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Marlene P. Freeman, Christopher B. Wiegand, Alan J. Gelenberg: Chapter 35. Lithium, in The American Psychiatric
Publishing Textbook of Psychopharmacology, 4th Edition. Edited by Alan F. Schatzberg, Charles B. Nemeroff. Copyright
©2009 American Psychiatric Publishing, Inc. DOI: 10.1176/appi.books.9781585623860.413828. Printed 5/10/2009 from
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Chapter 35. Lithium
HISTORY AND DISCOVERY
First used in the 1800s as a medicinal treatment, lithium was touted for a wide range of medical
woes—including gout and neurological and gastrointestinal ailments—and was used as a table salt
substitute and even sold in bottled beverages (El-Mallakh and Jefferson 1999). After noting its
sedating properties in animals, Cade (1949) first described the successful treatment of mania with
lithium salts. The U.S. Food and Drug Administration (FDA) approved lithium for use in treating
acute mania in 1970 and for the prophylaxis of bipolar disorder 4 years later (Jefferson and Greist
1977). However, lithium did not come onto the market easily in the United States. Pharmaceutical
companies were reluctant to produce this inexpensive drug that they could not patent (Kline 1973).
Lithium has stood the test of time. Despite a growing number of choices for the treatment of bipolar
disorder, lithium remains a cost-effective and efficacious treatment. Baldessarini and Tondo (2000)
questioned whether lithium has remained stable in efficacy across the decades. Analyzing 11
controlled and 13 open studies of lithium treatment, as well as their own data, they concluded that
lithium’s efficacy has remained constant but that some clinical research settings may serve a more
complex and refractory patient population than the population typically seen in psychiatric practice.
Wyatt et al. (2001) computed the savings from lithium use during the years 1970 and 1991,
estimating that more than $8 million was saved annually, after consideration of treatment costs,
lost earnings, and lost productivity. Lithium is still a highly cost-effective treatment for bipolar
disorder (Chisholm et al. 2005). In contrast to most other medications for bipolar disorder, lithium
is available generically and is relatively inexpensive. The pharmaceutical industry spends
considerable funds for research and marketing for drugs still on patent, and therefore lithium has
achieved an orphan status, with little incentive for private funding of studies with lithium
(Rosenthal 2001).
Lithium is effective and well tolerated, especially at moderate serum lithium concentrations. . . . One
factor that may be responsible for lithium’s fall from grace among clinicians and patients is its status as
an “orphan” or “poor relative.” Since lithium is cheap and unpatented, no wealthy drug company has any
interest in demonstrating its merits as a mood stabilizer. There are no lavishly catered all-star symposia
at major psychiatric meetings to sing the praises of this humble salt. And when did you last see a pen,
notepad, calendar, or trinket with “Lithium” embossed on it? Finally, lithium is regarded as old news and,
as such, is less appealing to psychiatric researchers eager to make their mark on the field. (Rosenthal
2001, p. 973)
STRUCTURE–ACTIVITY RELATIONS
Lithium is the lightest alkali metal and a monovalent cation, and it shares some properties with
sodium, potassium, and calcium (Baldessarini 1996; Ward et al. 1994). It is the third element of the
periodic table. Substitution or competition with other cations may contribute to its effects (Ward et
- 1994).
PHARMACOLOGICAL PROFILE
Lithium is minimally protein bound, does not undergo biotransformation, and is renally eliminated
(Kilts 2000). The narrow therapeutic index necessitates careful drug monitoring. Lithium appears to
affect multiple neurotransmitter systems and affects second-messenger systems such as cyclicPrint: Chapter 35. Lithium
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adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) (Ward et al.
1994).
PHARMACOKINETICS AND DISPOSITION
Lithium is available in multiple preparations, including lithium carbonate tablets and capsules,
lithium citrate, and slow-release forms (Jefferson et al. 1983). Lithium is absorbed from the
gastrointestinal tract and renally excreted unchanged in approximately 24 hours (Baldessarini and
Tarazi 2001). Peak plasma concentrations are reached within 1–2 hours with rapid-release
preparations and 4–5 hours after sustained-release formulations (Finley et al. 1995). Brain levels,
as measured by in vivo nuclear magnetic resonance, are highest 0–2 hours after peak serum
concentrations are achieved (Komoroski et al. 1993). Lithium is not protein bound and is evenly
distributed in total body water space (Jermain et al. 1991). Lithium excretion is controlled by
osmotic factors and is a function of renal sufficiency (Birch et al. 1980). Steady-state
concentrations are achieved within 4–5 days (Keck and McElroy 2002).
MECHANISM OF ACTION
Despite extensive research, the exact mechanism of action of lithium as a mood stabilizer has yet to
be elucidated. The importance of defining lithium’s mechanism of action is twofold: 1) to shed light
on the disorder’s etiology and 2) to open up investigation into new treatments for bipolar disorder
(Phiel and Klein 2001). Multiple theories, based on animal models and limited studies in humans,
have been proposed; those with the most compelling evidence are reviewed here.
Eventually, an integrated theory of lithium’s action will be necessary because it has numerous
physiological effects. Ikonomov and Manji (1999) have offered the “initiation and adaptation
paradigm” as a nicely integrated view of lithium’s actions: lithium has both immediate short-term
effects and effects that emerge only after long-term treatment. They propose that the immediate
effects eventually cause downstream changes in gene expression.
Inositol Depletion
There has been much focus on the role of the inositol cycle in the clinical effects of lithium. Lithium
is a noncompetitive inhibitor of inositol monophosphatase, depleting free inositol within 5 days of
treatment initiation (Berridge et al. 1989). These changes last for 3–4 weeks after lithium’s
discontinuation (Moore et al. 1997). Depletion of free inositol can lead to effects on
neurotransmitter and second-messenger systems linked to the inositol cycle. For example,
adrenergic, serotonergic, and cholinergic receptor subtypes are coupled to the cycle via G proteins,
and the cycle in turn regulates protein kinase C action, which appears to be influenced by lithium
treatment in mania (Hahn et al. 2005). Lithium decreases levels of protein kinase C isoenzymes in
the frontal cortex and hippocampus, two areas of the brain known to be involved in the
pathophysiology of mood disorders (Drevets et al. 1997; Ketter et al. 1997; Manji et al. 1993, 1999;
Rajkowska et al. 1999).
Berridge et al. (1989) suggested that lithium, because it is a noncompetitive inhibitor of inositol
monophosphatase, only affects activated systems via the inositol-depletion mechanism; basal
functioning of the cycle is not affected. This would account for lithium’s profound effects on mood
in bipolar and depressive disorders and its relatively minor effects on mood in control subjects
(Judd 1979).
Lithium affects rearing behavior in rats, which is reversible by inositol administration. Also,
administration of inositol inhibits the epileptogenic effects of pilocarpine challenge after lithium
administration in rats (Belmaker et al. 1996). Of note, depression is associated with low
cerebrospinal fluid inositol levels in humans (Barkai et al. 1978). Exogenous inositol can alleviate
depression (Levine et al. 1993, 1995) and panic attacks (Benjamin et al. 1995). Belmaker et al.
