September 17th 2003

 

According to JAMA (The Journal of American Medical Association--read full study below) Lithium, an inexpensive drug for bipolar disorder (Which is not patentable, which is why it has been shunted aside in favor of newer, more heavily marketed drugs) is actually much more effective at preventing suicides and should be the drug of choice for first treatment of such patients. Lithium is just as effective as the newer Depakote at preventing the wild mood swings associated with this widespread, disabling disorder, but patients who take Depakote are 2.7 times as likely to commit suicide as those who take lithium, the report says. That is a major difference, because suicide is 10 to 20 times more common among bipolar patients than in society at large.

"Psychiatry has never been able to say that what we do saves lives, which is the ultimate goal of medicine," said Dr. Frederick Goodwin of the George Washington University Medical Center, who led the study of more than 20,000 patients. "With lithium, now we can." The new study, reported today in the Journal of the American Medical Assn., "makes an argument that lithium should be reconsidered as the first-line treatment [for bipolar disorder], which is probably where it should have been all along," added Dr. Norman Sussman, a psychopharmacologist at New York University who was not involved in the study. "If we can reduce the risk of suicide, that is a good argument for using the drug."

Bipolar disorder — in which patients swing between deep depression and manic highs — is one of the most common mental problems in the United States, affecting 1.3% to 1.5% of the population. As many as one in every five bipolar patients attempt suicide at some time in their lives. Thirty years ago, there were no drugs to treat the disorder. Then researchers discovered that lithium smoothed the mood swings in as many as two-thirds of the patients. It was the first important drug for mental problems of any sort. But the drug could not be patented, so pharmaceutical companies couldn't afford research and promotion. Nonetheless, lithium was widely used until Depakote — generically known as divalproex — became available in the early 1990s.

As recently as 1994, Goodwin said, lithium accounted for 80% of prescriptions for bipolar disorder. In 2001, divalproex accounted for more than 70%. Annual sales of lithium are now about $43 million per year, while those of Depakote are more than $1 billion, he said. Many young psychiatrists, he noted, have not even received any training in using lithium. Some have been swayed by reports of excessive side effects associated with lithium, Goodwin added, but the two drugs actually have about the same risks. Goodwin and his colleagues studied the records of 20,638 bipolar patients who were members of two HMOs, the Kaiser Permanente Medical Care Program in Oakland and the Group Health Cooperative in Seattle.

They did not consider the efficacy of the two drugs, but rather looked at deaths and hospital admissions resulting from suicide attempts. They found 31.3 suicide attempts per 1,000 people per year among those taking divalproex compared with 10.8 attempts among those taking lithium. There were 1.7 suicides per 1,000 people per year in the first group, compared with 0.7 in the second group. Goodwin conceded that the team does not know why the rates were so much better for lithium users. Lithium is effective at reducing depression, and most suicide attempts occur during the depressive stages of bipolar disorder. But other effective antidepressants do not reduce suicide risk, so it is unlikely that that is the primary reason, he said. Independent studies have also shown that lithium is good at reducing both impulsive and aggressive behavior. "Suicide is a very aggressive act," Goodwin said, and it is also an impulsive one, so the answer might lie in that direction. Neither Goodwin nor Sussman is advocating stopping the use of divalproex. "There is no single drug that is best for everyone," Goodwin said. "Some patients respond better to one than to the other." In fact, the two drugs are often used now in combination, which may provide the reduced suicide risk of using lithium alone. But no one knows. Because most patients in the study received only one or the other, there were not enough receiving both to reach any conclusions about the effect on suicides. Goodwin also noted that there are newer drugs, such as lamotrigine (trade named Lamictal), that may be better than divalproex. But so far, there have been no studies on whether they reduce the risk of suicide.

 

Suicide Risk and Treatments for Patients With Bipolar Disorder

Ross J. Baldessarini, MD; Leonardo Tondo, MD

JAMA. 2003;290:1517-1519.

