Medical Progress
Refer to: Maletzky BM, Shore JH: Lithium treatment for psychiatric disorders (Medical Progress). West J Med 128:488-498, Jun 1978
Lithium Treatment for Psychiatric
Disorders BARRY M. MALETZKY, MD, and JAMES H. SHORE, MD, Portland, Oregon
Although used, around the world since 1949, lithium has come into extensive use in psychiatry in the United States only within the past decade. Before initiating treatment with this drug, physicians must be familiar with the diagnostic scheme of the major affective disorders, the indications and contraindications to lithium's use, and its principles of treatment, including evaluation before lithium therapy, criteria for monitoring blood levels and signs of impending toxicity. Despite earlier reports about the toxicity of lithium when it was promoted as a salt substitute, lithium is a safe drug. Its use not only has revolutionized the treatment of the major affective disorders, but has opened up new and broad avenues of research into the regulation of man's emotions.
IT IS GENERALLY ASSUMED that the present era of
psychopharmacology began with the discovery of chlorpromazine (Thorazine®) in the early 1950's. It is less widely recognized that a far simpler agent, lithium, was introduced as early as 1949 for the specific disorder of mania. Lithium remains today one of our most striking yet enigmatic psychotropic drugs, its very simplicity at once intriguing and bewildering to clinicians and researchers alike. How can such an elemental substance, a mere concoction of three neutrons, protons and electrons, exert such profound effects on complex human behavior? Indeed, if such a substance does exert such effects, then might it From the Department of Psychiatry, University of Oregon Health Sciences Center, Portland. The authors would like to dedicate this article to the memory of Paul H. Blachly, MD, who provided continuous encouragement for the study and treatment of patients with lithium therapy. Reprint requests to: James H. Shore, MD, Professor and Chairman, Dept. of Psychiatry, University of Oregon Health Sciences Center, Portland, OR 97201.
488
JUNE 1978 * 128 * 6
not be a useful compass with which to explore the biology of all human emotions? Research continues today into these fascinating areas. The purpose of the present review is to acquaint the non-psychiatric practitioner with the use of lithium in psychiatry today by tracing its development as a drug and describing its use in common and uncommon indications, the principles of its clinical employment and its associated toxicity. This review will also briefly survey the theories of lithium's mode of action and highlight important research questions remaining in elucidating lithium's effects upon the central nervous system.
History Lithium was first identified in 1817 and isolated in 1855. It is the third element in the periodic table, the lightest of all solids, and closely
LITHIUM TREATMENT
allied chemically to sodium and potassium. During the 20th century, lithium has become an important component in the manufacture of aircraft parts, lasers and even hydrogen bombs. In contrast to its increasing usefulness in technology, lithium has enjoyed a less consistent history in its medical applications. Medicinal springs contain the element and claims were made a century ago that such "alkaline waters" exerted a "calmative" effect.1 Before 1900 lithium had also been promoted as a cure for gout2 (it dissolves urates) and was used as a sedative and anticonvulsant,l 3 particularly as the bromide salt. With the decline of bromides, the medical community paid little attention to lithium until the late 1940's when evidence accumulated to incriminate sodium chloride as a factor in hypertension and cardiovascular disease. Manufacturers began to promote lithium chloride as the perfect salt substitute. Its unrestricted use by thousands already suffering from pathologic changes in the cardiovascular system not surprisingly prompted many reports of toxicity.4'5 Following alarming publicity, lithium chloride was removed from the market in 1950. The discovery by an Australian researcher, one year earlier, of lithium's usefulness in treating mania consequently went scantly heeded,6 despite several promising confirmatory observations in the early 1950'S.7-9 It took the work of a Dane, Mogens Schou, and his group'0-12 to focus the attention of the medical world on the fact that this simplest of all drugs could exert profound effects upon manic-depressive illness. So sharp were the memories of lithium's toxicity as a salt substitute that the drug was only approved for general use in this country as recently as 1969. Since 1960 a host of carefully documented studies has unequivocally shown its efficacy in aborting attacks of mania, preventing most manic episodes, and preventing the majority of depressive episodes from occurring as well. Its use in these conditions is considered standard in the medical community today.
