Lithium and the Anticonvulsants in Bipolar Disorder
Joseph R. Calabrese and Charles Bowden
Although many believe lithium (LI) remains the treatment of choice for bipolar disorder, only 60-80% of classic bipolar
patients have a satisfactory clinical response. Fewer than half of all bipolar patients have classical, elated syndromes.
When the response rate of LI is considered across the wider spectrum of bipolar disorders permitted by the most recent edition
of the Diagnostic and Statistical Manual of Mental Disorders (Diagnostic and Statistical Manual of Mental Disorders 1995),
it is less than 50% of patients who respond to it (Gitlin et al 1995, Swann et al 1997, Vestergaard et al 1998). Among mixed
manics who account for 16 to 67% of all bipolar patients, only 30-40% respond to LI (Calabrese et al 1993 a). Rapid cycling
patients who constitute 13-20% of all bipolar disorders also have low (20-30%) response rates to LI (Bauer et al 1994, Dunner
and Fieve 1974, Kukopulos et al 1980). Although there are numerous other predictors of LI non-response, these two variants
appear to account for the largest proportion of those who exhibit poor response to LI. Serendipitously, these two predictors
of LI non-response may be putative predictors of positive response to both carbamazepine (CBZ) (Post et al 1989) and valproate
(VPA) (Calabrese et al 1993 b, Freeman et al 1992, Swann et al 1997).
Although controlled trials have demonstrated the efficacy of CBZ in the acute treatment of mania, initial responsiveness
is often lost over time (Post et al 1990, Frankenburg et al 1988). Recent data also suggest that only one-third of acutely
manic patients have moderate to marked improvement during the first two months of treatment with either LI or CBZ as monotherapy
(Small et al 1991). In addition, more severe mania was noted to predict nonresponse to CBZ. Such findings suggest that large
numbers of bipolar patients are non-responsive to LI and that substantial numbers of both classic and rapid cycling bipolar
patients eventually become resistant to CBZ. Recent multicenter controlled data demonstrating that divalproex sodium has efficacy
equal to lithium in the acute management of mania has led to this drug's approval by the US Food and Drug Administration in
1995 for use in the management of manic episodes associated with bipolar disorder (Bowden et al 1994, Pope et al 1991). The
data regarding the efficacy of divalproex sodium in the prevention of relapse and recurrence in bipolar disorder is unclear
(Bowden et al 1997).
At present, lithium, divalproex sodium, and the antipsychotic medications have all been approved for use in the management
of the manic phase of bipolar disorder. However, there have been no medications approved for use in the management of the
depressed phase of the illness and less is known about the antidepressant effects of lithium, and to an even greater extent,
divalproex sodium; there have been no published studies on the acute efficacy of lithium in bipolar I depression in the last
20 years. Although controversial, lithium (Fieve et al 1968) and divalproex sodium (Calabrese et al 1990) appear to be less
effective in the treatment of the depressed phase of the illness, as well as depressive symptoms associated with mania (Swann
et al 1997). The adjunctive use of antidepressant medication is common, but this practice can put patients with bipolar disorder
at increased risk for the development of hypomania, mania, or cycle acceleration (Post et al 1997). This has led to the development
of another anticonvulsant, lamotrigine, for use in the treatment of bipolar I depression (Calabrese et al in press a, Calabrese
et al in press b).
This chapter will critically review recent information regarding the efficacy of lithium and its use in the treatment
of bipolar disorder and the rapidly developing data regarding the evolving role of CBZ, divalproex sodium, and more recently,
lamotrigine. In addition, there will be some discussion of the various methodologies employed in studies of bipolar disorder.
Extrapolation of results generated from these controlled, blinded clinical trials to clinical practice is difficult. It is
plausible that results from the better designed trials emphasized here may actually underestimate patient outcome. Factors
such as the enrollment of refractory patients in trials with monotherapy arms that allow for only the limited use of adjunctive
medications depart substantially from the practice of psychiatry in the community.
Acute Mania: Recent studies have indicated that approximately half of acutely manic patients respond well to LI (Kukopulos
et al 1980, Small et al 1988, Small et al 1991). The benefits of response appear to be more compromised by adverse effects
than previously thought (Grof et al 1987, Vestergaard and Aagaard 1991). Such reports have led to reassessment of the data
on which approval of LI was based and new studies to clarify these issues, utilizing improved research methodologies and patient
samples that reflect the full diagnostic spectrum of bipolar disorder in the current nomenclature. The evidence for the efficacy
of LI in acute mania largely came from three double-blind, placebo controlled crossover studies of a total of 78 patients
(Goodwin and Jamison 1990). Outcome criteria were variable across the studies and diagnostic criteria were not consistently
specified. In one, patients with any degree of improvement on a nurse rated 7 point global scale were reported as responders.
