MAN|C—DEPRESS|VE
`
`ILLNESS
`
`FREDERICK K. GOODWIN, I'VI.D.
`Administrator
`
`Alcohol, Drug Abuse and Mental Health Administration
`and
`
`Senior Investigator
`National Institute of Mental Health
`
`KAY REDFIELD JAMISON, Ph.D.
`Associate Professor of Psychiatry
`The Johns Hopkins University School of Medicine
`
`New York Oxford
`
`OXFORD UNIVERSITY PRESS
`
`1990
`
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`Oxford University Press
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`
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`Copyright (C3 1990 by Oxford University Press, Inc.
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`
`Library of Congress Caialoging—in-Puhlir:au'on Date
`Goodwin. Frederick K.. [936-
`Menic-depressive illness
`by Frederick K. Goodwin, Kay Rcdfi¢idJEI1'I1iSDIl.
`p.
`cm Includes bibliographical references.
`ISBN 0- I9-503934-3
`I . Jamison. Key Redfield
`I. Manic-depressive psychoses.
`[DNLM: 1. Bipolar Disorder. WM 20'! G656:n]
`RC5 16.066
`I990
`6|fi.39'5-—-—dc1fl DNLMIDLC for Library u|'CoI1g1'I5s
`B9-16396 CIF
`
`1]. Title.
`
`987654321
`Printed in the United States of America
`on acid—free paper
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`21
`
`Medical Treatment
`
`of Manic Episodes
`
`No one predicts how long it will be before the drugs take hold & lRobert Lowell}
`begins to be himself again. Meanwhile he writes and revises translations furiously
`and with a kind {of} crooked brilliance, and talks about himself in connection with
`Achilles, Alexander, Hart Crane, Hitler and Christ, and breaks your heart.
`—Wil| iam Meredith '
`
`A patient in the throes of a manic episode can be
`intensely agitated, uncooperative, psychotic, ag-
`gressive. or dangerous. By the time the clinician
`is brought in. both patient and family are under-
`standably confused and distraught. The bizarre,
`frightening behavior obviously must be con-
`trolled humanely, but the clinician has little time
`to ponder available choices. Which drugs are best
`for this patient in this situation? Should the pa-
`tient be hospitalized? Should electroconvulsive
`therapy he used? Each decision calls for balanc-
`ing the ravages of the illness against the conse-
`quences of intewention—a medication ‘ s potency
`against
`its side effects,
`for example, or the
`patient‘s safety against
`the stigma of hospi-
`talization.
`
`This chapter focuses on such issues in the med-
`ical management of acute manic episodes. Like
`others in this section, the chapter begins with a
`discussion of practical issues of clinical manage-
`ment, an approach to treatment drawn front the
`research evidence and our own clinical experi-
`ence. The research literature is reviewed in the
`
`second part of the chapter, which some readers
`may choose to read first.
`We are convinced that medical management is
`necessary for all patients who are truly manic or
`are hypomanic and likely to become manic.
`Based on that assumption. we devote the follow-
`
`ing discussion largely to criteria for appropriate
`pharmacological treatment for acute mania. One
`important caveat is in order, however. Not all
`activated patients are necessarily manic, or even
`hypomanic, and not all mildly hypornanic pa-
`tients inevitably progress to mania. The Line be-
`tween normal exuberance and clinical hypornania
`is sometimes difficult to discern, and clinicians
`
`must approach the task of differential diagnosis
`with care (see Chapters 4 and 5). Once the diag-
`nosis has been made, skillful psychological man-
`agement must accompany the drug treatment of
`emerging or acute mania, especially if the patient
`or family resists the idea of medications (see
`Chapter 25).
`Lithium,
`
`the first of the modern antimanic
`
`agents, remains the most important. Its therapeu-
`tic value was discovered by the Australian physi-
`cian lohn Cade (1949), whose post-World War II
`experiments with guinea pigs signaled a revolu-
`tion in the treatment of manic-depressive illness.