Common Indications The Affective Illnesses The main indication for lithium's use is in those illnesses characterized by cycles of mood, both "high" and "low." Although the term bipolar in this case refers to opposite swings of mania and
depression, in fact evidence indicates that these mood states may not be polar opposites at all but rather points on a continuum away from a normal mood state, mania being more distant than depression. The manic state is typified by signs of overactivity and gregariousness. The manic, under the sway of an attack, hardly feels ill at all but rather feels marvelously well, indeed euphoric. Never still and rarely quiet, he constantly seeks out and accepts new tasks beyond his capacities. His judgment atrophied, he invests money unwisely, occasionally becoming inappropriately expansive in donating his last penny to some charity or friend. He has no time for sleep, perhaps averaging two to three hours each night, and may either eat little or consume enormous quantities of food. His appetite may also be aroused for sexual gratification and hypersexual "binges" are not uncommon. His emotions are labile and his verbal associations flighty. He is distractible and despite claims that he feels "on top of the world" he may nevertheless be irritable, argumentative and even volatile at times, especially when crossed. He may develop ideas of grandiosity. Needless to say, the manic patient quickly exhausts emotional and physical resources of family and friends and in full-blown mania he usually comes to psychiatric attention. Often more destructive and insidious is the condition of hypomania in which many of the symptoms described above occur but in attenuated form. The hypomanic patient rarely can be convinced he is in need of medical attention, yet rarely will anyone coerce him to accept such treatment, as his symptoms seem but an exaggerated form of normality. Nevertheless, he continues to place an emotional and financial drain on his family. The condition may persist for months. The state of depression is a less well-defined condition. The patient usually expresses feelings of hopelessness and pessimism. He may believe he is responsible for some wrongdoing, consequently suffering extreme guilt, or he may develop delusions about a bodily illness. He may move slowly, sitting rigidly with head and eyes downcast, or may not be able to sit or stand quietly at all but rather pace back and forth, wringing his hands, shaking his head and nervously clenching his teeth. He shuns social contacts, finds no pleasure in former recreations and indeed can THE WESTERN JOURNAL OF MEDICINE
489
LITHIUM TREATMENT
hardly express any emotion at all except sadness. He may have trouble concentrating and be slow to respond. When he does he may utter but brief statements as if the effort were hardly worthwhile. He will usually have difficulty sleeping, particularly in the early morning hours, and may have lost weight because of a pronounced diminution in appetite. Sexual desire is similarly reduced. Some manic-depressive patients alternate between episodes of mania and states of depression interspersed with periods of relative normality. Such patients are called manic-depressive cyclical type (bipolar illness). Other patients experience only manic episodes, the manic-depressive, manic type, while still others show only the depressed phases and are called "unipolar." The terminology is confusing at best. Some recent research indicates, in fact, that unipolar and bipolar illnesses can be differentiated on clinical,'3-'5 biochemical16-18 and genetic grounds.
Manic-depressive psychosis usually begins at an older age than schizophrenia and most writers sharply differentiate between these two syndromes. The manic lacks a well-formed delusional system and rarely hallucinates. He does not display the grossly illogical and bizarre thought patterns of the schizophrenic, and usually is able to preserve congruent emotional responses. Nonetheless, diagnostic boundaries between the two cannot always be sharply drawn. There is evidence that bipolar mood states and indeed almost all lithium-sensitive disorders are related in part to genetic'5 and biochemical17 abnormalities affecting the central nervous system. These endogenous disorders are to be differentiated from clearly exogenous conditions in which externally stressful agents are primary. Therefore, lithium may be very effective in patients with severe mood swings unconnected to changes in the immediate environment but would have no place in the treatment of patients with depression secondary to, for example, a divorce or a death in the family.
