Lithonate

Bipolar Disorder

Bipolar illness is a serious heritable mood disorder characterized by recurrent episodes of depression and mania. The mean age of onset is under 25 years of age, but the period of risk extends from prepuberty to senescence. Fifteen percent of persons with the disorder commit suicide. Bipolar disorder carries an increased risk of cardiovascular disease.

Although Falret,[1] in 1854, described a mood disorder characterized by recurrent depressive and manic episodes, his article was not published in English until 1983.[2] Consequently, Kraepelin[3] is given credit for having drawn what is arguably the most important distinction in the history of psychiatry when, in 1921, he emphasized the categoric difference between dementia praecox (schizophrenia) and manic-depressive insanity. Kraepelin defined manic-depressive insanity as a disease that included all circular and periodic disorders of mood. Thus, all patients with recurrent episodes of both depression and mania, or of depression only, were classified as having manic-depressive insanity. In 1962, Leonhard[4] drew the distinction between unipolar and bipolar affective disorders - the second most basic dichotomy in the field of affective disorders research.

Clinical Criteria

In bipolar disorder, episodes of minor to severe depression and episodes of hypomania or mania occur over a course of time. Rarely, patients have recurrent episodes of mania without ever having a depressive episode. Somewhat paradoxically, but for pragmatic reasons, these patients are also classified as having bipolar disorder. The most important considerations in the diagnosis of persons who have mania but no depression are the family histories of these patients and their responses to lithium (Eskalith, Lithane, Lithonate, etc.).

The operational definition of the form of depression typically occurring in bipolar illness is major depressive disorder. The criteria for major depressive disorder. The criteria for major depressive disorder, as established by the American Psychiatric Association,[5] require the presence of at least five of the symptoms listed in Table 1. The diagnostic criteria for mania are given in Table 2. Hypomania is distinguished from mania by severity. This distinction can border on the arbitrary. For example, cultural constraints and strong impulse control may alter the behavior of manic patients, allowing them to be classified as hypomanic. However, a patient who must be hospitalized while in a hypomanic state is automatically classified as manic.

Table : TABLE 1

Diagnostic Criteria for Major Depressive Episode

Note: A "Major Depressive Syndrome" is defined as criterion A below.

A. At least five of the following symptoms have been present during the same two-week period and represent a change from previous functioning; at least one of the symptoms is either (1) depressed mood, or (2) loss of interest or pleasure. (Do not include symptoms that are clearly due to a physical condition, mood-incongruent delusions or hallucinations, incoherence, or marked loosening of associations.)

(1) depressed mood (or can be irritable mood in children and adolescents)

most of the day, nearly every day, as indicated either by subjective

account or observation by others

(2) markedly diminished interest or pleasure in all, or almost all, activities

most of the day, nearly every day (as indicated either by subjective

account or observation by others of apathy most of the time)

(3) significant weight loss or weight gain when not dieting (e.g., more than

5% of body weight in a month), or decrease or increase in appetite

nearly every day (in children, consider failure to make expected weight

gains)

(4) insomnia or hypersomnia nearly every day

(5) psychomotor agitation or retardation nearly every day (observable by

others, not merely subjective feelings of restlessness or being slowed

down)

(6) fatigue or loss of energy nearly every day

(7) feelings of worthlessness or excessive or inappropriate guilt (which may

be delusional) nearly every day (not merely self-reproach or guilt about

being sick)

(8) diminished ability to think or concentrate, or indecisiveness, nearly

every day (either by subjective account or as observed by others)

(9) recurrent thoughts of death (not just fear of dying), recurrent suicidal

ideation without a specific plan, or a suicide attempt or a specific plan

for committing suicide

B. (1) It cannot be established that an organic factor initiated and maintained

the disturbance

(2) The disturbance is not a normal reaction to the death of a loved one

(Uncomplicated Bereavement)

Note: Morbid preoccupation with worthlessness, suicidal ideation,

marked functional impairment or psychomotor retardation, or prolonged

duration suggest bereavement complicated by Major Depression.

C. At no time during the disturbance have there been delusions or hallucinations for as long as two weeks in the absence of prominent mood symptoms (i.e., before the mood symptoms developed or after they have remitted).

D. Not superimposed on Schizophrenia, Schizophreniform Disorder, Delusional Disorder, or Psychotic Disorder NOS.

Table : TABLE 2

Diagnostic Criteria for Manic Episode

Note: A "Manic Syndrome" is defined as including criteria A, B, and C below. A "Hypomanic Syndrome" is defined as including criteria A and B, but not C, i.e., no marked impairment.