`Several years were to pass before the importance
`of Cade’s pioneering work was recognized. Euro-
`pean psychiatrists began to take notice in 1954,
`when his observations were confirmed and ex-
`tended by Mogens Schou in Denmark. Although
`a handful of American psychiatrists were among
`the pioneers, lithium was not widely used in the
`United States until the late 1960s. This slow ac-
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`ceptance was partly traceable to earlier adverse
`experiences with lithium as a salt substitute.
`Chlorproinazine, the prototypical antipsycho-
`tit: medication for controlling the symptoms of
`schizophrenia, was first used clinically for a psy-
`chiatric disorder in a manic patient (Schneider,
`1951, cited in Swazey, 1974). More extensive
`clinical observations in acutely manic patients
`followed (Lehmann and I-lanrahan, 1954). Since
`lithiurn was still essentially unknown at
`that
`time, particularly to American psychiatrists,
`chlorpromazine quickly became the treatment
`of choice for acute mania. Haloperidol, a butyro-
`pbenone that also controls psychotic symptoms,
`was introduced in the late 1960s and was found to
`
`control psychotic behavior as effectively as
`chlorpromazine while producing less sedation
`and hypotension. As a result, many clinicians
`now prefer haloperidol and other high~potency
`neuroleptics, such as thiothixene.
`The use of anticonvulsant drugs to treat manic
`episodes dates back to the l9'i'0s (0l<uIna et al.,
`19?3). Some anticonvulsant drugs that have
`shown considerable therapeutic promise, particu-
`larly carbamazepine. clonazepam. and valproate,
`are already widely used with manic patients. Al-
`though not yet approved by the U.S. Food and
`Drug Administration for marketing as antimanic
`agents, they can, of course, be used by physicians
`at their own discretion .3
`
`CLINICAL MANAGEMENT
`
`Clinical Factors Influencing Drug Choices
`
`Clinical decisions in managing mania are influ-
`enced by the treatment setting,
`the nature and
`overall severity of the syrnptoms, and the pres-
`ence of medical complications. The following
`recommendations are based on findings of the
`studies reviewed later in this chapter, modified
`and amplified by our own clinical experience and
`that of colleagues we surveyed.
`
`Symptoms
`
`The most important consideration in choosing a
`treatment for manic symptoms is their nature and
`severity. Mild manic symptoms {hypomania or
`stage-I mania) usually respond well to lithium
`alone. Restoring a nonnal sleep pattern (Hudson
`
`TREATMENT
`
`et al., 1989) can often avert escalation to more
`
`severe stages of mania. This might be accom-
`plished by using an adjunctive sedative hypnotic,
`such as
`the benzodiazepines clonazepam or
`lorazepam, during the evening.
`A neuroleptic may be needed to control severe
`symptoms, particularly gross hyperactivity and
`psychotic features. Whether to chose a neurolep-
`tic of high potency (e.g., haloperidol. thiothix-
`ene) or low potency (e.g., chlorpromazine, thic-
`ridazine) is still an unsettled issue. Hi gh-potency
`drugs have a relatively low level of hypotensive
`and sedative side effects, a feature that allows
`
`more rapid initial dose escalation and, therefore.
`presumably more rapid control of die psychosis.
`Low-potency neuroleptics, on the other hand, are
`more sedating—actually an advantage in achiev-
`ing early control of the acute mania. In addition,
`low-potency drugs carry less of a risk of extra-
`pyramidal effects,3 including tardive dyskinesia,
`and neurotoxic reactions, and also the rare neu-
`
`roleptic malignant syndrome‘
`Pope et al., 1986).
`Both the research literature and our own clini-
`
`(Casey, 1984;
`
`cal experience suggest that the anticonvulsants
`and neuroleptics are superior to lithium in the
`early phase of treating severe mania, that is, dur-
`ing the first week or two. After the first 2 weeks,
`lithium and, perhaps, carbamazepine are more
`effective than neuroleptics. Because of their
`greater specificity,
`lithium and carbarnazepine
`calm the patient with a minimum of sedation and
`nonspecific tranquilization. These drugs are also
`superior because they are less likely to be associ-
`ated with posrrnania depressions and, even more
`important, carry no appreciable risk of tardive
`dysldnesia.