In two of the studies initial assignment to study medication was not randomized. No placebo controlled study of LI in acute
mania was published from 1971 through 1993.
The one parallel group, randomized, double-blind study of LI in acutely manic patients reported that 49% had moderate
or better improvement in manic symptoms during the three week trial, a rate of response significantly greater than the 28
% seen in placebo treated patients (Bowden et al 1994). The efficacy of LI did not differ from that of VPA. Thirty-one percent
of LI-treated patients had some degree of worsening of manic symptoms at the end of the trial. The percentage of patients
discontinuing due to medication intolerance was non-significantly higher among LI-treated than VPA-treated patients (11% vs.
6%). No neuroleptics were used during the study and the only other psychotropic medication allowed was lorazepam during the
first week of study medication. These results generally conform to recent impressionistic data, and indicate that although
LI is clearly effective, substantial numbers of patients remain unresponsive during monotherapy of an acute episode.
Clinical improvement with LI is relatively slow, with an initial response generally occurring 7 to 14 days after initiation
of LI. Initial improvement may not occur sooner than the fourth week for some patients. Because of aggressive, disruptive
behavior of the acutely manic patient, adjunctive medications are often required during this lag period. Lithium plasma concentrations
required for acutely manic patients are often higher than needed for maintenance therapy. Although a loading dose strategy
is ineffective, dosage should be increased as rapidly as tolerated until response occurs or a plasma level of around 1.2 mEq/l
is reached. The side effects of LI are generally less apparent during acute treatment than maintenance therapy.
Acute Bipolar Depression: Six of seven placebo controlled studies have reported significant antidepressant effects of
LI (Goodwin and Jamison 1990). However, methodological problems limit generalizability. Most included unipolar as well as
bipolar depressed patients. Most studies comparing tricyclic antidepressants with lithium lacked placebo (PBO) controls. The
single study which compared LI, imipramine and PBO in bipolar depressed patients found imipramine more effective than LI (Fieve
et al 1968). The protective effect of LI against subsequent episodes appears to be lower for depressive episodes than for
manic episodes (Davis 1976, Dunner and Fieve 1976). Additionally, most depressive episodes in bipolar patients will occur
in patients already taking LI, or alternative mood stabilizing agents. Therefore, early use of other antidepressant agents
is important if the patient does not respond to an increase in LI dosage.
Prophylaxis: Maintenance phase studies of LI are more extensive, better designed, and more conclusive than acute treatment
studies regarding LI's efficacy in preventing relapses (Baastrup et al 1970, Davis 1976). However, no PBO-controlled maintenance
treatment study of LI's efficacy in bipolar disorder has been published in over 20 years. Several recent naturalistic studies
suggest that at present a substantial number of bipolar patients have inadequate responses to LI. Harrow and colleagues reported
that 40 percent of LI-treated patients had a manic relapse during a mean 1.7 year period of treatment, a result similar to
that of patients on no medication (Harrow et al 1990). Coryell reported that whereas lithium treatment yielded fewer relapses
than no medication for the first 32 month of prophylaxis, subsequent relapse rates did not differ with or without lithium
(Coryell et al 1997). Gitlin and colleagues reported that 17% of bipolar patients had good outcomes over 2 to 5 years. Average
mood symptomatology was much more strongly associated with occupational, social and family disruption than were relapses (Gitlin
et al 1995). Tohen and colleagues also reported that 46 percent of patients remained stable for four years after their first
episode, with outcome being unrelated to treatment (Tohen et al 1990). Other recent prospective, open, naturalistic trials
also report good outcomes in approximately on-third of patients (Maj et al 1998, Vestergaard et al 1998).