(1996) suggested a complex “pendulum” relationship between inositol and lithium, which may be a
basis for understanding lithium’s antimanic and antidepressant effects.
In rats and humans, inositol attenuates some of the side effects of lithium, particularly polyuriaPrint: Chapter 35. Lithium
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(Bersudsky et al. 1993; Geisler et al. 1972) resulting from either lithium’s effects on the inositol
cycle or inositol’s osmotic effects (P.A. Garcia and Burg 1991). Death due to lithium toxicity in rats
is not prevented by inositol administration, suggesting a different mechanism (Belmaker et al.
1996).
Glycogen Synthase Kinase Inhibition
Lithium inhibits glycogen synthase kinase–3 (GSK-3) (Klein and Melton 1996; Li et al. 2007).
Valproic acid also inhibits GSK-3, making this theory attractive because it involves a common
mechanism in two known mood stabilizers (G. Chen et al. 1999). GSK-3 is an inhibitor of the Wnt
protein signaling pathway, which affects neuronal signal transduction. Lithium thus would be
predicted to mimic Wnt signaling (Phiel and Klein 2001). Wnt signaling stimulates a cascade of
events that leads to stimulation of protein kinase C activity (Grahame-Smith 1998; Williams and
Harwood 2000). Thus, lithium’s actions on both the inositol cycle and the GSK 3 signaling pathway
lead to a common effect on protein kinase C.
Wnt signaling, which is inhibited by and in turn inhibits GSK-3 activity, also causes axonal
remodeling in mouse cerebellar cells (Hall et al. 2000). GSK-3 activity elevation can cause
breakdown of catenins, which can cause structural changes in cytoskeleton (Cotter et al. 1998).
-Catenin produces changes in gene expression that are related to cytoskeletal structures. Lithium
stabilizes cytoskeleton structures (Williams and Harwood 2000).
Lithium’s Effects on Neurotransmitter Systems
Perhaps because of its effects on second-messenger systems, lithium brings about changes in all of
the major neurotransmitter systems in the brain. Chronic administration of lithium in mice
increases and stabilizes glutamate uptake. This could, in part, explain lithium’s antimanic effect
because it results in overall reduction of an excitatory neurotransmitter (Dixon and Hokin 1998).
Lithium also normalizes low cerebrospinal fluid -aminobutyric acid levels in bipolar subjects (see
Berrettini et al. 1983, 1986).
Lithium enhances norepinephrine and serotonin function in the central nervous system, which could
explain its antidepressant effects (Price et al. 1990; Schildkraut et al. 1969; D. N. Stern et al.
1969). Of particular interest is lithium’s confirmed antagonistic action at serotonin1A (5-HT1A) and
serotonin1B (5-HT1B) autoreceptors (Haddjeri et al. 2000; Massot et al. 1999); such action would
increase serotonin availability in the synaptic cleft (Shaldubina et al. 2001). Clinically, 5-HT1A may
be involved in alleviation of depression, and 5-HT1B receptors may play a role in the regulation of
sleep, sensorimotor inhibition, and locomotor activity (Monti et al. 1995; Sipes and Geyer 1996).
Lithium, Mood Disorders, and Circadian Rhythms
Bipolar disorder and depression are associated with disturbances in the body’s natural rhythms; the
most clinically evident of these is the disruption of the sleep–wake cycle, but the temperature
cycle, cortisol cycle, and others are also affected (Hallonquist et al. 1986; Healy and Waterhouse
1995). Associated with such changes is a decoupling of the major and minor oscillators located in
the hypothalamus, which in healthy subjects work in a synchronized fashion. Lithium
administration causes the oscillators to resynchronize (DeMet and Chicz-Demet 1987; Klemfuss
1992). The mechanism by which resynchronization occurs is unknown; it is likely not via the
inositol depletion mechanism (Lakin-Thomas 1992, 1993). Also, a cause–effect relation has not
been established for circadian rhythm abnormalities and mood disorders; the changes seen in
circadian rhythms could be a cause of bipolar disorder and/or unipolar depression or could be an
effect of the disease process.
INDICATIONS AND EFFICACY
Bipolar Disorder
Acute ManiaPrint: Chapter 35. Lithium
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Cade (1949) first published data on the efficacy of lithium in mania more than half a century ago.
As we begin the twenty-first century, lithium remains one of the most efficacious treatments for
bipolar disorder.
Lithium versus placebo
Lithium has been shown to be more efficacious than placebo in acute mania in randomized trials
(Bowden et al. 1994, 2005; Goodwin et al. 1969; Maggs 1963; Schou et al. 1954; Stokes et al.
1971). Analysis of response rates in these studies indicates that lithium was at least somewhat
efficacious in the treatment of mania in 87 of 124 patients (70%) (Keck et al. 2000).
Lithium versus typical antipsychotics
In studies that used various designs, lithium was more effective than chlorpromazine and other
traditional antipsychotic medications in the treatment of acute mania. In a review of studies,
Goodwin and Zis (1979) found lithium efficacious in at least 70% of patients, as defined by
remission or marked improvement. Lithium also worked more quickly than typical antipsychotics
and was better tolerated (Takahashi et al. 1975). In addition, patients with psychotic symptoms
during a manic episode tend to have a better response to lithium prophylactic treatment than do
those without psychosis (see Rosenthal et al. 1979).
In a 3-week double-blind study of lithium, haloperidol, and their combination for acute mania,
patients who received haloperidol or haloperidol plus lithium had more significant improvement
than did those who received lithium alone (Garfinkel et al. 1980). The combination of lithium and
haloperidol was as well tolerated as haloperidol alone. In patients with schizoaffective disorder,
lithium was as effective as chlorpromazine in acute mania (Brockington et al. 1978). More recently,
Segal et al. (1998) reported that inpatients with acute mania responded equally well to lithium,
haloperidol, and risperidone. Lithium has been used as a comparator in trials versus atypical
(second-generation) antipsychotic medications, but these studies primarily assess the efficacy of
the antipsychotic in a noninferiority approach rather than demonstrate significant differences
between lithium and the atypicals. To date, there is no obvious effect-size difference between any
agent and lithium for antimanic effects. By and large, antipsychotics appear to work faster. Most
probably, genetic variables mediate the likelihood and magnitude of treatment response to
different agents in different patients, so although we can detect no overall efficacy differences, for
individual patients there are likely great differences.
Lithium versus calcium channel blockers
Lithium appears superior to verapamil in the treatment of mania (Walton et al. 1996).
Lithium versus electroconvulsive therapy
Small et al. (1988) compared the effects of lithium with those of electroconvulsive therapy (ECT)
for acute mania. Patients who received ECT had significantly more improvement during the first 2
months of treatment than did those who received lithium carbonate, especially those with mixed
mania. After 8 weeks, no significant differences were found between the groups.
