compromise patient tolerability and acceptance of the treatment. In Europe, doctors tend to aim more for 0.6 to 0.8 mmol/L during long-term treatment."
Another way to reduce side effects during the day is for patients to take most of their lithium dose at night. However, some patients may not be able to tolerate gastrointestinal side effects of large single doses.
Discontinuing lithium safely
Many patients with bipolar disorder stop taking lithium at some point — for any number of reasons. Some patients can't tolerate the side effects. Women who want to get pregnant often stop lithium because of risk to a developing fetus, especially in the first trimester. And of course, people with bipolar disorder, like people with all sorts of chronic illnesses, may find it hard to adhere to medication regimens and lifestyle changes year after year, especially when they are feeling well.
Regardless of the reason for stopping lithium, it's important to reduce the dose slowly rather than stop abruptly. Otherwise, patients greatly increase their risks of relapse and of suicide.
In one analysis, Dr. Baldessarini and colleagues found that the risk of experiencing a new episode of mania or bipolar depression was markedly increased for several months after stopping lithium treatment — far more than would be expected if treatment had never begun. This recurrence risk was several times greater among patients who reduced lithium doses rapidly (within one to 14 days) than among those who reduced doses gradually (over two weeks or longer).
The impact of lithium discontinuation on suicide risk is even more stark. One analysis found that patients with bipolar disorder who stopped taking lithium were 20 times more likely to commit suicide within 12 months than patients still taking lithium. After a year, suicide risk subsided back to pretreatment levels. Gradual discontinuation of lithium therapy offered some protection, but suicide risk remained significant.
"Lithium is far from being an ideal medicine, but it's the best agent we have for reducing the risk of suicide in bipolar disorder," Dr. Baldessarini says, "and it is our best-established mood-stabilizing treatment." If patients find they can't tolerate lithium, the safest option is to reduce the dose as gradually as possible, to give the brain time to adjust. The approach could be lifesaving.
Baldessarini RJ, et al. "Suicide in Bipolar Disorder: Risks and Management,"CNS Spectrum(June 2006): Vol. 11, No. 6, pp. 465–71.
Baldessarini RJ, et al. "Discontinuing Lithium Maintenance Treatment in Bipolar Disorders: Risks and Implications,"Bipolar Disorders(Sept. 1999): Vol. 1, No. 1, pp. 17–24.
Freeman MP, et al. "Lithium: Clinical Considerations in Internal Medicine,"American Journal of Medicine(June 2006): Vol. 119, No. 6, pp. 478–81.
Sachs GS, et al. "Effectiveness of Adjunctive Antidepressant Treatment for Bipolar Depression,"New England Journal of Medicine(April 26, 2007): Vol. 356, No. 17, pp. 1711–22.
'Surprising' study suggests exercise may make dementia worse
Exercise does not slow down mental decline and may even make dementia worse, a newstudysuggests.
Oxford Universityfound that people with mild to moderate dementia who went to the gym twice a week for up to 90 minutes went downhill faster than those who abstained.
Although the difference between the two groups was small, the researchers say exercise should not be recommended for people with dementia and called for future trials to ‘consider the possibility that some types of exercise intervention might worsen cognitive impairment.’
Previous research had suggested that exercise could prevent mental decline, and stave off diseases like Alzheimer’s, so experts and charities said they were surprised by the findings.
Commenting on the study, which was published in theBMJ, Rob Howard, Professor of Old Age Psychiatry atUniversity College Londonsaid: “Had this been instead an improvement in cognitive functioning with exercise we would all have been excited about finding something positive in the, so far, depressing fight against dementia.
“On this basis, I don’t think we should ignore the possibility that exercise might actually be slightly harmful to people with dementia.”
Dr James Pickett, Head of Research and Development atAlzheimer's Society, added :“The results are somewhat surprising as we would anticipate that exercise would have positive effects.”
Around 850,000 people in Britain currently suffer from dementia and there are currently no treatments to reverse or slow down the condition. The numbers are expected to rise as the population ages.