Issues of dosage and approach to discontinuation of LI have been clarified by recent studies. Discontinuation of LI therapy
in bipolar patients is followed by a high rate of relapse, with most episodes being manic rather than depressed (Suppes et
al 1991). This study by Suppes et al, as well as other withdrawal study data, strongly suggest that LI's prophylactic effect
is principally in reducing the frequency of manic rather than depressive episodes (Nilsson and Axelsson 1990). Furthermore,
abrupt discontinuation is followed early on by a much higher rate of relapse than is discontinuation over two or more weeks
(Faedda et al 1992). Relapse rates following discontinuation were 50 percent higher among bipolar I than bipolar II patients
(Baldessarini et al 1996). Among patients with two or fewer prior episodes, maintenance LI levels of 0.8 to 1.0 mEq/l were
associated with lower rates of relapse than were levels of 0.4 to 0.6 mEq/l. Relapse rates into depression did not differ
between the two groups. The severity of adverse effects was greater in the higher plasma level group (Gelenberg et al 1989).
Predictors of Response to Lithium: As evidence has developed that a substantial percentage fail to do well with acute
or maintenance treatment with LI, and as alternative treatments for bipolar disorder have developed, it has become important
to know which illness characteristics are associated with a favorable, or unfavorable response to LI, as well as alternative
treatments. Acutely, patients with elated, less severe episodes without psychotic features, also referred to as classical
mania, appear to have the best response to LI during an acute manic episode (Goodwin and Jamison 1990). Patients who move
from a depressive episode into a period of euthymia, and then mania do better than those who move directly from a depressive
episode into a manic episode (Grof et al 1987). It is not well established that these differences hold equally during maintenance
treatment. Patient with more lifetime illness episodes consistently have less good longterm outcome with lithium (Gitlin et
Several syndromal variants of bipolar disorder are associated with relatively low response rates to LI. The best studied
is mixed mania, with more than half a dozen studies consistently indicating lower acute and chronic response rates to LI treatment
(Goodwin and Jamison 1990). Rapid cycling patients also respond less well to LI (Dunner and Fieve 1976, Kukopulos et al 1980).
This illness course of bipolar disorder will be defined in the DSM-IV as 4 or more depressions, hypomanias, or manias in the
prior 12 month period, with episodes being demarcated by a switch to an episode of opposite polarity or by a period of remission.
This phenomenon appears to be late in onset, occurs most commonly in bipolar type II females, and is not usually associated
with antidepressant use (Bauer et al 1994, Dunner and Fieve 1976, Kukopulos et al 1980). Rapid cycling, and possibly mixed
states, appear to be non-familial modifiers of state and course that transiently come and go during the natural history of
bipolar disorder and its treatment (Coryell et al 1992). When these variants are present during treatment with LI therapy,
prognosis worsens and the morbidity and mortality associated with the illness increases (Calabrese et al 1993 b, Fawcett et
al 1987). As evidence has emerged that antidepressant medications increase the likelihood of rapid cycling, it is prudent
to be cautious in interpreting the data about rapid cycling, as a component of the poor response may have been secondary to
recent antidepressant therapy. Patients with bipolar disorder which appears to be secondary to other medical disorders respond
poorly to lithium. Patients with comorbid substance respond relatively poorly to lithium therapy, although this may be simply
because of the conservative management of their substance abuse.
During maintenance therapy with LI, the development of hypomania is strongly predictive of a subsequent full manic episode,
with 65 percent having a subsequent major manic relapse. By contrast, minor depressive episodes were not usefully predictive
of either subsequent manic or depressive episodes, as 61 percent of the minor depressive episodes were not followed by any
major relapse (Keller et al 1992).
Pharmacokinetics and Adverse Effects of Lithium. The clearance of LI is delayed by most non-steroidal anti-inflammatory
drugs. Several of the non-steroidal anti-inflammatory agents have been marketed in recent years, with most not assessed regarding
effects on LI clearance. A conservative approach is to monitor LI plasma levels closely for several months following introduction
of non-steroidal anti-inflammatory drugs.
Lithium consistently impairs urinary concentrating ability. The ensuing frequent day and night time urination are often
functionally impairing to the patient. Use of sustained release lithium is associated with less renal concentrating impairment
(Miller et al 1985). If such symptoms remain prominent, one should consider discontinuing LI and utilizing VPA or CBZ, or
possibly, adding a diuretic that reduces the concentration impairment. Both loop diuretics and thiazides are effective. Although
thiazides usually increase the plasma concentration of lithium, this can be managed by dosage adjustment. It is plausible,
though not studied, that the reduction in distal tubule exposure to LI associated with thiazide use could reduce long-term
risk of renal impairment.