`The proper role of the anticonvulsants in treat-
`ing acute rnania has not yet been fully estab-
`lished. As reviewed later, carbarnazepine is
`clearly effective, even when used alone (although
`in most trials it was given in combination with
`lithium or neuroleptics). Existing data suggest
`that carbarnazepine may be as effective in acute
`mania as lithium or neuroleptics, but its overall
`efficacy requires more study. Compared with
`lithium, carbamazepine is similar in its relative
`specificity against the affective core of mania and
`often faster in achieving its antimanic effects.
`Less clear is whether it can match the effective-
`
`ness of neuroleptics in the short-term control of
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`MEDICAL TREATMENT OF MANIC EPISODES
`
`the extreme hyperactivity seen in psychotic ma-
`nia, although some evidence is encouraging.
`As a treatment for manic-depressive illness,
`carbamazepine is best established as an alterna-
`tive for patients who do not respond to lithium or
`cannot tolerate it.5 Thus, carbamazepine is the
`treatment of choice for managing acute mania in
`
`patients with a history of lithium-resistant rapid
`cycles, lithium failure or intolerance, or kidney
`dysfunction. Because of its antidepressant prop-
`erties, carbamazepine, alone or combined with
`lithium, may be particularly useful in the acute
`treatment of mixed states, which may not respond
`well to lithium alone (Secunda et al., 1985}. Be-
`cause it lessens aggression, carbamazepine may
`also be a good choice for suicidal patients. Until
`further information is available, the other anti-
`
`convulsants should generally be reserved for pa-
`tients who do not respond satisfactorily to car-
`bamazepine. A possible exception to this rule
`may be clonazepam, which. because of its seda-
`tive profile and safety, can be an important ad-
`junct in the initial treatment of mania.“
`
`Setting
`
`The treatment setting also influences the choice
`of drugs or electroconvulsive therapy {E'.CT). Ma-
`nia subsides more gradually with lithium than
`with neuroleptics, the anticonvulsants, or ECT-
`This lithium lag, 7 to 12 days when the mania is
`moderate to severe, might be tolerable in a well-
`staffed inpatient research unit, but very rapid con-
`trol of symptoms has priority in most settings and
`is clearly a necessity in some, such as an emer-
`gency room without a closed psychiatric unit for
`backup? In these settings, neuroleptics andfor
`anticonvulsants (or, selectively, ECT} are prefer-
`able for highly agitated patients. A decision tree
`outlining the choice of treatments for mania is
`illustrated in Figure 21-1.
`
`Contraindications
`
`Medical conditions or medication needs some-
`
`times limit the choice of drugs.3 Although we are
`concerned here with the short-term use of drugs in
`treating acute mania,
`the medical factors dis-
`cussed subsequently are also relevant to discus-
`sions of long-term prophylactic treatment {see
`Chapter 23). Medical contraindications for anti-
`manic drugs, although rare, must always be bal-
`
`605
`
`anced against the risks of untreated mania. Table
`21-1 lists, in approximate rank order, contrain-
`dications to antimanic drugs. (The subjective and
`behavioral side effects of lithium and its effect on
`
`organ systems are fully reviewed in Chapter 23.)
`Impaired kidney function is a relative contrain-
`dication for lithium treatment because lithium is
`
`eliminated principally through the kidney and can
`influence renal tubular activity. Lithium can be
`used for patients with moderate or stable impair-
`ment, but
`the blood level should be carefully
`monitored, since a therapeutic level usually can
`be reached with lower doses than those needed for
`
`patients with normally functioning kidneys. Car-
`bamazepine can be substituted for lithium when
`severe renal impairment precludes its use.
`Cardiac disease is another important con-
`sideration in treating mania. By virtue of its ionic
`properties and especially its ability to substitute
`for potassium, lithium produces changes in the
`electrocardiogram (particularly T-wave flatten-
`ing) that are generally benign and reversible.
`There are, however, rare and scattered case re-
`
`ports of patients with certain kinds of cardiac pa-
`thology who experience lithium-induced com-
`plications (lefferson et al., 1937).