Acute Mania For years the phenothiazines, especialy chlorpromazine, were prescribed for acutely manic patients, and for good reason: such a patient not only could exhaust others with his behavior, he could exhaust himself as well. The phenothiazines were effective in calming the patient within 24 to 72 hours but they rarely seemed to alter the basic
490
JUNE 1978 * 128 * 6
symptomatology or course of the disease; many assumed they merely muffled manic symptoms until a natural remission occurred. A multitude of uncontrolled and controlled studies'9-29 have now documented lithium's efficacy in aborting acute manic attacks. In dosages ranging from 900 to 1,800 mg per day, lithium will almost invariably end manic episodes within four to ten days. (For more extensive recommendations regarding dosage and the monitoring of serum lithium levels, see "Principles of Treatment" later in this review.) It must be emphasized, however, that four to ten days may be too long to allow such an episode to go unchecked. Many authorities recommend the adjunctive use of a phenothiazine, typically chlorpromazine or haloperidol, to more quickly sedate the patient while lithium is beginning to take effect. Almost always the phenothiazine can be discontinued once this has occurred. With the use of lithium in this manner one notices a qualitatively different remission than that formerly produced by the phenothiazines alone. The patient is not unduly sedated; he is calmer and less hyperactive, and in a truly stabilized mood rather than a suppressed condition. Lithium has appeared to produce a truly normalizing as opposed to a tranquilizing effect. Prophylactic Lithium Perhaps even surpassing lithium's dramatic effect in the treatment of mania is its efficacy in preventing further episodes of mania or depression in bipolar patients. Some of psychiatry's most elegant studies have clearly shown this prophylactic effect,"0-:" one which has revolutionized the treatment of manic-depressive illness in the past decade. Moreover, lithium exerts its prophylactic effect even against recurrences of depression as well as mania, although to a slightly less significant degree. Figure 1, taken from an early study by Furlong and associates,"4 convincingly shows this ability to prevent further episodes of both mania and depression. It should be noted that this prophylactic effect may not become evident for six months or more; patients must be cautioned not to expect immediate responses. Recently a variety of manic-depressive patients with rapid fluctuations of mood, generally stated in terms of hours or days, as opposed to weeks or months, has been described. Such rapid cycles usually do not respond as well to lithium, though further study is warranted.35
LITHIUM TREATMENT
the diagnosis of manic-depressive disorder is certain (usually more than one manic or depressive episode is required), lithium should be continued indefinitely.
When used prophylactically, less lithium is usually required. Though 900 mg per day has been regarded as a standard maintenance dose, 600 mg and even 300 mg have been reported effective in occasional patients.36 Individually tailoring the dosage by monitoring serum lithium levels and clinical responses can permit a wide range of dosages to be employed. While the manic-depressive patient continuously taking lithium may appear "normalized," minor mood swings, especially depressions, can occur. These occasionally may require the addition of an antidepressant. Even after many years a patient can suffer a relapse should the drug be discontinued. Therefore while lithium may be prophylactic it is obviously not curative for manicdepression. Most authorities now agree that once
69
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72
71
Acute Depression
Because lithium can prevent the occurrence of a depressive episode in manic-depressive disorders, it is natural to assume that the drug can also lift a manic-depressive patient out of a depression. Unfortunately, this is not always so. Patients encountered in a depression but known to be bipolar may require an antidepressant medication at first to alleviate the depression. Lithium only rarely produces or aggravates a preexisting depression. Therefore, frequently an antidepressant is administered along with lithium
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Refer to: Maletzky BM, Shore JH: Lithium treatment for psychiatric disorders (Medical Progress). West J Med 128:488-498, Jun 1978
Lithium Treatment for Psychiatric
Disorders BARRY M. MALETZKY, MD, and JAMES H. SHORE, MD, Portland, Oregon
Although used, around the world since 1949, lithium has come into extensive use in psychiatry in the United States only within the past decade. Before initiating treatment with this drug, physicians must be familiar with the diagnostic scheme of the major affective disorders, the indications and contraindications to lithium's use, and its principles of treatment, including evaluation before lithium therapy, criteria for monitoring blood levels and signs of impending toxicity. Despite earlier reports about the toxicity of lithium when it was promoted as a salt substitute, lithium is a safe drug. Its use not only has revolutionized the treatment of the major affective disorders, but has opened up new and broad avenues of research into the regulation of man's emotions.
IT IS GENERALLY ASSUMED that the present era of
psychopharmacology began with the discovery of chlorpromazine (Thorazine®) in the early 1950's. It is less widely recognized that a far simpler agent, lithium, was introduced as early as 1949 for the specific disorder of mania. Lithium remains today one of our most striking yet enigmatic psychotropic drugs, its very simplicity at once intriguing and bewildering to clinicians and researchers alike. How can such an elemental substance, a mere concoction of three neutrons, protons and electrons, exert such profound effects on complex human behavior? Indeed, if such a substance does exert such effects, then might it From the Department of Psychiatry, University of Oregon Health Sciences Center, Portland. The authors would like to dedicate this article to the memory of Paul H. Blachly, MD, who provided continuous encouragement for the study and treatment of patients with lithium therapy. Reprint requests to: James H. Shore, MD, Professor and Chairman, Dept. of Psychiatry, University of Oregon Health Sciences Center, Portland, OR 97201.
488
JUNE 1978 * 128 * 6
not be a useful compass with which to explore the biology of all human emotions? Research continues today into these fascinating areas. The purpose of the present review is to acquaint the non-psychiatric practitioner with the use of lithium in psychiatry today by tracing its development as a drug and describing its use in common and uncommon indications, the principles of its clinical employment and its associated toxicity. This review will also briefly survey the theories of lithium's mode of action and highlight important research questions remaining in elucidating lithium's effects upon the central nervous system.