In a retrospective chart review, Black et al. (1987) found that a significantly greater percentage of
patients who received ECT (78%) had “marked improvement” than those who received lithium,
either “adequately or inadequately” (62%, 56%). Almost 70% of the patients who did not respond
to lithium experienced “marked improvement” after treatment with ECT.
Lithium versus anticonvulsants
Double-blind, randomized studies have suggested that carbamazepine and lithium are equally
effective for acute mania (Lerer et al. 1987; Small et al. 1991). However, neither trial included a
placebo arm. Swann et al. (1999) reported that for patients who had experienced a greater number
of previous episodes, divalproex was more effective than lithium for acute mania, as determined by
a 3-week double-blind study. For patients with a history of fewer episodes, lithium had no
significantly different effect compared with divalproex in acute mania. Bowden et al. (1994)Print: Chapter 35. Lithium
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reported that both lithium and divalproex sodium were significantly more effective than placebo in
the treatment of acute mania. Almost one-third of the patients receiving either lithium or
divalproex dropped out of the study secondary to lack of efficacy, compared with approximately
half of the patients who received placebo.
In a meta-analysis of the efficacy of lithium, valproate, and carbamazepine in mania, no significant
differences in efficacy were found among the three groups (Emilien et al. 1996). Only some of the
included studies were placebo controlled. Anticonvulsants were generally better tolerated than
lithium. Neurological abnormalities may predict a better response to anticonvulsants than to lithium
in mania. Patients with electroencephalogram abnormalities are more likely to respond to valproate
than to lithium (Reeves et al. 2001). One double-blind study suggested that lamotrigine may be as
effective as lithium for acute mania (Ichim et al. 2000).
Mixed mania, the co-occurrence of mania with depression, may predict a poor response to lithium.
In a double-blind study of acute mania, depressive symptoms were associated with a poorer
response to lithium (Swann et al. 1997). Other predictors of a poor antimanic response to lithium
include rapid cycling and substance abuse (Dunner and Fieve 1974; Goodwin and Jamison 1990;
Himmelhoch et al. 1976).
Rapid efficacy is desirable in a mood stabilizer, and rapid administration of lithium has been
preliminarily studied. Lynn et al. (1971) discussed lithium “loading” for acute mania. More recently,
Keck et al. (2001) assessed the safety and efficacy of rapid lithium administration in the treatment
of acute mania; in an open-label study of 15 inpatients, 20 mg/kg/day appeared well tolerated and
efficacious for acute mania.
Bipolar Depression
Lithium is a first-line treatment for acute bipolar depression (Compton and Nemeroff 2000). In
2004, an expert consensus report found lithium monotherapy to be both a preferred initial
medication for mild to moderate depression in bipolar I disorder and a component of an initial
medication regimen in severe nonpsychotic and psychotic depression in bipolar I disorder (Keck et
- 2004). The American Psychiatric Association’s (2002) “Practice Guideline for the Treatment of
Patients With Bipolar Disorder” states that the first-line treatment for bipolar depression is
pharmacotherapy with either lithium or lamotrigine, with the former approach as the
better-supported option.
Placebo-controlled studies of lithium in bipolar depression generally have reported efficacy.
Goodwin and Jamison (1990) analyzed the placebo-controlled trials that have been completed in
bipolar depression and found that 79% of the bipolar patients in those trials had either a complete
or a partial response to lithium. Placebo-controlled trials that show the efficacy of lithium in bipolar
depression include those by Baron et al. (1975), Donnelly et al. (1978), Fieve et al. (1968),
Goodwin et al. (1969, 1972), Greenspan et al. (1970), Mendels (1975), and Noyes et al. (1974).
These studies generally were small (involving between 3 and 40 patients [Goodwin et al. 1972]).
One study, by Stokes et al. (1971), did not show a significant benefit of lithium over placebo, but
lithium was administered for only a 10-day period in that trial.
Suicide: Is Lithium Protective?
Twenty-five percent to 50% of bipolar patients attempt suicide during their lifetime (Compton and
Nemeroff 2000). On average, studies of deaths among individuals with bipolar disorder indicate
that 19% complete suicide (see Goodwin and Jamison 1990). In an analysis of studies of lithium
treatment (Schou 1998), patients treated with lithium had a lower overall mortality rate than
bipolar patients in general. Schou (1998) studied a population of approximately 2,000 patients who
received lithium and found that these patients did not have a significantly higher suicide rate than
the general population. After discontinuation of the lithium, the mortality rate increased. Fewer
patients attempted or committed suicide while treated prophylactically with lithium than when they
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Also, Tondo et al. (1997) reviewed studies of the use of lithium in the treatment of major mood
disorders; these included 28 studies that involved more than 17,000 patients. Risks of completed
and attempted suicides were 8.6-fold higher in patients who were not given lithium compared with
those who were. They also found increased rates of suicide after lithium discontinuation
(Baldessarini et al. 1999). The risk of suicide with lithium discontinuation may be decreased with
gradual discontinuation. Lithium may have a specific antisuicidal effect in addition to
mood-stabilizing properties (Aherns and Muller-Oerlinghausen 2001). In addition to a marked
reduction in suicide attempts in lithium responders, lithium seems to reduce suicide attempts
independent of classification of clinical response (i.e., excellent, moderate, poor).
In meta-analyses of studies of lithium treatment in major mood disorders, Tondo et al. (2001) and
Baldessarini et al. (2006) found significantly lower suicide risk for subjects who were receiving
treatment with lithium. However, Coryell et al. (2001) conducted a case–control study in which
patients with major mood disorders who completed or attempted suicide were matched with control
subjects who were receiving similar treatment (antidepressant and/or mood-stabilizing
medication). The patients who committed suicide were slightly less likely to be using lithium, but
the difference was not statistically significant.
Methodological problems exist in the studies that have examined lithium and suicide risk, and
large-scale prospective studies are necessary for definitive recommendations to inform treatment
decisions (Gelenberg 2001).
Prophylaxis and Maintenance
Once the diagnosis of bipolar disorder is established, a patient will be afflicted for the rest of his or
her lifetime, with ongoing risks of relapse and recurrence. Therefore, prophylactic or maintenance
therapy is often considered after the resolution of an acute mood episode. Lithium is the
best-studied drug for this indication.
Tondo et al. (2001) found lithium effective in long-term use (more than 1 year) in decreasing
frequency of mood episodes and “time ill” in patients with bipolar I and bipolar II disorders.
Benefits of lithium treatment were not significantly different among patients with psychosis or
mixed episodes, rapid cycling, or more classic forms. There was no decrease in efficacy with
long-term use. Early commencement of lithium therapy and a diagnosis of bipolar II disorder may
predict a better course of illness (Tondo et al. 1998).
Rosenthal et al. (1979) also found that psychotic symptoms during manic episodes predicted a good
response to lithium prophylaxis in bipolar I patients. The chronological pattern of illness also may
predict response to lithium prophylaxis: the pattern mania–depression–euthymia is associated with
better response than depression–mania or rapid-cycling bipolar disorder (Maj 1990). Additionally, a
poorer response after 1 year of lithium therapy is associated with poor response to lithium within
the first 6 months, more severe episodes, higher ratio of manic episodes to depressive episodes,
and being unmarried (Yazici et al. 1999).
