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.
For more references, please see www.health.harvard.edu/mentalextra.
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