`Myocardial infarction requires a balancing of
`risks. Lithium can conceivably produce com-
`plications in an already compromised myocar-
`dium (primarily because it can increase irri-
`tability). This risk must be weighed against
`possibly even greater risks, such as the effect of
`the untreated manic patient's uncontrolled ac-
`tivity, psychophysiological stress, and uncertain
`compliance with cardiac medication, as well as
`the hypotension that may result from taking neu-
`roleptics. Lithium should,
`therefore, be con-
`sidered for managing a manic or hypomanic epi-
`sode, even during or shortly -after myocardial
`infarction. Carbamazepine or perhaps clonaze-
`pam may provide useful alternatives to lithium or
`neuroleptics in this situation. (For comprehensive
`reviews of the cardiac effects of lithium, see Al-
`
`brecht and Miiller-Oerlinghausen, 1930; Jeffer-
`son et al., 1987.)
`Neurological conditions that influence treat-
`ment decisions in mania include epilepsy, parkin-
`sonism, dementia, cerebellar disease, and my-
`asthenia gravis. The risk of neuroleptic-induced
`tardive dyskinesia increases with age, particular-
`ly in women. in addition. the risk appears to be
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`TREATMENT
`
`Hypomanla
`
`{Stage - I or - ll Mania)
`
`Lithium
`
`Lithium
`[+ Clonazepam
`for sleep}
`
`.
`.
`Lithium +
`
`Carbarnazepino a
`‘J’
`a
`Clonazepam
`or
`tialproate 3
`
`Mania
`
`(Stage - II or - III}
`Lithium
`{+ Clonazaparn
`1-or sleep)
`
`Lithium + Neuroloptic
`
`Lm-Hum +
`
`\ Em /
`
`3
`
`Carbarnazepine
`or
`Valproata 3
`OF
`Clonazepam 3
`
`Figure 21-1. A treatment decision tree for mania. “The anticonvulsants are more likely to be indicated when there
`is a history of rapid cycles, lithium resistance, or temporal lobe—like symptoms.
`
`substantially greater for patients with affective
`illness than for those with schizophrenia (Casey.
`1984). Intermittent use of a neuroleptic, more
`typical in manic-depressive illness than in schizo-
`phrenia. may also be associated with a greater
`risk of tardive dyskinesia, but this association is
`controversial.
`
`Neither lithium not the neuroleptics are con-
`traindicated fot acute mania in patients with
`classic epilepsy, although both drugs can produce
`activation of the electroencephalogram (EEG).
`The obvious choice for treating manic-depressive
`illness in patients with seizure disorders is car-
`bamazepine, which has anticonvulsant activity.
`Lithium can aggravate preexisting Pa.rkinsor1‘s
`disease, an effect that is not surprising, since
`lithium decreases dopamine synthesis in the brain
`(see Chapter 13) (Malteeva et al., 19'?4).‘—" Car-
`bamazepine, which does not markedly affect the
`
`dopamine system, is preferable to neuroleptics in
`managing the mania that can emerge when par-
`kinsonian patients are treated with 1.-dopa. It is
`also best for manic patients with preexisting tar-
`dive dyskinesia.
`Neuroleptics or anticonvulsants may be better
`than lithium for manic patients with dementia,
`cerebellar disease, or other pathology of the CNS
`because lithium is more likely to intensify the
`underlying dysfunctions. However. some pa-
`tients with dementia are particularly sensitive to
`the organic confusional effects of neuroleptics or
`anticonvulsants. In the neuroleptics. this effect is
`probably due to their potent hypotensive action.
