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Back To Vidyya Lithium

An Effective Treatment For More Than 50 Years

In 1949, Australian psychiatrist John Cade published a paper detailing the value of using lithium salts to treat acute mania. Half a century later, lithium is still used in the treatment of mood disorders, particularly bipolar illness, and ongoing research is providing evidence for other benefits of the drug, including an antisuicidal effect.

The therapeutic benefits of lithium were appreciated prior to Cade's research, said James W. Jefferson, MD, of the Lithium Information Center at Madison Institute of Medicine in Wisconsin. Lithium, an alkali metal and the lightest of the solid elements, was discovered in 1817. Not long after its discovery, physicians began to use the drug in the treatment of diseases such as gout, and in the latter part of the 1800s, British physician Sir Alfred Garrod detailed lithium's therapeutic merits in treating mood disorders, which he believed were caused by "gout retroceding to the head."

Claims for the healthful benefits of lithium fueled the market for products such as Lithia Beer, brewed at West Bend, Wis.

Claims for lithium's healing powers expanded in the late 1800s and early 1900s. Natural waters purported to contain high concentrations of this element were bottled and advertised as a cure for just about anything, said Jefferson. When these promises were not realized, lithium fell out of favor and came to be regarded as an "old and flourishing blunder in medicinal chemistry," as an anonymous pundit described it.

Cade's publication (Med J Aust. 1949;36:349-352) revitalized interest in lithium, and the drug gained acceptance worldwide in the next two decades. A delayed endorsement in the United States--the drug did not win US Food and Drug Administration approval until 1970--resulted in part from reports of lithium chloride's toxicity when used as a salt substitute for patients on low sodium diets (JAMA. 1949;36:685-688). Although the therapeutic armamentarium of psychiatry had grown by this time, lithium was considered the most effective medication for stabilizing patients with bipolar disorder.

Recently, however, questions about lithium's usefulness have been raised by a number of studies that indicate it is less effective in treating mood disorders than earlier reports suggested, said Samuel Gershon, MD, of Western Psychiatric Institute and Clinic, University of Pittsburg School of Medicine. The reported decline in the drug's efficacy, he said, may be explained in part by the fact that more atypical cases, many of which fail to respond to lithium, are seen in academic medical centers. Changes in the diagnosis of mood disorders and the therapeutic use of lithium that have occurred over the years may also contribute to a rise in numbers of patients who do not respond to it.



Some researchers have used differences in lithium response as a means of selecting a more homogenous group of bipolar patients for study. One of these investigators, Paul Grof, MD, of the University of Ottawa, and his colleagues studied patients shown to be "excellent responders" to lithium in terms of episode prevention.

Patients for this study were gathered by the International Group for the Study of Lithium-Treated Patients (IGSLI), a group that pools data of well-documented, long-term lithium-treated patients from centers that specialize in this therapy. The group identified 163 patients with bipolar disorder who were diagnosed according to the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders (DSM-III-R), 96 of whom were from Canada, 43 from Central Europe, and 24 from Scandinavia. The average age of onset of the disease was 28.5 years. All of the patients exhibited both a history of frequent recurrences prior to therapy (average, 8.9 episodes) and complete freedom from recurrences during long-term lithium therapy (average, 15.2 years, with the interval extending to 30 years in some patients). Cases were reviewed by one investigator and all patients except the Scandinavians were personally interviewed and underwent psychological testing with that investigator to ensure uniformity of observation.

Grof said that identification of this group of excellent lithium responders will be helpful in carrying out psychobiological research, including genetic studies, into bipolar disorder. Observation of this group also has provided useful clinical insights into characteristics of patients who are likely to respond to lithium treatment. For example, these patients experienced full remissions between episodes, remissions that were not only free from abnormal moods but also from any signs of other psychopathology.

A popular drink at the turn of the last century, Bear Lithia Water was bottled from springs allegedly high in lithium content.

Researchers also noted that in this patient population, no loss of efficacy of treatment was seen over time. This observation stands in contrast with several anecdotal reports that suggest lithium's effectiveness may lessen the longer the drug is taken, said Grof. Nor was efficacy of lithium reduced or lost in the 79 patients who discontinued and resumed treatment. Interruption of treatment is a common occurrence in patients with bipolar disorder, and some reports suggest that discontinuation and resumption of lithium also can lessen the drug's efficacy.

An unexpected finding from this study showed that there may be two subtypes of episodic bipolar disorder that exhibit excellent response to lithium treatment--classical bipolar disorders and cycloid bipolar disorders--based on differences in behavior before lithium treatment and after its discontinuation. The majority of patients exhibited a classical bipolar disorder, characterized by typical manic and depressive episodes alternating with complete, well-defined remissions. Patients with cycloid bipolar disorder also experienced complete remissions; however, manic periods of overactivity appeared more often than depressive episodes, and overactivity was sometimes accompanied by confusion, hallucinations, delusions, and incoherence. Low moods were characterized more by apathy and emptiness than by sadness and hopelessness, as is common in classical bipolar depression.