Kulhara et al. (1999) found that only 24% of the patients with bipolar disorder followed up in a
lithium clinic were free of mood episodes while receiving lithium prophylaxis (duration of
monitoring: average = 11 years, range = 2–27 years). Noncompliance and/or subtherapeutic
lithium blood levels (<0.4 mEq/L), high number of psychosocial stressors, higher number of
depressive episodes before lithium treatment, and poor social supports may predict poorer
response to lithium prophylaxis (Kulhara et al. 1999). Patients had significantly fewer mood
episodes after starting lithium.
Starting lithium early in the course of illness predicts a better response to treatment (Franchini et
- 1999). Time of onset of lithium prophylaxis was significantly related to outcome of lithium
treatment (P <0.001), after polarity, sex, age at onset, duration of illness, and duration of lithium
prophylaxis were accounted for.
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lithium prophylaxis (Rosenthal et al. 1979).
Lithium appears superior to carbamazepine in the prophylactic treatment of classic bipolar I
disorder. Denicoff et al. (1997) compared the efficacy of lithium, carbamazepine, and their
combination in the prophylactic treatment of bipolar disorder. Patients were randomly assigned to
double-blind treatment for 1 year with lithium or carbamazepine, experienced a crossover to the
other drug in the second year, and received a combination of the two in the third year. Thirty-one
percent failed to complete a full year of lithium therapy because of lack of efficacy, 37% failed to
complete a full year of carbamazepine therapy because of lack of efficacy, and 24% failed to
complete a full year of combination therapy because of lack of efficacy. Lithium was more effective
than carbamazepine for prophylaxis of mania; patients with rapid cycling did poorly with either
monotherapy (28% responded to lithium, compared with 19% to carbamazepine), and patients
with rapid cycling did significantly better on the combination of the two drugs than on either alone.
In a randomized study, Kleindienst and Greil (2000) found that lithium was superior to
carbamazepine in treating classic mania, but carbamazepine was more efficacious for nonclassic
features, such as mixed episodes and comorbidity.
In a comparison of lithium, divalproex, and placebo in a 1-year treatment study of patients with
bipolar I disorder after recovery from an index manic episode, Bowden et al. (2000) found that
median times to 50% survival without mood episode were 40 weeks for divalproex, 24 weeks for
lithium, and 28 weeks for placebo, although the differences were not statistically significant.
Patients who received divalproex remained in treatment significantly longer than did those who
received lithium. Calabrese et al. (2005) found similarly high rates of relapse in patients with
rapid-cycling bipolar disorder randomly assigned to either lithium or valproate monotherapy (56%
and 50% relapse rates, respectively). In patients with mixed or manic episodes who responded to
cotreatment with lithium and olanzapine, investigators conducted a double-blind, randomized
maintenance trial of lithium versus olanzapine (Tohen et al. 2005). Recurrence rates were similar
between groups, with 38.8% of those on lithium and 30.0% on olanzapine experiencing relapse,
with similar prophylaxis for depressive episodes among treatments and some advantage for
prevention of mania and mixed episodes with olanzapine.
The combination of lithium and valproate also has been studied as maintenance therapy for bipolar
disorder: the two may work synergistically (Solomon et al. 1998).
Quitkin et al. (1981) assessed the efficacy of lithium with and without the antidepressant
imipramine in the prophylaxis of bipolar I disorder. Few depressive episodes occurred in either
group, and the risk of mania increased with the addition of imipramine. Most relapses occurred in
the first 6 months of treatment.
Maintenance dosing
To be effective in prophylaxis, lithium must be administered daily. Lithium administration every
other day is not as effective as daily dosing (Jensen et al. 1995). Perry et al. (1984) formulated
tables to assist in the determination of maintenance dosage requirements, based on 24-hour serum
lithium levels after the administration of a 1,200-mg test dose. Once-daily dosing at bedtime yields
higher brain-to-serum ratios of lithium levels than twice-daily dosing schedules (Soares et al.
2001). Investigators have observed substantial variation in brain lithium levels among individuals
with similar serum lithium levels (Gonzalez et al. 1993).
Unipolar Depression
Analysis of five controlled trials of lithium augmentation for unipolar depression found significant
improvement in 56%–96% of patients (Austin et al. 1991; Heit and Nemeroff 1998; Heninger et al.
1983; Kantor et al. 1986; Schopf et al. 1989; Stein and Bernadt 1993; Zusky et al. 1988). In
treatment-refractory depression, open-label data support the addition of lithium to antidepressants,
including tricyclics, trazodone, and selective serotonin reuptake inhibitors (SSRIs) (De Montigny et
- 1981, 1983, 1985; Dinan 1993; Fontaine et al. 1991; Price et al. 1986). Double-blind studiesPrint: Chapter 35. Lithium
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support the use of lithium for augmentation of tricyclics, monoamine oxidase inhibitors (MAOIs),
trazodone, and SSRIs (Baumann et al. 1996; Fava et al. 1994; Heninger et al. 1983; Joffe et al.
1993; Kantor et al. 1986; Katona et al. 1995; Nierenberg et al. 2006; Schopf et al. 1989; Zusky et al.
1988). In the large Sequenced Treatment Alternatives to Relieve Depression (STAR*D) multisite
trial, 15.9% of subjects who did not experience remission with citalopram monotherapy and
another medication trial experienced remission after the addition of lithium (Nierenberg et al.
2006).
Time of onset of lithium action as an adjunct to antidepressants remains unclear. Also, new studies
are needed to determine the appropriate duration of treatment with lithium augmentation and the
appropriate serum lithium levels (Heit and Nemeroff 1998).
Personality Disorders
In a double-blind crossover study, Rifkin et al. (1972) studied lithium and placebo in patients with
“emotionally unstable character disorder,” consisting of “short mood swings, both depressive and
hypomanic, lasting hours to a few days” as well as “chronically maladaptive behavior.” Patients
were significantly more likely to show improvement while receiving treatment with lithium. LaWall
and Wesselius (1982) reported five cases in which patients with borderline personality disorder
(DSM-III; American Psychiatric Association 1980) showed clinical improvement with lithium
treatment.
Aggression and Impulsivity
In placebo-controlled trials of adults without bipolar disorder, lithium has been effective for
aggressive behavior (Worrall et al. 1975). Lithium reduced the frequency of aggressive episodes in
patients with mental retardation, per retrospective chart reviews (Luchins and Dojka 1989; Spreat
et al. 1989) and prospective double-blind, placebo-controlled clinical trial data (Craft et al. 1987).