`The tendency of lithium to produce muscle
`weakness makes it unsuitable for treating manic
`patients with myasthenia gravis. It has been used
`successfully to treat the pathological mood la-
`biljty associated with multiple sclerosis without
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`Table 21 -1. Relative Contraindications
`tor Anlimanio Dmgs
`
`Lithium
`
`Usually contraindicated:
`Renal lunclion impairment
`Acute myocardial infarction
`Myaslhenia gravis
`Pregnancy - 15‘ trimester
`Breast feeding
`Cornprornised fluid or salt balance
`
`Use with close medical supervision, including limited
`dosage:
`other cardiac pathology
`Parltinson’s disease
`Pregnancy - 2"“ or 3“-1 trimester
`Delivery
`Epilepsy
`Thyroid disorders
`
`Use with caution. including limited dosage:
`Cerebellar disorders
`Dementia
`other CNS disorders
`Diabetes mellitus
`Ulcerative colitis
`Psoriasis
`Senlle cataracts
`Osteoporosis
`Certain drugs (see text}
`
`NELIIOIEFIHCS
`
`Myocardial intarction
`F'arklnson’s disease
`compromised liver function
`Porphyria
`Hypolenslon
`Tardive clyskinesia
`
`Carbantazeplne
`
`Compromised liver tunction
`Porphyria
`Hematopoietic system abnormality
`A-V block
`
`CIDHBZEIJEI11
`
`Neurological disorders altecting balance
`CNS depression
`
`A previous history of allergic reaction to any antirnanic drug
`would be a contraindication lot that particular drug.
`
`aggravating the neurological disorder (see, e. g.,
`Kemp et al., 1977), although such patients may
`have a lower threshold for some of lithium's side
`effects in the CNS.
`
`Other medical conditions also may be affected
`by drug treatments for mania. Neurolcptics and
`perhaps carbamazepine should be ruled out for
`
`607
`
`patients with compromised liver function and
`porphyria, for example. Carbamazepine and the
`new atypical ncurolcptic, clozapine. both have
`been associated with bone marrow suppression
`and should be avoided in patients with disturbed
`hematopoietic function. Although lithium is not
`contraindicated for patients with diabetes,
`the
`disease process should be monitored closely once
`the drug is started since it has been reported to
`exacerbate diabetes, especially in patients taking
`it for several years (see, e.g., Mcllerup et al.,
`1933}.
`
`Thyroid disease can be aggravated by the
`chronic use of lithium, but in the relatively brief
`acute treatment phase, the administration of thy-
`roid horrnone can offset any effects of lithium.
`Hypothyroidism may also contribute to inade-
`quate lithium response. One severely manic pa-
`tient,
`for example, was unresponsive to a
`lithiurn—neuroIeptic combination until after her
`hypothyroidism was corrected (Balldin ct al.,
`1937). Similarly, postpartum mania may be asso-
`ciated with poor lithium response (Targurn et at . ,
`19'?9], which may be caused by a correctable low
`estrogen state (Wehr and Goodwin, 1981). Con-
`ditions in which electrolyte imbalance exists,
`such as Severe diarrhea, complicate the use of
`lithium and perhaps also of carbantazepine, and
`neuroleptics might be favored. Any abnormality
`in the hematopoietic system may complicate the
`use of carbamazepine. To our knowledge, there
`are no medical contraindications to the use of
`
`clonazepam or other benzodiazepines.
`
`Pregnancy
`
`Birth defects, principally involving the cardiac
`system, occur at rates that are significantly higher
`than normal rates in babies whose mothers re-
`
`ceived lithium in the first 3 months of pregnancy.
`Thus, lithium should be avoided during die first
`trimester whenever possible. Mild manic epi-
`sodes during pregnancy should probably be man-
`aged without drugs, but it is prudent to treat more
`severe episodes, since the possible consequences
`of an untreated episode (such as injury, psycho-
`physiological stress, dehydration and malnutri-
`tion, profound sieep deprivation, and suicide)
`could pose a greater risk to the fetus than the side
`effects of lithium. The risk—bencfit considera-
`
`tions for the use of lithium during pregnancy are
`thoroughly reviewed in Chapter 23. Clorlazcparn
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`TREATMENT
`
`is not known to be associated with fetal abnor-
`
`malities and, therefore, might be used in these
`circumstances. Another option is ECT, which
`can be used without special risk to the fetus. The
`clinical management of mania during pregnancy
`has been reviewed by Nurnberg (1980) and by
`Sitland-Marken and colleagues (1989).