History Lithium was first identified in 1817 and isolated in 1855. It is the third element in the periodic table, the lightest of all solids, and closely
LITHIUM TREATMENT
allied chemically to sodium and potassium. During the 20th century, lithium has become an important component in the manufacture of aircraft parts, lasers and even hydrogen bombs. In contrast to its increasing usefulness in technology, lithium has enjoyed a less consistent history in its medical applications. Medicinal springs contain the element and claims were made a century ago that such "alkaline waters" exerted a "calmative" effect.1 Before 1900 lithium had also been promoted as a cure for gout2 (it dissolves urates) and was used as a sedative and anticonvulsant,l 3 particularly as the bromide salt. With the decline of bromides, the medical community paid little attention to lithium until the late 1940's when evidence accumulated to incriminate sodium chloride as a factor in hypertension and cardiovascular disease. Manufacturers began to promote lithium chloride as the perfect salt substitute. Its unrestricted use by thousands already suffering from pathologic changes in the cardiovascular system not surprisingly prompted many reports of toxicity.4'5 Following alarming publicity, lithium chloride was removed from the market in 1950. The discovery by an Australian researcher, one year earlier, of lithium's usefulness in treating mania consequently went scantly heeded,6 despite several promising confirmatory observations in the early 1950'S.7-9 It took the work of a Dane, Mogens Schou, and his group'0-12 to focus the attention of the medical world on the fact that this simplest of all drugs could exert profound effects upon manic-depressive illness. So sharp were the memories of lithium's toxicity as a salt substitute that the drug was only approved for general use in this country as recently as 1969. Since 1960 a host of carefully documented studies has unequivocally shown its efficacy in aborting attacks of mania, preventing most manic episodes, and preventing the majority of depressive episodes from occurring as well. Its use in these conditions is considered standard in the medical community today.
Common Indications The Affective Illnesses The main indication for lithium's use is in those illnesses characterized by cycles of mood, both "high" and "low." Although the term bipolar in this case refers to opposite swings of mania and
depression, in fact evidence indicates that these mood states may not be polar opposites at all but rather points on a continuum away from a normal mood state, mania being more distant than depression. The manic state is typified by signs of overactivity and gregariousness. The manic, under the sway of an attack, hardly feels ill at all but rather feels marvelously well, indeed euphoric. Never still and rarely quiet, he constantly seeks out and accepts new tasks beyond his capacities. His judgment atrophied, he invests money unwisely, occasionally becoming inappropriately expansive in donating his last penny to some charity or friend. He has no time for sleep, perhaps averaging two to three hours each night, and may either eat little or consume enormous quantities of food. His appetite may also be aroused for sexual gratification and hypersexual "binges" are not uncommon. His emotions are labile and his verbal associations flighty. He is distractible and despite claims that he feels "on top of the world" he may nevertheless be irritable, argumentative and even volatile at times, especially when crossed. He may develop ideas of grandiosity. Needless to say, the manic patient quickly exhausts emotional and physical resources of family and friends and in full-blown mania he usually comes to psychiatric attention. Often more destructive and insidious is the condition of hypomania in which many of the symptoms described above occur but in attenuated form. The hypomanic patient rarely can be convinced he is in need of medical attention, yet rarely will anyone coerce him to accept such treatment, as his symptoms seem but an exaggerated form of normality. Nevertheless, he continues to place an emotional and financial drain on his family. The condition may persist for months. The state of depression is a less well-defined condition. The patient usually expresses feelings of hopelessness and pessimism. He may believe he is responsible for some wrongdoing, consequently suffering extreme guilt, or he may develop delusions about a bodily illness. He may move slowly, sitting rigidly with head and eyes downcast, or may not be able to sit or stand quietly at all but rather pace back and forth, wringing his hands, shaking his head and nervously clenching his teeth. He shuns social contacts, finds no pleasure in former recreations and indeed can THE WESTERN JOURNAL OF MEDICINE
489
LITHIUM TREATMENT
hardly express any emotion at all except sadness. He may have trouble concentrating and be slow to respond. When he does he may utter but brief statements as if the effort were hardly worthwhile. He will usually have difficulty sleeping, particularly in the early morning hours, and may have lost weight because of a pronounced diminution in appetite. Sexual desire is similarly reduced. Some manic-depressive patients alternate between episodes of mania and states of depression interspersed with periods of relative normality. Such patients are called manic-depressive cyclical type (bipolar illness). Other patients experience only manic episodes, the manic-depressive, manic type, while still others show only the depressed phases and are called "unipolar." The terminology is confusing at best. Some recent research indicates, in fact, that unipolar and bipolar illnesses can be differentiated on clinical,'3-'5 biochemical16-18 and genetic grounds.