Both open-label and double-blind, placebo-controlled data have found lithium to be effective in
reducing aggression in children with conduct disorder (Campbell et al. 1995; Malone et al. 1994,
2000). There may be broad public health implications for the relation between lithium and
aggression. In one study, counties with higher lithium levels in drinking water had lower rates of
suicide, homicide, and rape than did counties with lower lithium levels (Schrauzer and Shrestha
1990). Lithium treatment has been demonstrated to decrease impulsive gambling in individuals
with bipolar spectrum disorders (Hollander et al. 2005).
Anxiety
Information on the use of lithium in anxiety disorders is limited. Open-label (Van der Kolk 1983)
and case-report (Forster et al. 1995; Kitchner and Greenstein 1985) data suggest efficacy in
posttraumatic stress disorder. Case reports support a role for lithium in treating refractory panic
disorder (Feder 1988) and obsessive-compulsive disorder (Golden et al. 1988; T. A. Stern and
Jenike 1983). However, two controlled trials failed to demonstrate efficacy for lithium in the
treatment of obsessive-compulsive disorder (McDougle et al. 1991; Pigott et al. 1991).
USE IN SPECIAL POPULATIONS
Children and Adolescents
Lithium is FDA approved for the treatment of bipolar disorder in adolescents (Ryan et al. 1999).
Lithium has a large effect size in the open-label treatment of acute mania or mixed episodes in
children and adolescents (Kowatch et al. 2000). Geller et al. (1998a) conducted a randomized trial
of lithium for adolescents with bipolar disorder and secondary substance abuse and found that
lithium was significantly more efficacious than placebo for both bipolar disorder and substance
abuse. Geller et al. (1998b) found no significant differences in treatment outcomes between lithium
and placebo in a double-blind trial of prepubertal major depression. In an open study of lithium for
bipolar depression in adolescents with bipolar I disorder, investigators found a large effect size and
noted response and remission rates of 48% and 30%, respectively (Patel et al. 2006). Findling et
- (2005) conducted a randomized, double-blind maintenance trial of lithium versus divalproex inPrint: Chapter 35. Lithium
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children 5–17 years of age who were initially stabilized for mania/hypomania on a combination of
lithium and divalproex. They observed similar time to relapse with both treatments.
Saliva and serum lithium levels have been correlated in children receiving lithium maintenance
treatment, and monitoring of saliva levels may someday play a role in monitoring lithium levels
(Spencer et al. 1990). After weight and serum lithium levels were controlled for, younger age is
associated with more side effects (Campbell et al. 1991).
The Elderly
S.T. Chen et al. (1999) retrospectively assessed the response of patients at least 55 years old with
mania to either lithium or valproate. Overall, significantly more patients improved with lithium,
especially in cases of classic mania, whereas the two drugs had similar results when considering
only the cases of mixed mania. They also found the therapeutic range for elderly patients to be
similar to that for younger adults: 0.8 mmol/L.
Despite possibly greater efficacy, lithium may cause more side effects and be more costly in the
elderly. Although a year’s supply of lithium costs less than divalproex, these savings were offset by
higher annual laboratory costs (Conney and Kaston 1999). The lithium group also experienced more
adverse events, further increasing medical expenditures. Elderly patients with neurological or other
medical conditions may respond less well to and experience more side effects from lithium than
from anticonvulsant mood stabilizers (McDonald and Nemeroff 1996). Elderly patients may respond
less well to lithium augmentation for refractory unipolar depression, and older age may predict
increased incidence of side effects (Flint and Rifat 1994). On the basis of pharmacokinetic
differences, Hardy et al. (1987) suggested that elderly patients may require up to one-third or
one-half less lithium than younger patients. However, Slater et al. (1984) did not find a correlation
between age and required lithium dosage in adults.
Medical comorbidity may be a consideration in elderly patients. Volume depletion, use of
nonsteroidal anti-inflammatory drugs, and use of thiazide diuretics can increase lithium levels
(Stoudemire et al. 1990). Also, patients with kidney disease receiving hemodialysis do not
eliminate lithium other than through dialysis. Lithium should only be given after a dialysis
treatment and need not be given daily (Stoudemire et al. 1990).
Lithium appears to have neuroprotective effects, decreasing oxidative damage, and could play a
role in the prevention of neurocognitive decline in aging, although the clinical implications of this
remain to be determined (Bachmann et al. 2005; Cui et al. 2007; Shao et al. 2005; Tsaltas et al.
2007). Animal models suggest lithium may prevent Alzheimer’s disease by inhibition of GSK-3 and
its effect on tau protein phosphorylation and role in neurofibrillary tangle formation (Engle et al.
2006; Phiel et al. 2003; Su et al. 2004; Yoshida et al. 2006). In addition to neuroprotective effects,
lithium appears to exert neurotrophic factors and aid in neurogenesis as demonstrated in animal
models (G. Chen et al. 2000).
Pregnant/Lactating Women
The risks and benefits of lithium treatment must be carefully assessed in the context of pregnancy
and breast feeding. Data suggest that lithium exposure during pregnancy is less harmful than
experts believed in past decades. In an analysis of published studies of lithium exposure during
pregnancy, the association between lithium use and teratogenicity appeared weaker than was
assumed in the 1970s (L. S. Cohen et al. 1994). Ebstein’s anomaly, a cardiac malformation, was in
the past thought to be a relatively high risk of lithium use in the first trimester of pregnancy
(Weinstein and Goldfield 1975). In Ebstein’s anomaly, a dysplastic tricuspid valve may yield
tricuspid regurgitation, and clinical manifestations include cyanosis and atrial tachyarrhythmias.
The condition can be surgically treated. In fact, although the overall risk of Ebstein’s anomaly may
be higher with lithium use than without, because the condition is quite rare in the general
population (1 per 20,000 live births), prevalence associated with lithium use is still low.
First-trimester exposure to lithium results in 0.05%–0.1% prevalence of Ebstein’s anomaly, and
relative risk is 10–20 compared with the general population (L. S. Cohen and Rosenbaum 1998). ByPrint: Chapter 35. Lithium
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comparison, this risk is substantially lower than the risk of neural tube defects with some
anticonvulsants used for mood stabilization.
Many mood stabilizers are potentially teratogenic (see Llewellyn et al. 1998). For example, up to
5% prevalence of neural tube defects or other neurological problems is reported with valproate
exposure during the first trimester (Viguera and Cohen 1998). Reports have suggested that overall
lithium is not a high-risk teratogen. For example, in a prospective study of women who took lithium
during the first trimester (N = 148) and control subjects matched for age, rates of major
malformations did not differ between the lithium and control groups (2.8% and 2.4%,
respectively), although women in the lithium group were significantly more likely to be smokers
(Jacobson et al. 1992). The authors concluded that pregnant women with mood disorders may
continue taking lithium, provided that adequate screening of level II ultrasounds and fetal
echocardiography are performed. Maternal serum -fetoprotein screening is also recommended for
women taking mood stabilizers during pregnancy (American Psychiatric Association 2002). Also, in
a cohort study (N = 350), 7% of the women who used lithium early in pregnancy had infants with
cardiac defects, although none had Ebstein’s anomaly (Kallen and Tandberg 1983). However, there
was no statistically significant difference between delivery outcome with lithium and that with
other psychotropics.