Bipolar disorder, one of the most common severe mental illnesses, includes type 1 (with mania and usually recurrent depression) and type 2 (recurrent major depression with hypomania).^1-2 Lifetime prevalence for type 1 bipolar disorder is approximately 1%, but inclusion of more broadly defined conditions increases this rate to 2% to 5%.³ Bipolar disorder can begin in childhood or adolescence,⁴ continues throughout life, and is extraordinarily costly—financially as well as clinically and socially.⁵ The course of bipolar disorder is episodic but highly variable, with potential for high levels of severity and recurrence intensity, disproportionately high depressive morbidity, and comorbidity with substance abuse and anxiety disorders.³ Bipolar depression can be present during 20% to 30% of patients' time, even during prophylactic treatment,^6-8 and is closely associated with disability and mortality.^{3, 9-10} Bipolar disorder proves fatal in a high proportion of patients from complications of risk-taking behavior, comorbid stress-sensitive medical illnesses, and especially suicide.^{3, 9-10} These characteristics mark bipolar disorder as a major unsolved public health challenge.

Treatment for bipolar disorder was revolutionized in the early 1970s by the introduction of US Food and Drug Administration (FDA)–approved long-term prophylactic treatment with lithium carbonate for preventing recurrences of mania and bipolar depression. Lithium remains the international standard of comparison for an increasing number of innovative treatments introduced in recent years, including several anticonvulsants and modern antipsychotics.^11-12 However, evidence for long-term prophylactic effectiveness of agents other than lithium remains limited, and comparisons of specific agents in particular phases of bipolar disorder are needed.¹¹ No currently available treatment provides full protection from recurrences of manic, mixed manic-depressive, major depressive, or highly prevalent milder depressive states.^11-12

Among patients with type 1 or 2 bipolar disorder, long-term lithium monotherapy can reduce mania or hypomania and depression similarly, by about two thirds.^11-12 Most other agents with proposed mood-stabilizing effects appear to be more effective against mania and hypomania than against bipolar depression, with the possible exception of lamotrigine.^{11, 13} For example, in well-designed comparisons with other agents, divalproex has yielded considerably less long-term protective effects against bipolar depression or mixed dysphoric-agitated states than against mania,^14-15 although divalproex has been shown to limit depression by some measures.¹⁶ Addition of an antidepressant is unlikely to resolve the problem of residual depression, owing to inconsistent responsiveness of bipolar depression to antidepressants and their risk of inducing mania or emotional instability in patients with bipolar disorder.^17-18

As a cause of premature death in patients with bipolar disorder, suicide represents an extraordinarily high risk, with an estimated rate of 0.40% per year vs the international general population average of 0.017% per year, with a standardized mortality ratio of 22.^19-20 For comparison, the average standardized mortality ratio for suicide is about 20 among persons with unipolar major depression and 8.4 for those with schizophrenia.¹⁹ Moreover, suicide attempts by patients with bipolar disorder have an increased lethal potential. Among patients with bipolar disorder, rates of suicide attempts are only 5 times the rates of completed suicides, whereas in the general population, rates of suicide attempts are 10 to 20 times the rates of completed suicides.²¹ Suicide in patients with bipolar disorder is strongly associated with depressive and dysphoric-agitated (mixed) states.^21-22 Suicidal risk may be greater in type 2 bipolar disorder,^23-24 characterized by less severe episodes of elevated mood than type 1 but with severe recurrent depression, often misdiagnosed as nonbipolar major depression and not consistently treated with mood-stabilizing agents.²⁵

Long-term use of lithium is the only treatment consistently associated with much lower rates of suicide and life-threatening suicide attempts in bipolar disorder. In a recent meta-analysis of 22 studies with data permitting estimates of annual rates of suicide in patients with mainly bipolar disorder, the computed risk of completed suicide was 8.85 times less with long-term lithium treatment than without it.²⁶ Nevertheless, the rate of completed suicides among patients treated with lithium remained 10 times higher than that in the general population.²⁷ Similarly large proportional reductions in the risk of suicide attempts (to levels close to population base rates) also were associated with lithium treatment.^20-21,27 These benefits were sustained over many years, but discontinuation of lithium was associated with a sharp temporary increase in suicide risk for several months; this increase was half as large when lithium was discontinued gradually during a span of at least several weeks.²¹ Since some earlier studies included patients with recurrent unipolar major depression along with those with bipolar disorder,^26-27 this beneficial effect of lithium may extend to suicidal risk in patients with nonbipolar depression, but this hypothesis requires study.^26-27

Differential protective effects of specific mood-altering agents against bipolar depression are likely to be important for reducing suicide risk, but relevant direct comparisons are rare.^11-12,18 Such comparisons suggest less overall clinical benefit with long-term use of carbamazepine than with lithium²⁸ and greater suicide risk with this anticonvulsant than with lithium.²⁹ Valproic acid preparations have largely displaced lithium in the United States for treatment of mania and long-term prophylaxis for bipolar disorder despite limited research support for the prophylactic effectiveness of this anticonvulsant, particularly against recurrences of bipolar major depression.^{11, 13-14,16} Until now, there has been no specific studies of the effects of valproate on suicide risk among patients with bipolar disorder.