Grof said the study also revealed that patients who responded well to lithium often were prescribed a combination of medications that could have a confounding effect on their response to treatment.



Several researchers discussed the problem of suicide and the possibility that long-term lithium treatment may have an antisuicidal effect. Kay Redfield Jamison, PhD, of Johns Hopkins University School of Medicine, pointed out the tremendous extent of suicide as a public health problem. "World Bank studies on deaths in the world among men and women between the ages of 15 and 44 show that in women, suicide is the second leading cause of death, and in men it is fourth," she said. In the United States, suicide recently became the second most common cause of death among persons 15 to 24 years of age.

"Manic depression and depression carry with them elevated rates of suicide over the general population," said Jamison. "At least 90% of people who commit suicide have a diagnosable major psychiatric illness." However, illnesses that lead to suicide are consistently undertreated--a major problem that must be remedied by better diagnosis and aggressive treatment of these conditions.

But does aggressive treatment of affective disorders, regardless of the type of medication used, reduce the risk of suicide? "For many years it was a silent, self-evident assumption that rigorous treatment of depressive episodes would reduce suicide risk," said Bruno Müller-Oerlinghausen, MD, of the Free University of Berlin. "However, epidemiological studies, in spite of worldwide use of antidepressants, did not support such hope, which was a sobering and disappointing message."

Although evidence for an antisuicidal effect of antidepressants may be lacking, a number of findings accumulated in the last 15 years provide evidence that long-term lithium prophylaxis decreases the risk of suicide and normalizes mortality in patients with affective disorders, he said. An ad hoc analysis of findings from a German study called the Multicenter Study of Affective Psychoses (MAP) shows that lithium is superior to carbamazepine in preventing suicide. In this large, prospective controlled trial, the prophylactic efficacy of these two mood stabilizers was studied for 2.5 years in 378 patients with bipolar, schizoaffective, and unipolar disorders. Among these subjects, 146 were randomized to take lithium and 139 took carbamazepine.

Although the protocol of MAP did not include an analysis of suicides and suicide attempts as end points, said Müller-Oerlinghausen, he and his colleagues analyzed suicidal acts in these groups after the study was completed. "A total of nine suicide acts--four suicides and five suicide attempts--were observed," he said. "None occurred in the patients on lithium, and all occurred with patients taking carbamazepine, which is a statistically significant difference."

Müller-Oerlinghausen speculated that if it is true that lithium alone among psychotropic compounds counteracts suicide risk in patients at high risk, it may be because lithium has unique serotoninergic and antiaggressive properties. Lithium is marked by a combination of specific pharmacological properties, in particular serotonin agonistic effects, that other mood stabilizers and most antidepressants do not share, he explained. "It seems very likely that this serotoninergic action, possibly in connection with other effects, is related to lithium's very well-established antiaggressive effects in animals as well as humans. Such an effect would fit very well with the notion of suicidality and aggressivity as behavior caused by or related to deficits in serotoninergic neurotransmission."

Another more difficult question, said Müller-Oerlinghausen, is whether the antisuicidal effect of lithium acts independently of its general episode-reducing effect. He and his colleagues have found evidence for an independent suicide-preventive action of lithium in an analysis of patients at high risk for suicide seen at the Berlin Lithium Clinic. Although some patients were not classified as good responders in terms of episode prevention, they did show reduced suicide rates, which investigators attributed to lithium, he said.

These findings, said Müller-Oerlinghausen, were replicated in a recent analysis of a high-risk subgroup of lithium-treated patients taken from the IGSLI data pool. For this analysis, only patients with at least one suicide attempt before beginning lithium medication were selected. Patients were separated into three groups--excellent, questionable, and poor responders--on the basis of their response to the drug in terms of reduction of depressive inpatient episodes. Researchers found a statistically significant decrease in suicide attempts in all three groups, which, he said, supports the idea that lithium exerts a specific antisuicidal effect, independent of its episode-prevention effect. "Thus," said Müller-Oerlinghausen, "discontinuing lithium or switching to other medications in apparently nonresponding patients may be considered a rational step toward optimizing medication, but it may result in the death of the patient."

Evidence supporting the suicide-preventive effect of lithium is important to consider, particularly in light of the changes in prescription patterns for lithium, carbamazepine, and the anticonvulsant drug divalproex sodium that are occurring in the United States. According to Hopkins' Jamison, divalproex sodium recently became the number-one prescribed drug for bipolar illness in the United States. Such a change, she said, "has major public health implications for suicide, since we don't have any data that suggest that anticonvulsants have any effect against suicide."

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Editor: Susan K. Boyer, RN
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