Lithium today is considered a first-line alternative for the treatment of bipolar disorder during
pregnancy. However, many women may want to discontinue psychotropic medications during
pregnancy. Viguera et al. (2000) found that rates of relapse were similar in pregnant and
nonpregnant women but higher in the postpartum period. During the postpartum period,
significantly more women experienced a relapse after lithium discontinuation (followed by 40
weeks of euthymia) compared with nonpregnant patients matched for time after discontinuation
(70% vs. 24%). Despite continued treatment with lithium, three of nine (33%) women who were
maintained on lithium during pregnancy experienced a relapse postpartum, underscoring the high
risk of postpartum relapse in women with bipolar disorder. This high risk has led to experts in the
field recommending prophylactic treatment with a mood stabilizer for postpartum women (L. S.
Cohen et al. 1995). Newport et al. (2005) studied lithium levels in maternal blood and umbilical
cord blood and found that lithium equilibrates across the placenta. They observed that infants with
higher lithium levels experienced more neonatal complications and suggested withholding lithium
therapy 24–48 hours before an anticipated delivery to minimize risk to the baby.
Despite a general paucity of documented adverse effects to breast-feeding infants of mothers
taking lithium, the American Academy of Pediatrics has contraindicated lithium use in
breast-feeding women (Chaudron and Jefferson 2000). As reviewed by Chaudron and Jefferson
(2000), lithium is passed on to breast-feeding infants and is found in breast milk and infant serum.
Concentration in breast milk ranges from 24% to 72% of maternal serum concentration. A wide
range of infant serum levels has been reported (5%–200% of mother’s level), and two cases of
adverse events in breast-feeding infants have been published. Burt et al. (2001) found
documentation of only 13 infants exposed to lithium in breast milk—4 had no adverse effects;
clinical status was not reported for 8; and 1 infant who was exposed both in utero and while breast
feeding had serious adverse reactions, including cyanosis, heart murmur, and hypotonia
(Tunnessen and Hertz 1972). Viguera et al. (2007) recently assessed babies who were breast fed
while their mothers were treated with lithium monotherapy for bipolar disorder. They assessed 10
mother–baby pairs. Serum lithium levels in the babies ranged from 0.09 to 0.3 mEq/L (mean 0.16).
Transient elevations in infant thyroid-stimulating hormone (TSH), blood urea nitrogen (BUN), and
creatinine level were observed without evident long-term effects. They recommended that breast
feeding in the context of lithium therapy may be considered reasonable for a healthy infant when
the mother’s bipolar disorder is clinically stable, lithium monotherapy or a simple medication
regimen is being utilized, and the pediatrician supports breast feeding while the mother is treated
with lithium. They recommend monitoring of serum lithium, TSH, BUN, and creatinine level in the
infant immediately postpartum, 4–6 weeks after delivery, and then every 8–12 weeks while the
mother is breast feeding.Print: Chapter 35. Lithium
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SIDE EFFECTS AND TOXICOLOGY
Psychological issues ultimately proved far more important than side effects in my prolonged resistance to
lithium. I simply did not want to believe that I needed to take medication. I had become addicted to my
high moods. . .. I couldn’t give them up. (Jamison 1995, pp. 98–99)
Laboratory Monitoring
Before lithium therapy is started, medical history should be obtained, as well as baseline renal
laboratory tests (BUN, creatinine level), thyroid function tests, and an electrocardiogram for
patients older than 40 years (American Psychiatric Association 2002). The American Psychiatric
Association practice guideline suggests that renal function should be assessed every 2–3 months
and thyroid function tested once or twice during the first 6 months of treatment. After the first 6
months, renal laboratory tests and thyroid function tests should be monitored every 6–12 months
or whenever clinically indicated (American Psychiatric Association 2002).
Side Effects
Cognitive side effects and weight gain have been reported to be the most disturbing side effects to
patients receiving lithium maintenance treatment, whereas self-reported noncompliance was
mostly associated with effects on cognition and coordination (Gitlin et al. 1989). Weight gain may
be a greater risk for patients who are obese before commencement of lithium treatment, compared
with normal-weight individuals (Bowden et al. 2006). Keck et al. (1996) reported that 64% of the
patients hospitalized for bipolar disorder were noncompliant within the month prior to admission.
Lack of compliance was associated with mania severity and polypharmacy (Keck et al. 1996). Most
patients who receive treatment with lithium will experience signs or symptoms of toxicity at some
time (Groleau 1994). However, a minority (27.8%) of patients with excessive levels of lithium ( 1.5
mmol/L) manifested symptoms of toxicity when hospitalized (Webb et al. 2001). Women and the
elderly were most likely to have excessive levels.
Neurotoxicity
Neurotoxicity, delirium, and encephalopathy have been reported with lithium use. Specific
populations have been noted to be at higher risk. Also, certain circumstances such as concomitant
ECT or other psychotropics—especially neuroleptics—have been implicated in increasing the risk of
such adverse effects of lithium treatment. West and Meltzer (1979) reported five cases in which
patients experienced severe neurotoxic reactions, with lithium levels ranging from 0.75 to 1.7
mEq/L, and suggested that those with greater levels of psychotic symptomatology and anxiety may
be at higher risk for neurotoxic reactions.
Neurotoxic reactions are potentially irreversible. Permanent neurological deficits have been
reported after episodes of lithium intoxication (Apte and Langston 1983; Donaldson and Cuningham
1983). These have included deficits in recent memory, ataxia, and movement disorders. Early
hemodialysis may help prevent permanent sequelae. Donaldson and Cuningham (1983) also
reported persistent neurological sequelae of lithium toxicity involving multiple sites within the
nervous system. Himmelhoch et al. (1980) found a greater incidence of neurotoxicity secondary to
lithium treatment in the elderly. Squire et al. (1980) reported that lithium treatment may adversely
affect fine motor skills. In a double-blind, placebo-controlled crossover study (N = 16), patients
were given lithium or placebo for 2 weeks after a washout period and were then crossed over to
placebo or lithium, respectively. Neuropsychiatric test results showed a slowing of performance
rate. Stoll et al. (1996) reported a case series in which 7 patients who experienced
lithium-associated cognitive deficits improved when switched to treatment with divalproex sodium.
Productivity and Creativity
Reports on the effects of lithium on associative productivity and creativity are inconsistent. Shaw et
- (1986) assessed 28 outpatients receiving chronic lithium treatment. Euthymic patients who had
received chronic lithium treatment completed a protocol consisting of 2 weeks of lithium treatmentPrint: Chapter 35. Lithium
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and 2 weeks of placebo. Patients had been treated with lithium for an average of 9.4 years and had
average lithium levels of 0.80 ± 0.23 mEq/L. During the lithium phase of the study, patients had
significantly lower mean associations and lower idiosyncratic associations compared with the
placebo phase. Kocsis et al. (1993) also found lower associative productivity in patients during
lithium treatment when compared with placebo. However, an anecdotal report by Schou (1979) did
not indicate a negative effect of lithium on creativity and productivity. In a study of 24 bipolar
artists treated with lithium, 12 reported increased artistic productivity, 6 reported unaltered
productivity, and 6 reported lowered artistic productivity.