A. A distinct period of abnormally and persistently elevated, expansive, or irritable mood.

B. During the period of mood disturbance, at least three of the following symptoms have persisted (four if the mood is only irritable) and have been present to a significant degree:

(1) inflated self-esteem or grandiosity

(2) decreased need for sleep, e.g., feels rested after only three hours of sleep

(3) more talkative than usual or pressure to keep talking

(4) flight of ideas or subjective experience that thoughts are racing

(5) distractibility, i.e., attention too easily drawn to unimportant or irrelevant external

stimuli

(6) increase in goal-directed activity (either socially, at work or school, or sexually) or

psychomotor agitation

(7) excessive involvement in pleasurable activities which have a high potential for painful

consequences,

e.g., the person engages in unrestrained buying sprees, sexual indiscretions, or foolish

business investments

C. Mood disturbance sufficiently severe to cause marked impairment in occupational functioning or in usual social activities or relationships with others, or to necessitate hospitalization to prevent harm to self or others.

D. At no time during the disturbance have there been delusions or hallucinations for as long as two weeks in the absence of prominent mood symptoms (i.e., before the mood symptoms developed or after they have remitted).

E. Not superimposed on Schizophrenia, Schizophreniform Disorder, Delusional Disorder, or Psychotic Disorder NOS.

F. It cannot be established that an organic factor initiated and maintained the disturbance. Note: Somatic Antidepressant treatment (e.g., drugs, ECT) that apparently precipitates a mood disturbance should not be considered an etiologic organic factor.

The distinction between patients who have episodes of major depressive disorder and mania (bipolar I disorder) and patients with episodes of major depressive disorder and hypomania (bipolar II disorder) does, however, have value. Bipolar I and II patients may "breed true." The relative frequency of relatives with bipolar I disorder in the pedigrees of patients with bipolar I disorders may exceed that of bipolar II patients, and vice versa.[6]

The American Psychiatric Association describes hypomania as a clinical state in which the predominant mood is either elevated, expansive or irritable, accompanied by the symptoms associated with mania.[5] By definition, the hypomanic state is not severe enough to cause marked impairment of social or occupational functioning or to require hospitalization. The signs and symptoms of hypomania are the same as those of mania, except that hallucinations and delusions cannot be present and the condition is less severe.

Incidence

Current research efforts are altering estimations of the incidence and course of bipolar disorder. The lifetime (morbid) risk in the U.S. population for bipolar I disorder is 0.9 percent, based on a survey of 9,543 people.[7] Weissman and Myers[8] reported that 1.2 percent of the U.S. population has either bipolar I or bipolar II disorder. The Amish have an unusually high rate of bipolar illness.[9] Bipolar I disorder is equally distributed between the sexes, but more women than men have bipolar II disorder.[7]

As psychiatric epidemiologic methods become increasingly more sophisticated, the apparent age of onset of bipolar illness falls. One review[10] estimated the mean age of onset of bipolar disorder to be 32.2 years in men and 31.7 years in women. However, bipolar disorder is now recognized as a common illness in adolescents.[11] Twenty percent of bipolar patients have onset before age 20. Although the median age of onset lies between 20 and 25 years of age, persons of any age can develop the disorder. Ten percent of bipolar patients have onset after age 50.[10-12]

Bipolar disorder is the prototype of a heritable psychiatric illness. Adoption studies demonstrate the genetic component of the illness.[13] The concordance rates for monozygotic and dizygotic twins are 67 percent and 20 percent, respectively.[14] Of the first-degree relatives of bipolar I patients, 24 percent have either bipolar or unipolar disorder. Twenty-five percent of the relatives of bipolar II patients have a mood disorder.[15] Multiple studies indicate that the rate of affective illness among first-degree relatives of bipolar patients is at least 20 percent.[16] Unipolar disorder is the most common affective illness in the pedigrees of bipolar patients.[15]

Schizoaffective disorder (Table 3) is now thought to be a variant of bipolar disorder.[16-23] Gershon and colleagues[15] reported the frequency of affective disorders among first-degree relatives of schizoaffective patients to be 37 percent, and the frequency of mood disorders among first-degree relatives of patients with bipolar disorder to be 24 to 25 percent. Schizoaffective patients may have a particularly virulent form of bipolar illness, which carries a higher probability of being phenotypically expressed (as bipolar I, bipolar II, schizoaffective disorder or unipolar depressive disorder) in their first-degree relatives.

Table : Table 3

Diagnostic Criteria for Schizoaffective Disorder

A. A disturbance during which, at some time, there is either a Major Depressive or a Manic Syndrome

concurrent with symptoms that meet the A criterion of Schizophrenia. B. During an episode of the disturbance, there have been delusions or hallucinations for at least

two weeks,

but no prominent mood symptoms.

C. Schizophrenia has been ruled out, i.e., the durationof all episodes of a mood syndrome has not

been

brief relative to the total duration of the psychotic disturbance.