`
`Concurrent Medications
`
`Although several drugs interact with lithium,
`neuroleptics, and the anticonvulsants, only a few
`combinations are contraindicated (see Table 23-5
`
`and discussion in this chapter). Knowledge of
`these interactions will influence the choice of one
`
`drug over another, but potential drug interactions
`generally should not take precedence over the
`clinical indications outlined previously.
`The concurrent use of lithium and diuretics de-
`
`serves special attention. Loop diuretics, such as
`furosemide. do not substantially alter lithium ex-
`cretion and can be administered together safely
`(Saffer and Coppen, 1983; Jefferson et al.,
`198?). The thiazide drugs are more problematic,
`since they decrease tubular reabsorption of so-
`dium and indirectly increase lithium reabsorption
`and decrease its excretion. When these drugs are
`used, lithium should be started at a low dose and
`
`increased very gradually, with frequent monitor-
`ing of the blood level.
`Other medical drugs with potential lithium in-
`teractions include anti-inflammatory agents, such
`as indomethacin and phenylbutazone, which in-
`crease lithium levels [Reirnann et al.. 1983); car-
`diovascular medications, especially the anti-
`hypertensive methyldopa, which decreases renal
`clearance; and digoxin, which has been shown
`to reduce the acute manic efficacy of lithium
`(Chambers et al., 1982}. Finally, some antibio-
`tics prescribed for lithium-associated acne have
`nephrotoxic potential.
`Because they compete for hepatic metabolism,
`certain drugs may significantly increase car-
`bamazepine blood levels and produce toxicity.
`Consequently, the combination of valproic acid
`and carbamazepine is contraindicated {Meyer et
`al., 1984; Lambert and Venaud, I987; Meijer et
`al., 1984]. Among the other drugs that should be
`used cautiously with carbamazepine for this same
`reason are verapamil, isoniazid, diltiazem. and
`erythromycin and related antibiotics (Berrettini,
`1986; Sovner. 1983). By contrast, other drugs-
`
`phenobarbital, prirnidone, and pl1enytoih—can
`decrease carbamazepine blood levels, presum-
`ably by inducing hepatic metabolism (Post et al.,
`1985).
`Concurrent administration of carbamazepine
`and neuroleptics has been reported in more than
`100 patients. The two drugs produce some addi-
`tive effects in the CNS, and there is some evi-
`dence that they enhance each other’s effects. Car-
`hamazepine does not appear to alter lithium
`levels. Additive CNS effects, especially sedation
`and cognitive and memory functions, should be
`kept in mind when deciding how fast to increase
`dosages and the ultimate dose level. Patients with
`preexisting CNS disease may be especially vul-
`nerable to neurotoxicity with this combination
`(Shukla et al., I984).
`
`Determining Medication Dosage
`
`Neurolepties
`
`Clinicians traditionally have used larger doses of
`neuroleptics for acute mania than for schizo-
`phrenia, but recent experience suggests that more
`modest doses can be effective. The lower dose is
`
`feasible if the patient is carefully monitored for
`early signs of improvement and takes lithium
`along with the neuroleptic. Chlorprornazine
`doses averaged more than 1 g per day in con-
`trolled studies. and comparably high doses have
`been reported for the high—potency neuroleptics,
`such as haloperidol and thiothixene. Blood level
`determinations for neuroleptics are not yet rou-
`tinely available as they are for lithium. Clinical
`state, age, sex, and weight must be considered in
`setting dose levels; higher doses are required for
`more disturbed and highly active patients and
`for patients who are male, young, or heavy.
`I-laloperidol is usually started at 5 to 15 mg intra-
`muscularly (or 10 to 25 mg orally) every 4 to 6
`hours. For chlorpromazine, the preferred dosage
`is 50 to 100 mg, which can be administered intra-
`muscularly every 6 hours and then gradually re-
`placed by oral doses. '9 The need for such high
`doses of neuroleptics should be reevaluated con-
`tinually throughout trean-nent of the acute manic
`episode. To minimize the possibility ofneurotox-
`icity, extrapyramidal side effects, or postrnania
`depression, dosage should be reduced as soon as
`manic symptoms begin to subside.