Manic-depressive psychosis usually begins at an older age than schizophrenia and most writers sharply differentiate between these two syndromes. The manic lacks a well-formed delusional system and rarely hallucinates. He does not display the grossly illogical and bizarre thought patterns of the schizophrenic, and usually is able to preserve congruent emotional responses. Nonetheless, diagnostic boundaries between the two cannot always be sharply drawn. There is evidence that bipolar mood states and indeed almost all lithium-sensitive disorders are related in part to genetic'5 and biochemical17 abnormalities affecting the central nervous system. These endogenous disorders are to be differentiated from clearly exogenous conditions in which externally stressful agents are primary. Therefore, lithium may be very effective in patients with severe mood swings unconnected to changes in the immediate environment but would have no place in the treatment of patients with depression secondary to, for example, a divorce or a death in the family.
Acute Mania For years the phenothiazines, especialy chlorpromazine, were prescribed for acutely manic patients, and for good reason: such a patient not only could exhaust others with his behavior, he could exhaust himself as well. The phenothiazines were effective in calming the patient within 24 to 72 hours but they rarely seemed to alter the basic
490
JUNE 1978 * 128 * 6
symptomatology or course of the disease; many assumed they merely muffled manic symptoms until a natural remission occurred. A multitude of uncontrolled and controlled studies'9-29 have now documented lithium's efficacy in aborting acute manic attacks. In dosages ranging from 900 to 1,800 mg per day, lithium will almost invariably end manic episodes within four to ten days. (For more extensive recommendations regarding dosage and the monitoring of serum lithium levels, see "Principles of Treatment" later in this review.) It must be emphasized, however, that four to ten days may be too long to allow such an episode to go unchecked. Many authorities recommend the adjunctive use of a phenothiazine, typically chlorpromazine or haloperidol, to more quickly sedate the patient while lithium is beginning to take effect. Almost always the phenothiazine can be discontinued once this has occurred. With the use of lithium in this manner one notices a qualitatively different remission than that formerly produced by the phenothiazines alone. The patient is not unduly sedated; he is calmer and less hyperactive, and in a truly stabilized mood rather than a suppressed condition. Lithium has appeared to produce a truly normalizing as opposed to a tranquilizing effect. Prophylactic Lithium Perhaps even surpassing lithium's dramatic effect in the treatment of mania is its efficacy in preventing further episodes of mania or depression in bipolar patients. Some of psychiatry's most elegant studies have clearly shown this prophylactic effect,"0-:" one which has revolutionized the treatment of manic-depressive illness in the past decade. Moreover, lithium exerts its prophylactic effect even against recurrences of depression as well as mania, although to a slightly less significant degree. Figure 1, taken from an early study by Furlong and associates,"4 convincingly shows this ability to prevent further episodes of both mania and depression. It should be noted that this prophylactic effect may not become evident for six months or more; patients must be cautioned not to expect immediate responses. Recently a variety of manic-depressive patients with rapid fluctuations of mood, generally stated in terms of hours or days, as opposed to weeks or months, has been described. Such rapid cycles usually do not respond as well to lithium, though further study is warranted.35
LITHIUM TREATMENT
the diagnosis of manic-depressive disorder is certain (usually more than one manic or depressive episode is required), lithium should be continued indefinitely.
When used prophylactically, less lithium is usually required. Though 900 mg per day has been regarded as a standard maintenance dose, 600 mg and even 300 mg have been reported effective in occasional patients.36 Individually tailoring the dosage by monitoring serum lithium levels and clinical responses can permit a wide range of dosages to be employed. While the manic-depressive patient continuously taking lithium may appear "normalized," minor mood swings, especially depressions, can occur. These occasionally may require the addition of an antidepressant. Even after many years a patient can suffer a relapse should the drug be discontinued. Therefore while lithium may be prophylactic it is obviously not curative for manicdepression. Most authorities now agree that once
69
70
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72
71
Acute Depression
Because lithium can prevent the occurrence of a depressive episode in manic-depressive disorders, it is natural to assume that the drug can also lift a manic-depressive patient out of a depression. Unfortunately, this is not always so. Patients encountered in a depression but known to be bipolar may require an antidepressant medication at first to alleviate the depression. Lithium only rarely produces or aggravates a preexisting depression. Therefore, frequently an antidepressant is administered along with lithium
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