D. It cannot be established that an organic factor initiated and maintained the disturbance.

Specify: bipolar type (current or previous Manic Syndrome) or depressive type (no current or previous Manic Syndrome)

The A Criterion for Schizophrenia A. Presence of characteristic psychotic symptoms in the active phase: either (1), (2), or (3) for

at least one

week (unless the symptoms are successfully treated):

(1) two of the following:

(a) delusions

(b) prominent hallucinations (throughout the day for several days or several times a week for

several weeks, each hallucinatory experience not being limited to a few brief moments)

(c) incoherence or marked loosening of associations

(d) catatonic behavior

(e) flat or grossly inappropriate affect

(2) bizarre delusions (i.e., involving a phenomenon that the person's culture would regard as

totally

implausible, e.g., thought broadcasting, being controlled by a dead person)

(3) prominent hallucinations (as defined in (1) (b) above) of a voice with content having no

apparent

relation to depression or elation, or a voice keeping up a running commentary on the

person's behavior or thoughts, or two or more voices conversing with each other

Clinical Course

Bipolar disorder has an interesting natural history. The age of onset of bipolar disorder,[24] the current age of the patient[25] and the number of episodes[26] of depression and mania are all related to the probability of another affective episode within a given period of time - that is, the age of onset, the patient's age and the number of episodes are related to the course of the illness.

Latency period is the lag between the first and second episodes of affective illness. The older a patient is at the age of onset, the shorter (on average) the latency period.

Cycle length is the interval between the start of any two successive episodes. Median cycle lengths in a sample of 95 patients were 48, 22, 24, 14 and 12 months for the first through fifth cycles, respectively.[26] A statistical analysis indicated that both the age of onset and the number of episodes are independently related to cycle length.[10] Thus, a shortening of the cycle interval with age is not merely a function of the number of previous episodes. The effect of the number of episodes tends to decrease after the third or fourth cycle.

The Author

STEVEN C. DILSAVER, M.D. is associate professor of psychiatry and neuroscience and director of the psychopharmacology program at the Ohio State University College of Medicine, Columbus. Dr. Dilsaver is a graduate of the University of California, San Diego, School of Medicine. He completed a psychiatric residency and research training at the University of Michigan Medical School, Ann Arbor.

Reprinted with permission from Diagnosis and statistical manual of mental disorders. 3rd ed rev. Washington D.C.: American Phychiatric Association, 1987:222-3. Copyright 1987 American Phychiatric Association.

The relationship of age of onset and number of episodes to cycle length has important clinical implications. A 50-year-old patient presenting with a first episode of mania and without a prior history of depression would typically require more careful attention during follow-up and longer, more aggressive prophylaxis than would a 20-year-old patient. Indefinite prophylaxis can be justified after a single episode of severe mania in a middle-aged or elderly patient, because of the shortening of the latency interval that occurs with age. A 20-year-old patient with a first episode of mania might be treated with lithium prophylactically for a year following the complete resolution of symptoms. However, two such episodes of mania or severe depression within five years of an episode of mania would indicate the necessity for indefinite prophylaxis with an antimanic/anticycling agent.

CYCLING

Rapid cycling is defined as the occurence of four or more episodes of depression and/or hypomania or mania within a period of 12 months in either a unipolar or bipolar patient.[27] Some unipolar patients have pedigrees notable for the presence of bipolar illness. These patients may have onset of illness in their early 20s and may cycle rapidly. Anticycling drugs can be effective in this population.[28]

Rapid cycling is often associated with subclinical hypothyroidism.[29] This condition is not detected by the measurement of triiodothyronine [(T.sub.3)], thyroxine [(T.sub.4)] or thyroid-stimulating hormone (TSH) levels. Challenge with thyrotropin-releasing hormone (TRH) is used to diagnose this condition.[30] Augmented release of TSH in response to challenge with TRH is the mark of subclinical hypothyroidism. More severe degrees of hypothyroidism are also associated with rapid cycling. Lithium[31] and carbamazepine (Tegretol),[32] the most commonly used antimanic/anticycling agents, can both produce various degrees of hypothyroidism that can be detected early by a rise in serum TSH level.

Tricyclic antidepressants and monoamine oxidase (MAO) inhibitors are generally thought to induce rapid cycling in susceptible bipolar patients by an unknown mechanism.[33,34] Investigators at the National Institute of Mental Health (NIMH) suggest that up to 40 percent of their rapidly cycling patients develop a rapid cycling course consequent to treatment with tricyclic agents and MAO inhibitors.[34]

There are three forms of rapid cycling. Forty-eight hour cycling is a rare phenomenon in which a new episode starts every 48 hours.[35] In some patients, a new cycle begins every 72 or 96 hours. It is notable that these cycles are all multiples of 24 hours. Hence, these phenomena are conceptually clustered. These forms of cycling are rare and of more interest to academic psychiatrist than to the vast majority of physicians who treat bipolar patients.