Tremor
A fine postural tremor affects between 4% and 65% of the patients who receive lithium (Gelenberg
and Jefferson 1995). The tremor may decrease with time; a severe tremor may indicate toxicity.
Elimination of caffeine may actually worsen tremor because renal lithium clearance can be reduced
with reduction of caffeine intake (Jefferson 1988). Lithium tremor, which resembles essential
tremor, may worsen with age.
Thyroid Function
In a chart review of 135 patients who received maintenance treatment with lithium, 38% were
found to have abnormal thyroid function tests (thyroid-stimulating hormone and/or free thyroxine
index), with an association between these laboratory abnormalities and length of time on lithium
(Fagiolini et al. 2006). In another retrospective study of 209 patients who received lithium, Kirov
(1998) found that 14.9% of the females and 3.4% of the males developed hypothyroidism. Female
patients and those older than 50 years were more likely to develop hypothyroidism. Some reports
suggested that clinical hypothyroidism with lithium use may not exceed the prevalence in the
general population (Bocchetta et al. 2001). Other reports suggested that subclinical hypothyroidism
is more frequent (Lombardi et al. 1993). A family history of thyroid disease may lead to earlier
onset of hypothyroidism that occurs with lithium use (Kusalic and Engelsmann 1999). Haggerty et
- (1990) found that the rate of antithyroid antibodies in patients with mood disorders is unrelated
to lithium exposure.
Renal Complications
Lithium treatment may lead to renal tubular damage, although clinically significant renal morbidity
is rare (Gitlin 1999). Risk factors for lithium-related renal complications include polypharmacy,
episodes of lithium intoxication, and concurrent medical illnesses (Gitlin 1999). Patients taking
lithium may experience polyuria as a result of impairment in renal concentrating ability. Although
uncommon, renal structural changes are possible (Gitlin 1999). Diabetes insipidus, caused by
unresponsiveness of the kidneys to antidiuretic hormone, occurs in approximately 10% of the
patients who receive long-term lithium therapy (Bendz and Aurell 1999). Treatment for diabetes
insipidus may include thiazides or amiloride.
Acute renal failure after lithium intoxication has been reported (Fenves et al. 1984). Acute lithium
intoxication may result in histopathological kidney changes, but little change is seen in patients
without acute episodes of lithium intoxication, and glomerular function and renal clearance are
preserved during long-term treatment with therapeutic dosages (Hetmar 1988). Renal function may
be evaluated by measuring serum creatinine every 2–3 months initially and then annually or
semiannually in stable patients (American Psychiatric Association 2002). In an assessment of 207
patients treated with lithium (between 1 and 30 years), no cases of renal insufficiency were
observed (Kallner and Petterson 1995). Studies in rats have indicated that dietary potassium
supplementation may reduce the risk of renal insults.
Cardiac Changes
Lithium intoxication has been reported to cause cardiac alterations, including sinus bradycardia and
sinus node dysfunction (Steckler 1994). Sinus node dysfunction is more prevalent in patients who
have been taking lithium for at least a year when compared with age-matched control subjects,Print: Chapter 35. Lithium
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although clinically significant dysfunction is uncommon (Rosenqvist et al. 1993). Also, cases of
atrioventricular block in patients treated with therapeutic lithium levels have been reported (Martin
and Piascik 1985). Electrocardiographic T wave changes, as well as ventricular irritability, may
occur (Mitchell and Mackenzie 1982). In healthy male volunteers, administration of lithium was
shown to cause a reduction in T wave amplitude without clinically significant effects on cardiac
function (Dumovic et al. 1980). In patients with clinical indications for lithium use, cardiovascular
disease does not preclude the possibility of lithium use. Dosage adjustment and frequent cardiac
monitoring are essential for the safe use of lithium in patients with cardiac disease (Tilkian et al.
1976). Because of the risk of sinus node dysfunction and other cardiac effects, careful monitoring of
the pulse and electrocardiographic monitoring are recommended in patients older than 50 years
(Roose et al. 1979).
Sexual Functioning
Aizenberg et al. (1996) assessed sexual function in euthymic male patients (N = 35) with bipolar or
schizoaffective disorder who received treatment with lithium monotherapy. Sexual side effects
most frequently reported were reduced sexual thoughts (22.9%), diminished waking erections
(17.1%), and loss of erections during coitus (20%). Lithium levels were unrelated to levels of
sexual satisfaction. Cases have been reported of decreased libido and erectile dysfunction
associated with lithium use (Blay et al. 1982). However, Ghadirian et al. (1992) found that sexual
side effects with lithium were related to concomitant benzodiazepine use. A conceivable mechanism
for sexual effects of lithium may be increased serotonergic neurotransmission (Price et al. 1989).
DRUG–DRUG INTERACTIONS
Lithium and Other Mood Stabilizers
Polypharmacy is common in the treatment of bipolar disorder, and lithium is commonly used in
combination with other mood stabilizers. Multiple mood stabilizers can be synergistic, but
polypharmacy may introduce an increased risk of adverse reactions (Freeman and Stoll 1998; Lenox
et al. 1996). The combination of lithium and valproate is a strategy in the treatment of mania
refractory to monotherapy with either lithium or valproate (Frances et al. 1996). Double-blind,
placebo-controlled data support that lithium plus valproate is more effective in relapse prevention
than lithium alone (Solomon et al. 1997). The combination appears to confer benefit in mania,
bipolar depression, and rapid cycling (Mitchell et al. 1994; Schaff et al. 1993; Sharma and Persad
1992; Sharma et al. 1993). Interactions may include additive side effects, such as sedation, tremor,
or weight gain, but the pharmacokinetics of lithium are not altered by the addition of valproate
(Granneman et al. 1996).
Lithium and carbamazepine also have been combined for bipolar disorder refractory to lithium
alone (Frances et al. 1996) and may confer a more rapid antimanic effect than lithium alone for
some patients (Di Costanzo and Schifano 1991; Kramlinger and Post 1989). This combination is
better tolerated than and at least as effective as the combination of lithium and a typical
antipsychotic (Shukla et al. 1985; Small et al. 1995). The combination also may work synergistically
in the prophylaxis of mood episodes (Kishimoto 1992). Neurotoxicity, especially in patients with
central nervous system deficits, may be an increased risk with the combination of lithium and
carbamazepine (Chaudhry and Waters 1983; Shukla et al. 1984). Neurotoxic and other adverse
reactions have been associated with the concomitant administration of lithium with calcium channel
blockers (Dubovsky et al. 1987; Finley et al. 1995; Helmuth et al. 1989; Wright and Jarrett 1991).