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`Alkermes, Ex. 1065
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`

`
`MEDICAL TREATMENT OF MANIC EPISODES
`
`609
`
`Lithium
`
`The gap between therapeutic and toxic levels of
`lithium is the narrowest of any drug routinely
`used in psychiatry. Fortunately,
`the level of
`lithium in plasma is readily determined, and dos-
`age requirements have been studied extensively.
`In managing acute mania with lithium alone, it is
`best to use a dosage schedule that produces the
`highest plasma level consistent with acceptable
`side effects. These blood levels usually are higher
`than those considered necessary or safe for main-
`tenance therapy. The doselblood level relation-
`ship is influenced by the individual’s sex. age,
`weight (especially muscle mass), salt
`intake,
`amount of sweat, intrinsic renal clearance capaci-
`
`ty for lithium, and, as noted, other medications.
`A relatively higher dose! blood level ratio is asso-
`ciated with being younger, male, and heavier and
`having a higher salt intake.
`In the lithium treatment of acute mania,
`
`the
`
`patient's clinical state is one of the most impor-
`tant factors affecting the dose! blood level rela-
`tionship. Some patients, when manic,
`retain
`lithium in body pools outside the plasma, proba-
`bly largely in bone (Greenspan et al. , 1968; Alrny
`and Taylor, 1973). In practice, more lithium is
`needed to achieve a given blood level during ma-
`nia than during euthymia or depression (Goodwin
`et al., 1969; Serry, 1969; Kukopulos et al.,
`1935). When mania begins to subside, a dosage
`reduction usually is necessary to avoid lithium
`toxicity. Obviously, blood levels should be moni-
`tored more frequently when the clinical state is
`changing, especially from mania to euthyrnia or
`depression.
`To predict dosage requirements, some inves-
`tigators recommend a test dose of lithium fol-
`lowed 24 hours later by a plasma level determina-
`tion {Cooper and Simpson, 1976; Perry et al.,
`1984). Fava and colleagues (1984) showed that,
`by using this technique, therapeutic levels were
`obtained faster, and fewer blood level determina-
`
`tions were required. Although this technique
`probably can be applied reliably when the mood
`state is stable, its practical vaiue in treating acute
`mania is limited by the state-dependent kinetics
`of lithium. Errors in the predicted dose may, for
`example, be due to changes in patients‘ sleep and
`activity, which presumably cause changes in re-
`nal clearance (Perry et al. , 1984). In addition, use
`
`of this method necessitates a 24-hour delay in
`treatment. Norman and colleagues (1982) pro-
`posed a faster technique that can also account for
`changes in renal clearance. This technique may
`be impractical. however, since it requires a
`4-hour urine collection along with a blood
`sample.
`The plasma level of lithium needed to produce
`a clinical response differs substantially from one
`manic patient to another. The same is true of
`toxicity. These differences are partly caused by
`variability in tissue sensitivity, a variability en-
`countered with any drug. More important, how-
`ever, are individual differences in the ratio of
`
`plasma lithium to intracellular lithium, as re-
`flected in red blood cell (RBC) determinations.
`Toxic reactions
`reflect
`intracellular
`lithium,
`whereas serum levels reflect only the extracellu-
`lar compartment.
`These issues are important to treatment be-
`cause increasing plasma levels of lithium (up to
`1.4 mEq.’liter)
`are
`associated with propor-
`tionately higher rates of therapeutic response
`(Stokes et al., 1976). Although there is reason to
`push the dose in patients who fail to respond,
`blood levels above 1.5 mEq!liter are not gener-
`ally recommended, and even levels between 1.2
`and 1.5 mliqfljter require considerable care
`to avoid toxicity.
`Indeed, an increase in the
`RBC!plasma lithium ratio often precedes the de-
`velopment of neurotoxicity (see, e. g., Dunner et
`al., l9Tr'8; Carroll and Feinberg, I977). In most
`cases, blood levels in the therapeutic range can be
`achieved at doses between 900 and 1,800 mg
`daily of lithium carbonate.