Second, there are patients who cycle in association with a change in season. Some patients, for example, regularly become depressed every fall or winter and become hypomanic or manic in the spring.[36] Finally, there is simple rapid cycling.[27] Both seasonal and simple rapid cycling are common. For example, among the adult inhabitants of Montgomery County, Maryland, 4 percent met NIMH criteria for winter depression. Another 13 percent had subsyndromal episodes of winter depression. Many, but not all, seasonal cyclers have bipolar disorder.[37]

PSYCHOSIS

Delusions and hallucinations commonly occur in both depressed and manic bipolar patients. Hallucinations are more common in the manic phase.

Delusions in depressed patients are apt to involve notions of poverty, disease ("I have incurable cancer"), moral defect ("I committed an unforgivable sin"), absolute hopelessness (when a depressed patient is committed to the idea that he or she will never recover, this can be called a delusion) or the dreadfulness of the world (an attitude that transcends the bounds of the patient's religion or personal ethics).

Physicians occasionally encounter delusional patients who claim that their bodies, their minds or the world does not exist. Patients may also entertain delusions about their identities. It is common to encounter patients who believe they are the devil or the antichrist. There is no limit to the pain produced by delusions in depressed patients. These individuals may be tormented by auditory hallucinations in which they are accused of evil or threatened with further suffering.

The manic phase in bipolar illness is phenomenologically remarkable. Initially, manic patients may be euphoric and indefatigable, needing only two or three hours of sleep per day, and they are often quite gregarious and productive. As the manic phase evolves, these patients characteristically become increasingly sleepless, then angry and irritable. Manic patients may, however, retain a sense of playfulness, despite their propensity to irritability. Thus, the manic state is "brittle." Patients may oscillate between euphoria and playfulness and anger and irritability. An angry manic person is often suspicious or paranoid. Young, strong manic males are among the most terrifying patients encountered in all of psychiatry. When most normal people are confronted with a threat, they consider the feasibility of either fighting or fleeing. When confronted with real or imagined threat, the manic person almost invariably chooses to fight.

Manic delusions typically involve notions of grandeur, which may make the patient entertaining to others, or paranoia, which may make the patient dangerous. Following proper treatment, the angry, dangerous manic patient is generally quite pleasant. The manic person's potential for violence is almost always a product of untreated disease.

About 60 percent of manic patients develop delusions or hallucinations.[38] The delusions may focus on the intent of natural or supernatural powers, governmental agencies or private parties to inflict harm. Delusions of grandeur may include the firm belief that the patient is Jesus Christ, God or the President of the United States or some other important world figure. Although hypomanic patients may have grandiose notions, their grandiosity is not of a delusional magnitude.

Both auditory and visual hallucinations occur in mania. Reports of patients hearing the voice of God or having religious visions are common.

Any and all features of schizophrenia may be observed in either the depressed or the manic phase of bipolar disorder. A majority of catatonic patients are now thought to be affectively ill. Bizarre phenomena, such as thought broadcasting, thought insertion and experiences of influence (the patient believes that he or she is influenced by external forces), sometimes occur in mania.[18]

COMPLICATIONS

Affective disorders (including bipolar illness) carry an increased risk of mortality as a result of natural and unnatural causes, particularly a high risk of suicide. In an extensive retrospective study, Avery and Winokur[39] reported that 15 percent of patients with a mood disorder eventually commit suicide. Black and associates[40] recently reported the results of a prospective study of deaths from suicide and accidents in 5,412 patients hospitalized at the University of Iowa Psychopathic Hospital between January 1, 1972, and December 31, 1981. The expected rate of suicide for this group (adjusted for age and follow-up intervals) was compared with that of the general population, using vital statistics and census data. The suicide rate among males with affective disorders was 15.8 times the rate that was expected. The suicide rate was 61.9 times greater than the rate expected among women with affective disorders. Another recent study[41] suggests that inadequate treatment may be a contributing factor in the excess death rate from suicide among bipolar patients in the United Kingdom.

The risk of cardiovascular disease is also increased in bipolar patients. Weeke and colleagues[42] studied 2,662 bipolar males hospitalized in Denmark between 1969 and 1972 and reported that their risk of death from diseases of the cardiovascular system was 1.53 times greater than the risk in the general population. (The relative risk of death from cardiovascular disease was 1.87 times greater among 1,133 male patients admitted between 1950 and 1956.) Studies from both the United Kingdom and the United States indicate that hypertension may be more common among patients with affective disorders.[43]

PRESENTATION

Bipolar patients are most likely to present to a family physician or an internist when in the depressed stage, although some of these patients may not experience depression. It is quite unfortunate that the term "depression" is used to describe the depressed stage of bipolar disorder. Depression is a term taken from ordinary human experience; it is what most of us feel when we suffer personal setbacks or the loss of a loved one. This common term approximates what many people feel in a clinically significant state of dysphoria.

People with bipolar disorder frequently deny feeling depressed and focus instead on their physical symptoms. The depressive phase of bipolar illness is apt to bring a patient to a physician because the patient feels physically ill. Headaches, back pain, epigastric distress, shortness of breath, lack of energy and the general idea or delusion of being medically ill are common in all forms of affective illness. The astute clinician must therefore be prepared to diagnose these common psychiatric disorders in patients who present with physical complaints.