Although many investigators have reported the safe and efficacious results of combining lithium
and typical antipsychotics (Baastrup et al. 1976; Bigelow et al. 1981; Carman et al. 1981; Garfinkel
et al. 1980; Ghadirian et al. 1989; Goldney and Spence 1986; Juhl et al. 1977; Krishna et al. 1978;
Loew 1986; Miller and Menninger 1987; Perenyi et al. 1983), use of lithium with “typicals” may
increase the occurrence of side effects, including neurotoxicity and even tardive dyskinesia (Byrne
et al. 1994; W. J. Cohen and Cohen 1974; Dinan and Kohen 1989; Loudon and Waring 1976; Mani et
- 1996; Mann et al. 1983; Marhold et al. 1974; Menes et al. 1980; Miller et al. 1986; Perenyi et al. Print: Chapter 35. Lithium
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1984; Spring 1979; Spring and Frankel 1981). Goodwin and Jamison (1990) recommended that
when incorporating a typical antipsychotic into a regimen of lithium therapy, the antipsychotic
should be used in lower doses and the lithium levels should be maintained below 1.0 mEq/L.
The use of lithium with atypical antipsychotics also may result in adverse reactions. Clozapine and
lithium, when used concomitantly, have been reported to be efficacious for refractory bipolar
disorder (Fuchs 1994; Puri et al. 1995; Suppes et al. 1994), but adverse reactions, including
diabetic ketoacidosis, neuroleptic malignant syndrome, and neurological side effects, also have
been reported (Blake et al. 1992; G. Garcia et al. 1994; Lemus et al. 1989; Peterson and Byrd 1996;
Pope et al. 1986). Some investigators have reported safe and effective use of risperidone and
lithium (Ghaemi et al. 1997; Tohen et al. 1996), although adverse effects, including fever, increased
white blood cell counts and creatine phosphokinase levels, and delirium, also have been reported
(B. Chen and Cardasis 1996; Swanson et al. 1995).
Preliminary data suggest that the combination of lithium and olanzapine is efficacious and well
tolerated in acute mania (Madhusoodanan et al. 2000; Sanger et al. 2001). Gabapentin is also used
adjunctively in the treatment of bipolar disorder, and because gabapentin has no known drug
interactions, it is likely safe with lithium use (Frye et al. 1998; Vollmer et al. 1986).
Benzodiazepines are not especially problematic when used with lithium. Sachs et al. (1990a,
1990b) reported that benzodiazepines can be used successfully instead of antipsychotic
medications in some patients with bipolar disorder. Others have shown that clonazepam and
lorazepam are efficacious and well tolerated with lithium in the treatment of acute mania (Adler
1986; Modell et al. 1985).
Lithium and Antidepressants
Lithium is often used concomitantly with antidepressants in the treatment of bipolar depression and
refractory unipolar depression. Serotonin syndrome—a constellation of mental status and
behavioral changes (either agitation or sedation), motor symptoms (restlessness, weakness,
hyperreflexia, or ataxia), and autonomic dysfunction (nausea and/or vomiting, dizziness, sweating,
fever) (Lejoyeux et al. 1994)—has been reported with the use of lithium and serotonergic
antidepressants, including fluoxetine (Karle and Bjorndal 1995; Muly et al. 1993), paroxetine
(Sobanski et al. 1997), venlafaxine (Mekler and Woggon 1997), and fluvoxamine (Ohman and
Spigset 1993). Retrospective evaluation of clinical records by Fagiolini et al. (2001) suggested the
development of serotonin syndrome in 4 of 17 (24%) patients receiving the combination of lithium
and paroxetine.
Lithium and Electroconvulsive Therapy
Patients who undergo concurrent ECT and lithium treatment may experience neurotoxic reactions,
which include delirium and memory deficits (Ayd 1981; DePaulo et al. 1982; El-Mallakh 1988;
Jefferson et al. 1987; Mielke et al. 1984). Additionally, Small et al. (1980) retrospectively compared
adverse reactions of patients who received concurrent lithium and ECT with those of patients who
received ECT alone. The group that received both ECT and lithium experienced more memory loss
than did the group undergoing ECT without lithium treatment. However, Himmelhoch and Neil
(1980) found similar outcomes in 21 patients receiving ECT and lithium and in age- and
sex-matched control subjects receiving ECT alone. They did not find differences in adverse
reactions, including post-ECT confusion. To minimize adverse reactions, Ayd (1981) recommended
that lithium be discontinued at least 2 days prior to ECT and restarted 2–3 days after the last
treatment.
Lithium and Nonpsychotropic Medications
When lithium is used with concurrent nonsteroidal anti-inflammatory drugs, signs and symptoms of
toxicity and lithium levels must be monitored more carefully because nonsteroidal
anti-inflammatory drugs increase the risk of toxicity (Johnson et al. 1993). Because lithium
excretion relies on renal clearance, diuretic medications may affect lithium levels, depending on
their site of action. Thiazide diuretics trigger a compensatory increase in reabsorption in thePrint: Chapter 35. Lithium
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proximal tubule and lead to elevations in lithium levels, whereas loop diuretics do not promote
lithium reabsorption and do not greatly affect lithium levels (Finley et al. 1995). Osmotic diuretics
enhance lithium excretion and may serve to counteract lithium toxicity, and either no change or a
slight increase in lithium levels has been reported with potassium-sparing diuretics.
Angiotensin-converting enzyme inhibitors may raise lithium levels (DasGupta et al. 1992; Finley et
- 1996). Serum lithium levels may increase in the context of sodium restriction (Bennett 1997).
CONCLUSION
Lithium is an important option in the evidence-based rational treatment of bipolar disorder. Bipolar
disorder is a mental illness that affects between 1% and 5% of the population (Akiskal et al. 2000).
Bipolar disorder causes significant morbidity and mortality, and the diagnosis of bipolar disorder
carries a high risk for suicide. Of patients with bipolar disorder, 25%–50% attempt suicide and an
estimated 19% complete suicide (Goodwin and Jamison 1990).
Lithium has been shown to be effective for acute mania and bipolar depression and as a
prophylactic treatment for bipolar disorder. Some data suggest that conditions such as comorbid
neurological illness and mixed episodes favor other mood stabilizers rather than lithium. Evidence
also suggests that lithium can play a role in the treatment of refractory unipolar depression,
aggression, and personality disorders. Lithium may be less risky than anticonvulsants in pregnancy.
We seek new treatments in our field and hope that they will be more efficacious and better
tolerated than our “old” medications. At present, lithium remains an important treatment option.
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Copyright © 2009 American Psychiatric Publishing, Inc. All Rights Reserved.
Course Content
Introduction to Lithium: Properties and Applications
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Understanding Lithium: An Overview
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Chemical and Physical Properties of Lithium
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Lithium in Everyday Applications
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Environmental and Economic Impact of Lithium
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Quiz: Introduction to Lithium
Lithium Extraction and Refinement Techniques
Understanding Lithium-Ion Batteries: Design and Functionality
Innovations in Lithium Technology: Current Research and Future Trends
Conclusion: The Future of Lithium in Global Energy Solutions
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