`In deciding the maximum lithium level to use
`with a manic patient, the clinician should keep in
`mind that
`the most
`important potential
`toxic
`effects are those involving the CNS. This task is
`made more difficult by the fact that the delirium-
`like symptoms that can occur in severe mania
`may be nearly indistinguishable from neurotoxic
`effects. (Specific neurotoxic effects of lithium are
`discussed in Chapter 23.)
`Some authors have suggested using a loading
`dose strategy for treating mania with lithium,“
`both to achieve the maximum blood level quickly
`and to speed therapeutic onset. The value of this
`strategy is questionable, however, especially in
`light of animal and human data indicating that
`lithium is slow to enter the brain from the blood,
`
`9of89
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`Alkermes, Ex. 1065
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`9 of 89
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`Alkermes, Ex. 1065
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`

`
`610
`
`TREATMENT
`
`even when plasma levels are high. In one study,
`CSF lithium levels increased 50 percent, on aver-
`age, from the first to the third week on a constant
`lithium dose (Rey et al., 1979).
`
`Lithium Plus Neuroteprics
`
`The additive and possibly synergistic effects of
`lithium and neuroleptics must be considered
`when combining the two drugs. A severe enceph-
`alopathy syndrome was first reported in four
`manic patients treated with high doses of both
`lithium and haloperidol by Cohen and Cohen in
`l9?4. Since then, some 50 additional cases of
`
`neurotoxic syndromes resulting from the com-
`bination of lithium and a neuroleptic have been
`reported. Most of these conditions are reversible.
`On the other hand, eight prospective and retro-
`spective studies with a total of more than 600
`patients have generally failed to find any special
`neurotoxicity with this combination . 13 This liter-
`ature suggests that the risk of neurotoxicity is
`associated with pre-existing encephalopathy and
`high dose levels, especially of the neuroleptics. *3
`Thus neuroleptics should be used in substantially
`lower dosages when combined with lithium than
`when used alone. We also recommend that the
`
`lithium level be kept below 1.0 mfiqlliter, in part
`because neuroleptics increase the RBC!plasma
`lithium ratio (Von Knorring et al., 1982). Al-
`though lithium and neuroleptics generally can be
`combined safely and effectively when done in
`this way, it is importantto monitor CNS function
`and, in hospital settings, to alert the staff to watch
`for symptoms of neurotoxicity. Patients in seclu-
`sion rooms, who can rapidly become dehydrated,
`require special caution,
`including temperature
`monitoring (see later discussion of seclusion and
`restraints). One report of a high frequency of neu-
`rotoxicity with lithium—neuroleptic combina-
`tions in people over 65 suggests caution in this
`age group as well (Miller et al., 1986).
`
`Carbarmtzepine and ‘Vaipraate
`
`When carbamazepine is used alone. the starting
`dose is usually 200 to 400 mg, which is increased
`to the 800 to 1,000 mg range during the first
`week. Further increases (up to about 1,600 mg)
`are appropriate if no response is evident after the
`first 2 weeks and if not limited by unacceptable
`side effects. The blood level generally should be
`between 6 and 12 nglml. When carbamazepine is
`
`combined with lithium or neuroleptics, the close
`and target blood level are typically somewhat
`lower. Over time, carbamazepine can induce its
`own hepatic metabolism, and blood levels can
`fall. This problem is more troublesome in pro-
`phylactic treatment [see Chapter 23).
`Side effects are more likely to occur when dos-
`ages are increased rapidly in treating acute mania
`than when the dosage is built up slowly in the first
`phase of prophylactic treatment. These early side
`cffects—drowsiness_. dizziness. ataxia, confu-
`sion. double vision, and nausea
`usually do not
`
`persist beyond the first week or two and often
`respond to temporary dosage reduction.
`Carbamazepine produces side effects about as
`frequently as lithium and less often than neu-
`roleptics. Skin rashes of varying degrees of sever-
`ity are a frequent problem (It) to 15 percent of
`patients). T