Treatment

The treatment of bipolar patients can be difficult, and the care of these patients should be entrusted to physicians who are expert in the treatment of mood disorders. These physicians should be medically oriented and should demonstrate an understanding of the many nonpsychiatric disorders that can produce a manic syndrome.(44) The more common of these disorders are listed in Table 4.(44,45)

Table : TABLE 4

Causes of Secondary Mania

Substance abuse Amphetamines Bromides Caffeine Cocaine Diet pills (e.g., phenylpropanolamine) Methylphenidate (Ritalin)

Drug withdrawal states Ethanol Monoamine oxidase inhibitors Sympathomimetic agents Trycyclic antidepressants

Therapeutic agents Corticotropin (ACTH) Isoniazid (Laniazid, Nydrazid, Teebaconin) Levodopa (Dopar, Larodopa) Monoamine oxidase inhibitors Steroids Tricyclics and related antidepressants

Toxic/metabolic causes Hyperthyroidism Electrolyte abnormalities

Central nervous system dysfunctions Miscellaneous postoperative states Multiple sclerosis Brain tumors Sleep deprivation Structural damage to right (nondominant)

hemisphere Temporal lobe (complex partial) seizures

Infections Influenza Post-St. Louis type A encephalitis Rickettsial infection Syphilis of the central nervous system

Lithium salts are the mainstay of treatment in mania and bipolar illness. In the nineteenth century, lithium salts were used to treat gout. While studying the effect of lithium on purine metabolism, Cade(46) incidentally noticed that lithium produced a calming effect in his patients. He then used lithium to treat mentally ill "back ward" patients and discovered that manic individuals responded well to the drug. Clinical trials were begun shortly after the publication of the Cade report in 1949.

Control trials contrasting the efficacy of lithium and other drugs unequivocally verified the usefulness of lithium in bipolar disorder.(47-49) At present, more than 100 reports involving 3,000 patients in 20 nations indicate that lithium therapy is effective in 60 to 70 percent of manic patients. The effect of lithium is independent of sex, age or duration of illness. Research indicates that lithium, in addition to being an antimanic agent, possesses modest but significant antidepressant properties and is therefore a useful anticycling agent. Lithium decreases both the severity and frequency of affective episodes.(48,49)

Lithium salts were once used as a substitute for sodium chloride in the management of patients with congestive heart failure. The administration of lithium with concurrent restriction of sodium was implicated in several deaths. Because of these deaths, as well as lack of interest on the part of pharmaceutical firms in marketing an unpatentable drug, lithium carbonate did not become available in the United States until 1970.

Treatment in the initial phase of mania requires the concomitant use of antipsychotic drugs such as haloperidol (Haldol) or carbamazepine,(50-52) since lithium requires seven to ten days to exert its effect. Carbamazepine rapidly affects manic symptomatology, such as sleeplessness, while lithium salts do not.(52) However, the use of carbamazepine in the initial phase of mania is not yet common practice in the United States.

Antipsychotic agents should be used with caution in bipolar patients. There is evidence that bipolarity constitutes a risk factor for the development of tardive dyskinesia. It is not acceptable to uncritically maintain bipolar patients on antipsychotic agents for prolonged periods if these patients can be treated adequately with lithium or carbamazepine, alone or in combination, or with some other combination of drugs.

Lithium is provided as a salt in the form of lithium carbonate and lithium citrate. The latter is provided as a liquid (Cibalith-S). Lithium carbonate comes in regular and slow-release (Lithobid) forms; either form may be given twice daily. Lithium has a half-life of 24 to 36 hours in healthy young adults, and it is reasonable to administer the full dose once daily if it does not exceed 900 to 1,200 mg. Splitting the dose may attenuate nonspecific side effects such as tremor. The slow-release form may not be completely absorbed, and diarrhea may occur as a result of unabsorbed lithium ion in the large bowel. However, use of the slow-release form may diminish side effects related to the high blood levels of lithium ion that occur one to two hours after ingestion of regular lithium carbonate.

Healthy young adults can usually tolerate 600 mg of lithium carbonate twice daily at the start of therapy. The dose is increased over seven to ten days, until the plasma level is 0.80 to 1.40 mEq per L (0.80 to 1.40 mmol per L). Serum lithium levels are usually measured in blood samples drawn 12 hours after the preceding dose of lithium. Serum levels of 0.40 to 1.00 mEq per L (0.40 to 1.00 mmol per L) may be possible during long-term maintenance. If a patient becomes significantly depressed during lithium therapy, a tricyclic antidepressant or MAO inhibitor can be added.