Although several recent reviews have drawn sanguine conclusions regarding the effect of long-term LI treatment on renal
function, several other studies have reported a small number of cases of renal insufficiency, probably at incident rates no
higher than 1 percent (Schou 1988, Stancer and Forbath 1989). Duration of lithium use, dosage and plasma level, and prior
experiencing of polydipsia are possible, but not clearly established, risk factors in cases of renal insufficiency. Regular
monitoring of creatinine levels in plasma is warranted indefinitely, and consultation indicated if creatinine levels rise
to and remain above 1.6 mg/100 ml.
Long-term LI use is also associated with a significant increase in subclinical hypothyroidism, a risk which may be greater
in women. The duration of LI use was positively correlated to antithyroid antibody titer (Calabrese et al 1985). It thus seems
advisable to check thyroid function regularly in LI-treated patients, perhaps semiannually for the first two years of treatment.
Some authorities recommend addition of T4 to the regimen of any LI treated bipolar patient if indices of thyroid function
are in the low normal range, such as a thyroid stimulating hormone level greater than 5 microinternational units. This may
be particularly important if the patient exhibits signs of poor control of illness, such as subsyndromal depression.
The risks of use of LI in pregnancy remain an unresolved issue. Earlier studies suggested that LI increased the risk of
the cardiovascular anomaly Ebstein's atresia. The low base rate of Ebstein's atresia of approximately 1 in 20,000 live births
makes conclusive study of this risk difficult. A recent study suggested no increased risk, but was of such a small number
of subjects that its ability to recognize two to three fold increases in risk was negligible (Zalstein et al 1990). Another
recent study of 148 women using lithium during the first trimester of pregnancy indicated rates of major congenital malformations
did not differ between the lithium (2.8%) and control (2.4%) group and concluded that lithium is not an important human teratogen
(Jacobson et al 1992). Since neuroleptics may control some aspects of manic symptoms, it may be advisable to try discontinuing
LI as soon as pregnancy is recognized and, for any manic symptoms emergent during the first trimester, try neuroleptics first
with electroconvulsive therapy as an additional consideration.
Although the most frequently reported subjective side effects of lithium have been well recognized (excessive thirst,
polyuria, memory problems, tremor, and weight), the implications of lithium's adverse effects, especially their role in contributing
to non-compliance, have been reconsidered (Goodwin and Jamison 1990). It seems likely that the absence of alternatives to
LI inclined psychiatrists to try to manage adverse effects which seriously interfered with function with some form of continued
LI use. As evidence for the efficacy of alternative mood stabilizers has emerged, earlier consideration of alternative regimens
has become prudent. Recent studies underscore the frequency and degree to which LI impairs cognitive functions, and the contribution
of such adverse effects to poor compliance (Goodwin and Jamison 1990).
VIII. Combination Mood Stabilizer Therapy
Although there exists numerous anecdotal references highlighting the necessity of combination mood stabilizer therapy
in the clinical management of bipolar disorder, there are few studies that have compared the efficacy of combination therapy
to monotherapy. One such study compared the prophylactic efficacy of LI, CBZ, and the combination (Denicoff et al 1997a).
These investigators randomly assigned 52 patients with bipolar disorder in a double blind design for an intended one year
of treatment with LI or CBZ, a crossover to the opposite drug in the second year, and then a third year on the combination.
Their results suggested that LI was more effective than CBZ in the prophylaxis of mania but not depression, and the combination
of LI and CBZ was better than either monotherapy.
A subgroup of patients from this study who were non-responsive or intolerant to the combination of and CBZ were given
the option of entering an additional year of treatment (Denicoff et al 1997b). Of the 18 evaluable patients, six (33%) had
moderate to marked responses to VPA plus LI; four of these six had not responded to any previous treatment conditions. When
CBZ was added to the combination of LI and VPA for seven patients, three responded to the triple therapy. The authors concluded
that some patients with bipolar disorder refractory to LI and CBZ receive prophylactic benefit from VPA when used with LI.
Despite the absence of controlled studies employing random assignment to parallel groups, recently published expert consensus
surveys indicate that combination mood stabilizer therapy is commonly employed in the pharmacotherapy of treatment refractory
patients with bipolar disorder (Kusumakar et al 1997, Frances et al 1996).
J Neurochem. 1976 Nov;27(5):1237-9.
Related Articles, Links
Effect of lithium on dopamine uptake by brain synaptosomes.
Stefanini E, Argiolas A, Gessa GL, Fadda F.
Institute of Pharmacology, University of Cagliari, Italy.