The difference between dementia and Alzheimers – in 60 seconds
The new trial involved 494 people with an average age of 77 years who lived in England and all suffered from mild to moderate dementia.
The participants were assigned to a supervised exercise and support programme or usual care.
The programme consisted of 60-90 minute group sessions in a gym twice a week for four months, plus home exercises for one additional hour each week with ongoing support.
All were tested using the Alzheimer’s disease assessment score at the beginning of the study and then at six and 12 months.
After taking account of potentially influential factors, the researchers found that cognitive impairment declined over the 12-month follow-up in both groups.
The exercise group showed improved physical fitness in the short term, but higher ADAS-cog scores at 12 months (25.2 v 23.8) compared with the usual care group, indicating worse cognitive impairment.
Commenting on the findings, Dr Brendon Stubbs, Post-doctoral Research Physiotherapist at the Institute of Psychiatry, Psychology and Neuroscience,King's College London, said: "Whilst previous smaller studies have suggested that exercise can prevent or improve cognitive decline in people with Alzheimer’s disease, this robust and very large study provides the most definitive answer we have on the role of exercise in mild-moderate Alzheimer’s disease.
“The study finds that whilst it is possible for interested people with Alzheimer’s disease to engage in a robust supervised exercise program, this does not appear to delay cognitive decline and does not improve any other outcome besides physical fitness.
“The search for effective lifestyle interventions that can delay cognitive decline in dementia must continue.”
Dr Elizabeth Coulthard, Consultant Senior Lecturer in Dementia Neurology at theUniversity of Bristol, said: “The findings here are in keeping with the thrust of current research that suggests dementia is hard to modify once it is well established.
“There has been some promising work on exercise in people with milder symptoms such as those with Mild Cognitive Impairment. Physical activity still holds promise to delay dementia onset in people at risk of developing the disease.
“Broadly, physical activity and healthy ageing go hand in hand. However, targeting physical activity as an intervention to improve specific disease processes is a challenge."2330
New Horizons’ best view of Pluto’s craters, mountains and icy plains
This video includes the sharpest views of Pluto that NASA’s New Horizons spacecraft obtained during its flyby on July 14, 2015.(NASA.gov Video/ YouTube)
Three years ago, NASA’sNew Horizons, the fastest spaceship ever launched,raced past Pluto, spectacularly revealing the wonders of that newly seen world. This coming New Year’s Eve — if all goes well on board this small robot operating extremely far from home — it will treat us to images of themost distant body ever explored, provisionally named Ultima Thule. We know very little about it, but we do know it’s not a planet. Pluto, by contrast — despite what you’ve heard — is.
Why do we say this? We are planetary scientists, meaning we’ve spent our careers exploring and studying objects that orbit stars. We use “planet” to describe worlds with certain qualities. When wesee one like Pluto, with its many familiar features —mountains of ice, glaciers of nitrogen, a blue sky with layers of smog — we and our colleagues quite naturally find ourselves using the word “planet” to describe it and compare it to other planets that we know and love.
In 2006, the International Astronomical Union (IAU) announced an attempted redefinition of the word “planet” that excluded many objects, including Pluto. We think that decision was flawed, and that a logical and useful definition of planet will include many more worlds.
We find ourselves using the word planet to describe the largest “moons” in the solar system. Moon refers to the fact that they orbit around other worlds which themselves orbit our star, but when we discuss a world likeSaturn’s Titan, which is larger than theplanet Mercury, and has mountains, dunes and canyons, rivers, lakes and clouds, you will find us — in the literature and at our conferences — calling it a planet. This usage is not a mistake or a throwback. It is increasingly common in our profession and it is accurate.
New Horizons spacecraft heads to Pluto
The New Horizons spacecraft reached Pluto in 2015. NASA launched New Horizons in 2006.(NASA)
Most essentially, planetary worlds (including planetary moons) are those large enough to have pulled themselves into a ball by the strength of their own gravity. Below a certain size, the strength of ice and rock is enough to resist rounding by gravity, and so the smallest worlds are lumpy. This is how, even before New Horizons arrives, we know that Ultima Thule is not a planet. Among the few facts we’ve been able to ascertain about this body is that it is tiny (just 17 miles across) and distinctly nonspherical. This gives us a natural, physical criterion to separate planets from all the small bodies orbiting in space — boulders, icy comets or rocky and metallic asteroids, all of which are small and lumpy because their gravity is too weak for self-rounding.