Common side effects of lithium include polyuria, thirst, edema, weight gain (probably due to the ingestion of high-calorie beverages), fine tremor, mild nausea (especially if the drug is not taken with food) and mild diarrhea. Lithium toxicity is manifested by coarse tremor, stupor, ataxia, seizures, persistent headache, vomiting, slurred speech, confusion, incontinence and arrhythmias.(53,54) Toxicity may occur when a patient becomes ill and ceases to eat and drink normally but continues to take lithium as prescribed. A patient who cannot eat and drink normally should temporarily stop taking lithium.

Nonsteroidal anti-inflammatory drugs (NSAIDs), such as indomethacin (Indameth, Indocin) or aspirin, elevate the plasma lithium level.(55) Physicians who recommend these agents should remind patients of the effects that may occur when lithium levels rise abruptly. The treating psychiatrist should be consulted when NSAIDs are indicated, and lithium levels should be carefully monitored during their use. Lithium levels are thought to rise 20 to 25 percent when a patient begins treatment with the equivalent of 25 mg of chlorothiazide (Diachlor, Diurigen, Diuril).(56)

Thyroid and renal function must be evaluated before lithium therapy is started. It is standard practice to measure blood urea nitrogen, creatinine, electrolyte, fasting blood sugar, TSH, [T.sub.3] and [T.sub.4] levels prior to beginning treatment with lithium. It may also be useful to measure creatinine clearance before or shortly after lithium maintenance therapy is initiated.

In the early 1980s, there was some concern that lithium caused damage to the nephron.(57) Reports fueling this concern may have involved patients exposed to unusually high serum levels of lithium or those who developed damage to the nephron independent of treatment with lithium. Fear about the effects of lithium on the nephron has subsided despite the possibility that the drug can produce nonspecific benign changes in the microscopic structure of the nephron unrelated to function.(58)

Carbamazepine is now an accepted agent in the treatment of mania. Like lithium, this drug has antidepressant and antipsychotic properties and is an anticycling agent.(51) Carbamazepine is often useful in patients who do not respond to lithium. Occasionally, the combined use of lithium and carbamazepine is superior to the use of either agent alone. Response to carbamazepine does not correlate with plasma level but is related to the cerebrospinal fluid concentration of a metabolite (referred to as the 10, 11-epoxide).(59)

Carbamazepine is administered three to four times daily to minimize side effects. The most annoying of these side effects is diplopia, which almost always occurs only at toxic levels. Carbamazepine provides an excellent means of producing sleep in a hypomanic patient. When insomnia is a complaint (as it almost invariably is in hypomania/mania), a slightly higher proportion of the daily dose of carbamazepine can be administered two to three hours before bedtime.

Final Comment

Bipolar disorder is a common affective illness causing significant morbidity and mortality. The condition has strong genetic tendencies and is associated with an increased risk of suicide. The initial treatment of bipolar disorder is ordinarily carried out by psychiatrists experienced in the pharmacotherapy of this illness. Maintenance, however, can be managed by primary care physicians who are prepared to monitor serum lithium levels and thyroid status and who have access to expert assistance in the treatment of serious mood disorders.

REFERENCES

[1.] Falret JP. Memoire sur la folie circulaire. Bull de

l'Academie de Med 1854;19:382-415. [2.] Sedler MJ. Falret's discovery: the origin of the

concept of bipolar affective illness. Am J Psychiatry

1983;140:1127-33. [3.] Kraepelin E. Manic-depressive insanity and

paranoia. Edinburgh: Livingstone, 1921. [4.] Leonhard K, Korff I, Schultz H. Temperament

in families with monopolar and bipolar phasic

psychoses. Psychiatr Neurol 1962;143:416-34. [5.] American Psychiatric Association. Diagnostic

and statistical manual of mental disorders. 3d

ed rev. Washington, D.C.: American Psychiatric

Association, 1987. [6.] Dunner DL. Stability of bipolar II affective disorder

as a diagnostic entity. Psychiatr Ann

1987;17:18-20. [7.] Robins LN, Helzer JE, Weissman MM, et al.

Lifetime prevalence of specific psychiatric disorders

in three sites. Arch Gen Psychiatry

1984;41:949-58. [8.] Weissman MM, Myers JK. Affective disorders

in a U.S. urban community: the use of research

diagnostic criteria in an epidemiological survey.

Arch Gen Psychiatry 1978;35:1304-11. [9.] Egeland JA, Hostetter AM. Amish study. I.

Affective disorders among the Amish, 1976-1980.

Am J Psychiatry 1983;140:56-61. [10.] Goodwin FK, Jamison KR. The natural history

of manic-depressive illness. In: Post RM, Ballenger

JC, eds. Neurobiology of mood disorders.

Baltimore: Williams & Wilkins, 1984:21. [11.] Strober M, Carlson G. Bipolar illness in adolescents

with major depression: clinical, genetic,

and psychopharmacologic predictors in a three-to

four-year prospective follow-up investigation.