Lithium chloride exerts two opposite effects on dopamine uptake by synaptosomes isolated from rat caudate nucleus. Added
in vitro, it inhibits dopamine uptake; whereas administered chronically in vivo, it enhances dopamine uptake in vitro. Thus,
in vitro, 1, 2.5, 5 and 10 meqiv.l-1 of lithium chloride decrease [3H]dopamine uptake by 13, 17, 25 and 31%, respectively.
Synaptosomes isolated from rats treated with lithium chloride for 20 days, show a 23% increase in [3H]dopamine uptake with
respect to synaptosomes isolated from control rats. It is suggested that chronic lithium treatment stimulates a compensatory
mechanism which overcomes its direct inhibitory effect on [3H]dopamine uptake.
1: Therapie. 2004 Jan-Feb;59(1):105-12.
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[Drug-induced parkinson syndromes]
[Article in French]
Nguyen N, Pradel V, Micallef J, Montastruc JL, Blin O.
CPCET et Pharmacologie Clinique, Institut de Neurosciences Physiologiques et Cognitives, Faculte de Medecine, FRE 2109
CNRS-Universite de la Mediterranee, Assistance Publique Hopitaux de Marseille, Hopital de la Timone, Marseille, France.
Parkinsonism is defined by the association of akinesia with one of the following symptoms: extrapyramidal rigidity, tremor
at rest, or postural instability. A drug-induced aetiology must always be suspected when parkinsonian symptoms appear, or
increase in a patient receiving drug treatment. Indeed drug-induced is the more frequent aetiology of secondary parkinsonism.
The main treatments involved are antipsychotic and other neuroleptic drugs (accounting for up to two-thirds of drug-induced
parkinsonism), and calcium-channel entry blockers. The risk associated with antipsychotics is often dose dependent and related
to dopamine D2 striatal receptor occupancy induced by the antipsychotic drug. This risk is inferior for the second generation
antipsychotics. The other treatments more rarely involved are antidepressants (tricyclic and selective serotonin reuptake
inhibitors), lithium, valproic acid, and others. The main criterium for imputability is chronological, regression of symptoms
being observed in 40-74% of cases, after a mean delay of 3 months from cessation of treatment. However, 15% of cases persist
after drug withdrawal, leading to a diagnosis of underlying idiopathic Parkinson's disease.
J Clin Neurosci. 2002 May;9(3):310-1.
Related Articles, Links
A case of Parkinsonism due to lithium intoxication: treatment with Pramipexole.
Dallocchio C, Mazzarello P.
Divisione di Neurologia, Ospedale Civile di Voghera, ASL Pavia, Italy. email@example.com
We report the case of a 72-year-old woman with bipolar disorder treated with lithium for over a year, who suddenly developed
disabling Parkinsonism, apparently after a gastroenteric infection. On hospital admission lithium plasma levels were 3.7 mmol/l.
After lithium discontinuation, plasma levels decreased to 0.7 mmol/l, but without resolution of neurological symptoms. Biperidene
and levodopa-benserazide did not ameliorate her extrapyramidal symptoms. Pramipexole 0.25 mg TID improved dramatically the
Parkinsonism and all neurological symptoms resolved in a few days. Copyright 2002 Published by Elsevier Science Ltd.
JAMA. 2003 Sep 17;290(11):1467-73.
Related Articles, Links
• JAMA. 2003 Sep 17;290(11):1517-9.
• JAMA. 2004 Feb 25;291(8):939; author reply 940.
• JAMA. 2004 Feb 25;291(8):939; author reply 940.
Suicide risk in bipolar disorder during treatment with lithium and divalproex.
Goodwin FK, Fireman B, Simon GE, Hunkeler EM, Lee J, Revicki D.