The desire to reconsider the meaning of “planet” arose because of two thrilling discoveries about our universe: There are planets in unbelievable abundance beyond our solar system — called “exoplanets” — orbiting nearly every star we see in the sky. And there are a great many small icy objects orbiting our sun out in Pluto’s realm, beyond the zone of the rocky inner worlds or “terrestrial planets” (like Earth), the “gas giants” (like Jupiter) and the “ice giants” (like Neptune).
In light of these discoveries, it did then make sense to ask which objects discovered orbiting other stars should be considered planets. Some, at the largest end, are more like stars themselves. And just as stars like our sun are known as “dwarf stars” and still considered stars, it made some sense to consider small icy worlds like Pluto to occupy another subcategory of planet: “dwarf planet.”
But the process for redefining planet was deeply flawed and widely criticized even by those who accepted the outcome. At the 2006 IAU conference, which was held in Prague, the few scientists remaining at the very end of the week-long meeting (less than 4 percent of the world’s astronomers and even a smaller percentage of the world’s planetary scientists) ratified a hastily drawn definition that contains obvious flaws. For one thing, it defines a planet as an object orbiting around our sun — thereby disqualifying the planets around other stars, ignoring the exoplanet revolution, and decreeing that essentially all the planets in the universe are not, in fact, planets.
Even within our solar system, the IAU scientists defined “planet” in a strange way, declaring that if an orbiting world has “cleared its zone,” or thrown its weight around enough to eject all other nearby objects, it is a planet. Otherwise it is not. This criterion is imprecise and leaves many borderline cases, but what’s worse is that they chose a definition that discounts the actual physical properties of a potential planet, electing instead to define “planet” in terms of the other objects that are — or are not — orbiting nearby. This leads to many bizarre and absurd conclusions. For example, it would mean that Earth was not a planet for its first 500 million years of history, because it orbited among a swarm of debris until that time, and also that if you took Earth today and moved it somewhere else, say out to the asteroid belt, it would cease being a planet.
To add insult to injury, they amended their convoluted definition with the vindictive and linguistically paradoxical statement that “a dwarf planet is not a planet.” This seemingly served no purpose but to satisfy those motivated by a desire — for whatever reason — to ensure that Pluto was “demoted” by the new definition.
By and large, astronomers ignore the new definition of “planet” every time they discuss all of the exciting discoveries of planets orbiting other stars. And those of us who actually study planets for a living also discuss dwarf planets without adding an asterisk. But it gets old having to address the misconceptions among the public who think that because Pluto was “demoted” (not exactly a neutral term) that it must be more like a lumpy little asteroid than the complex and vibrant planet it is. It is this confusion among students and the public — fostered by journalists and textbook authors who mistakenly accepted the authority of the IAU as the final word — that makes this worth addressing.
Last March, in Houston, planetary scientists gathered to share new results and ideas at the annual Lunar and Planetary Science Conference. One presentation, titled “A Geophysical Planet Definition,” intended to set the record straight. It stated: “In keeping with both sound scientific classification and peoples’ intuition, we propose a geophysically-based definition of 'planet' that importantly emphasizes a body’s intrinsic physical properties over its extrinsic orbital properties.” After giving a precise and nerdy definition, it offered: “A simple paraphrase of our planet definition — especially suitable for elementary school students — could be, ‘round objects in space that are smaller than stars.’”
It seems very likely that at some point the IAU will reconsider its flawed definition. In the meantime, people will keep referring to the planets being discovered around other stars as planets, and we’ll keep referring to round objects in our solar system and elsewhere as planets. Eventually, “official” nomenclature will catch up to both common sense and scientific usage. The word “planet”predates and transcends science. Language is malleable and responsive to culture. Words are not defined by voting. Neither is scientific paradigm.