Arch Gen Psychiatry 1982;39:549-55. [12.] Yassa R, Nair V, Nastase C, Camille Y, Belzile

L. Prevalence of bipolar disorder in a psychogeriatric

population. J Affective Disord 1988;14:197-201. [13.] Rice J, Reich T, Andreasen NC, et al. The familial

transmission of bipolar illness. Arch Gen

Psychiatry 1987;44:441-7. [14.] Bertelsen A, Harvald B, Hauge M. A Danish

twin study of manic-depressive disorders. Br J

Psychiatry 1977;130:330-51. [15.] Gershon ES, Hamovit J, Guroff JJ, et al. A family

study of schizoaffective, bipolar I, bipolar

II, unipolar, and normal control probands.

Arch Gen Psychiatry 1982;39:1157-67. [16.] Clayton PJ, Rodin L, Winokur G. Family history

studies. III. Schizoaffective disorder,

clinical and genetic factors including a one to

two year follow-up. Compr Psychiatry 1968;9:31-49. [17.] Walinder J. Recurrent familial psychosis of the

schizo-affective type. Acta Psychiatr Scand

1972;48:274-83. [18.] Pope HG Jr, Lipinski JF Jr. Diagnosis in schizophrenia

and manic-depressive illness: a reassessment

of the specificity of "schizophrenic"

symptoms in the light of current research. Arch

Gen Psychiatry 1978;35:811-28. [19.] Van Eerdewegh MM, Van Eerdewegh P, Coryell

W, et al. Schizo-affective disorders: bipolar-unipolar

subtyping. Natural history variables:

a discriminant analysis approach. J Affective

Disord 1987;12:223-32. [20.] Levinson DF, Levitt ME. Schizoaffective mania

reconsidered. Am J Psychiatry 1987;144:415-25. [21.] Abrams R, Taylor MA. Mania and schizo-affective

disorder, main type: a comparison.

Am J Psychiatry 1976;133:445-7. [22.] Abrams R, Taylor MA. Importance of schizophrenic

symptoms in the diagnosis of mania.

Am J Psychiatry 1981;138:658-61. [23.] Coryell W, Grove W, Van Eerdewegh M, Keller

M, Endicott J. Outcome in RDC schizo-affective

depression: the importance of diagnostic

subtyping. J Affective Disord 1987;12:47-56. [24.] Zis AP, Grof P, Goodwin FK. The natural

course of affective disorders: implications for

lithium prophylaxis. In: Cooper TB, ed. Lithium,

controversies and unresolved issues. Princeton,

N.J.: Excerpta Medica, 1979:381-98. [25.] Angst J. The course of affective disorders. II.

Typology of bipolar manic-depressive illness.

Arch Psychiatr Nervenkr 1978;226:65-73. [26.] Angst J. Course of affective disorders. In: van

Praag HM, ed. Brain mechanisms and abnormal

behavior-chemistry. New York: Dekker,

1981:225-42. [27.] Dunner DL, Patrick V, Fieve RR. Rapid cycling

manic depressive patients. Compr Psychiatry

1977;18:561-6. [28.] Akiskal HS. The milder spectrum of bipolar

disorders: diagnostic, characterologic and pharmacologic

aspects. Psychiatr Ann 1987;17:32-7. [29.] Extein I, Gold MS. Psychiatric applications

of thyroid tests. J Clin Psychiatry 1986;47(1

Suppl):13-6. [30.] Loosen PT, Prange AJ Jr. Serum thyrotropin

response to thyrotropin-releasing hormone in

psychiatric patients: a review. Am J Psychiatry

1982;139:405-16. [31.] Luby ED, Schwartz D, Rosenbaum H. Lithium-carbonate-induced

myxedema. JAMA 1971;218:1298-9. [32.] Roy-Byrne PP, Joffe RT, Uhde TW, Post RM.

Carbamazepine and thyroid function in affectively

ill patients. Clinical and theoretical implications.

Arch Gen Psychiatry 1984;41:1150-3. [33.] Wehr TA, Goodwin FK. Rapid cycling in manic-depressives

induced by tricyclic antidepressants.

Arch Gen Psychiatry 1979;36:555-9. [34.] Wehr TA, Goodwin FK. Can antidepressants

cause mania and worsen the course of affective

illness? Am J Psychiatry 1987;144:1403-11. [35.] Wehr TA, Goodwin FK, Wirz-Justice A, Breitmaier

J, Craig C. 48-hour sleep-wake cycles in

manic-depressive illness: naturalistic observations

and sleep deprivation experiments. Arch

Gen Psychiatry 1982;39:559-65. [36.] Disalver SC, Coffman J. Seasonal depression.