In this issue of THE JOURNAL, Goodwin and colleagues³⁰ report evidence that anticonvulsant treatment (almost entirely with divalproex) among patients with bipolar disorder was associated with higher rates of suicide and suicide attempts than among those treated with lithium for varying periods of time. Goodwin et al analyzed data involving large numbers of adult and adolescent bipolar disorder outpatients (N = 20 638) obtained from computerized databases from 2 large health plans in California and Washington State, with efforts to avoid likely confounding. Such records can vary in accuracy and completeness, and estimates of drug exposure times require assumptions about the relationship of pharmacy records to actual drug taking and about combining periods with and without putative drug exposures fragmented over time. Nevertheless, such limitations should apply similarly among the 3 main treatment conditions analyzed (lithium, anticonvulsants divalproex or carbamazepine, or neither), and should not produce systematic bias.

The adjusted risk ratios for completed suicides and attempts during treatment with divalproex vs lithium were 2.7 and 1.8, respectively.³⁰ The observed suicide rate during lithium treatment was 0.066% per year (9 suicides per 13 597 person-years) and during use of anticonvulsants (mainly divalproex, with some carbamazepine) was 0.155% per year (16 per 10 333 person-years).³⁰ Suicide risk without treatment was 0.116% per year (25 per 21 562 person-years),³⁰ or 9.3 times higher than the California and Washington State base rates of about 0.0120% per year.³¹ The difference in risk with vs without lithium treatment was 8-fold (0.116/0.066)—very similar to previous experience (nearly 9-fold).²⁶ However, the rate was not decreased with anticonvulsant treatment (0.116/0.155 = 0.75). Also of interest, the observed ratio of suicide attempts to suicide deaths for all treatments was 6.4 to 1 (0.565/0.088),³⁰ again indicating high lethality of attempts among bipolar disorder patients, given comparable general population ratios of 10:1 to 20:1.²¹

The study by Goodwin et al not only has merits in its methods and findings but also represents a significant contribution to a newly emerging interest in suicide as the major unsolved medical problem that it is.³² Not until this year has the FDA approved any treatment to prevent suicidal behavior, with the recent approval of clozapine for such purposes among patients with schizophrenia or schizoaffective disorder. This approval was supported by a prospective randomized study showing about 32% lower risk of nonlethal suicidal behaviors with clozapine than with olanzapine,³³ which may also reduce risk of suicide.³⁴ Hopefully, such renewed interest in the potentially treatment-modifiable lethality of major mental disorders will be sustained and increasingly successful.

AUTHOR INFORMATION
Corresponding Author: Ross J. Baldessarini, MD, Mailman Research Center 306, McLean Hospital, 115 Mill St, Belmont, MA 02478 (e-mail: rjb@mclean.org).

Editorials represent the opinions of the authors and THE JOURNAL and not those of the American Medical Association.

Funding/Support: This work was supported in part by an award from the Bruce J. Anderson Foundation and the McLean Private Donors Neuropsychopharmacology Research Fund (Dr Baldessarini) and by the Stanley Institute for Medical Research (Dr Tondo).

Financial Disclosure: Dr Baldessarini occasionally serves as a consultant to and receives research grants from corporations that have developed treatments for bipolar disorder.

Author Affiliations: Department of Psychiatry and Neuroscience Program, Harvard Medical School, Boston, Mass (Drs Baldessarini and Tondo); Bipolar and Psychotic Disorders Program and International Consortium for Bipolar Disorder Research, McLean Division of Massachusetts General Hospital, Belmont (Drs Baldessarini and Tondo); Centro Bini–Stanley Medical Research Institute and Department of Psychology, University of Cagliari, Cagliari, Italy (Dr Tondo).

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