Department of Psychiatry, George Washington University Medical Center, Washington, DC 20037, USA. firstname.lastname@example.org
CONTEXT: Several studies have suggested that lithium treatment reduces risk of suicide in bipolar disorder, but no research
has examined suicide risk during treatment with divalproex, the most commonly prescribed mood-stabilizing drug in the United
States. OBJECTIVE: To compare risk of suicide attempt and suicide death during treatment with lithium with that during treatment
with divalproex. DESIGN AND SETTING: Retrospective cohort study conducted at 2 large integrated health plans in California
and Washington. PATIENTS: Population-based sample of 20 638 health plan members aged 14 years or older who had at least 1
outpatient diagnosis of bipolar disorder and at least 1 filled prescription for lithium, divalproex, or carbamazepine between
January 1, 1994, and December 31, 2001. Follow-up for each individual began with first qualifying prescription and ended with
death, disenrollment from the health plan, or end of the study period. MAIN OUTCOME MEASURES: Suicide attempt, recorded as
a hospital discharge diagnosis or an emergency department diagnosis; suicide death, recorded on death certificate. RESULTS:
In both health plans, unadjusted rates were greater during treatment with divalproex than during treatment with lithium for
emergency department suicide attempt (31.3 vs 10.8 per 1000 person-years; P<.001), suicide attempt resulting in hospitalization
(10.5 vs 4.2 per 1000 person-years; P<.001), and suicide death (1.7 vs 0.7 per 1000 person-years; P =.04). After adjustment
for age, sex, health plan, year of diagnosis, comorbid medical and psychiatric conditions, and concomitant use of other psychotropic
drugs, risk of suicide death was 2.7 times higher (95% confidence interval [CI], 1.1-6.3; P =.03) during treatment with divalproex
than during treatment with lithium. Corresponding hazard ratios for nonfatal attempts were 1.7 (95% CI, 1.2-2.3; P =.002)
for attempts resulting in hospitalization and 1.8 (95% CI, 1.4-2.2; P<.001) for attempts diagnosed in the emergency department.
CONCLUSION: Among patients treated for bipolar disorder, risk of suicide attempt and suicide death is lower during treatment
with lithium than during treatment with divalproex.
Lithium antagonizes dopamine-dependent behaviors
mediated by an AKT glycogen synthase kinase 3
Jean-Martin Beaulieu*, Tatyana D. Sotnikova*, Wei-Dong Yao*, Lisa Kockeritz
, James R. Woodgett
Raul R. Gainetdinov*, and Marc G. Caron*
*Howard Hughes Medical Institute, Department of Cell Biology and Center for Models of Human Disease, Institute of Genome
Sciences and Policy,
Duke University Medical Center, Durham, NC 27710; and
Ontario Cancer Institute, 610 University Avenue, Toronto, ON, Canada M5G 2M9
Edited by Erminio Costa, University of Illinois, Chicago, IL, and approved February 19, 2004 (received for review November
Dopamine (DA) is a neurotransmitter involved in the control of
locomotion, emotion, cognition, and reward. Administration of lith-
ium salts is known to inhibit DA-associated behaviors in experimental
animal models through unknown mechanisms. Here, we used a
pharmacogenetic approach to show that DA can exert its behavioral
effects by acting on a lithium-sensitive signaling cascade involving
Akt PKB and glycogen synthase kinase 3 (GSK-3). In the mouse
striatum, increased DA neurotransmission arising either from admin-
istration of amphetamine or from the lack of the DA transporter
results in inactivation of Akt and concomitant activation of GSK-3
and GSK-3 . These biochemical changes are not affected by activation
of the cAMP pathway but are effectively reversed either by inhibition
of DA synthesis, D2 receptor blockade, or administration of lithium
salts. Furthermore, pharmacological or genetic inhibition of GSK-3
significantly reduces DA-dependent locomotor behaviors. These data
support the involvement of GSK-3 as an important mediator of DA
and lithium action in vivo and suggest that modulation of the
Akt GSK-3 pathway might be relevant to DA-related disorders, such
as attention deficit hyperactivity disorder and schizo
March 12, 2004 Dr. R.K. Bhatnagar Antidepressants and Affective Disorders
Antidepressants & Affective Disorders 167 71:130 Dr. Bhatnagar 4. Antimanic agents or mood stabilizers
a. Lithium salts Mechanism of action. Lithium carbonate or citrate is the drug of choice for the treatment and prophylaxis
of bipolar illness. It takes several weeks of treatment for optimal therapeutic efficacy. Intermediate in size between
H+ and Na+, lithium ions substitutes for Na+. It produces a decrease in the release of norepinephrine and dopamine, but
not serotonin. Lithium salts enhance the uptake of choline and acetylcholine synthesis. Lithium salts uncouple neurotransmitter
receptors from their signaling pathways by involving adenylate cyclase and phospholipase-C and causing a decrease in second
messengers related to membrane phosphoinositides. This would explain why dopamine receptor supersensitivity usually seen
after denervation of dopaminergic neurons in the brain is blocked by lithium salts. Lithium salts do not alter amine receptor