Am Fam Physician 1988;38(4):173-6. [37.] Rosenthal NE, Wehr TA. Seasonal affective

disorders. Psychiatr Ann 1987;17:670-4. [38.] Pope HG Jr, Lipinski JF Jr. Diagnosis in schizo-phrenia

and manic-depressive illness. Arch

Gen Psychiatry 1978;35:811-28. [39.] Avery D, Winokur G. Mortality in depressed

patients treated with electroconvulsive therapy

and antidepressants. Arch Gen Psychiatry

1976;33:1029-37. [40.] Black DW, Warrack G, Winokur G. The Iowa

record-linkage study. I. Suicides and accidental

deaths among psychiatric patients. Arch Gen

Psychiatry 1985;42:71-5. [41.] Schou M, Weeke A. Did manic-depressive

patients who committed suicide receive prophylactic

or continuation treatment at the time?

Br J Psychiatry 1988;153:324-7. [42.] Weeke A, Juel K, Vaeth M. Cardiovascular

death and manic-depressive psychosis. J Affective

Disord 1987;13:287-92. [43.] Disalver SC, Coffman J. Depression and hypertension.

Psychiatr Res 1989;25:115-7. [44.] Krauthammer C, Klerman GL. Secondary

mania. Arch Gen Psychiatry 1978;35:1333-9. [45.] Cassem NH. Depression. In: Hackett TP, Cassem

NH, eds. Massachusetts General Hospital

handbook of general hospital psychiatry. 2d

ed. Littleton, Mass.: PSG, 1987:227-60. [46.] Cade JF. Lithium salts in the treatment of psychotic

excitement. Med J Aust 1949;2:349-52. [47.] Prien RF, Caffey EM Jr, Klett CJ. Prophylactic

efficacy of lithium carbonate in manic-depressive

illness. Report of the Veterans Administration

and National Institute of Mental Health

Collaborative Study Group. Arch Gen Psychiatry

1973;28:337-41. [48.] Prien RF, Kupfer DJ, Mansky PA, et al. Drug

therapy in the prevention of recurrences in unipolar

and bipolar affective disorders. Report of

the NIMH Collaborative Study Group comparing

lithium carbonate, imipramine, and a lithium

carbonate-imipramine combination. Arch Gen

Psychiatry 1984;41:1096-104. [49.] Prien RF, Caffey EM Jr, Klett CJ. Factors associated

with treatment success in lithium carbonate

prophylaxis. Report of the Veterans Administration

and National Institute of Mental Health

Collaborative Study Group. Arch Gen Psychiatry

1974;31:189-92. [50.] Ocuma T, Inanaga K, Otsuki S, et al. Comparison

of the antimanic efficacy of carbamazepine

and chlorpromazine: a double-blind controlled

study. Psychopharmacology [Berlin]

1979;66:211-7. [51.] Okuma T, Inanaga K, Otsuki S, et al. A preliminary

double-blind study on the efficacy of carbamazepine

in prophylaxis of manic-depressive

illness. Psychopharmacology [Berlin]

1981;73:95-6. [52.] Post RM, Ballenger JC, Ohde TW, Bunney WE.

Efficacy of carbamazepine in manic-depressive

illness. In: Post RM, Ballenger JC, eds. Neurobiology

of mood disorders. Baltimore: Williams

& Wilkins, 1984. [53.] Schou M. The recognition and management of

lithium intoxication. In: Johnson FN, ed. Handbook

of lithium therapy. Lancaster, Eng.: MTP,

1980:394-402. [54.] Hansen HE, Amdisen A. Lithium intoxication.

Report of 23 cases and review of 100 cases from

the literature. QJ Med 1978;47:123-44. [55.] Imbs JL, Singer L, Danion JM, Schmidt M,

Zawilslak R. Effects of indomethacin and methylprednisolone

on renal elimination of lithium

in the rat. Int Pharmacopsychiatry 1980;15:143-9. [56.] Himmelhock JM, Poust RI, Mallinger AG,

Hanin I, Neil JF. Adjustment of lithium dose

during lithium-chlorothiazide therapy. Clin

Pharmacol Ther 1977;22:225-7. [57.] Burrows GD, Davies B, Kincaid-Smith P. Unique

tubular lesion after lithium [Letter]. Lancet

1978;1(8077):1310. [58.] Vestergaard P, Schou M, Thomsen K. Monitoring

of patients in prophylactic lithium treatment.

An assessment based on recent kidney

studies. Br J Psychiatry 1982;140:185-7. [59.] Post RM, Uhde TW, Ballenger JC, Chatterji

DC, Greene RF, Bunney WE Jr. Carbamazepine

and its -10, 11-epoxide metabolite in plasma

and CSF. Relationship to antidepressant response.

Arch Gen Psychiatry 1983;40:673-6.

Adapted from Krauthammer C KlermanG. Secondary mania. Arch Gen Psychatry 1978; 1333-9 and Cassem NH. Depression. In: Hackett TP Casem NH eds. Massachusetts General Hospital handbook of general hospita psychiatry. 2d ed. Littleton, Mass.: PSG, 1987:227-60.

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