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Introduction ⬇

VA Class:CN750

AHFS Class:

Generic Name(s):

Lithium salts are antimanic agents.

Uses ⬆ ⬇

[Section Outline]

Lithium salts are used in the treatment of a variety of psychiatric disorders but are most commonly used in the treatment of affective (mood) disorders. 401,403,404,405,406,407,409,410,411,412,413,414,415,416,417,419,421,422 Currently, lithium salts are principally used in the treatment of bipolar disorder, 410,422 particularly in the treatment of acute manic or mixed episodes in patients with bipolar 1 or bipolar 2 disorder. 401,403,404,405,406,407,409,410,411,412,421,422 In addition, maintenance therapy with lithium salts has been shown to prevent or diminish the intensity of subsequent manic episodes in patients with bipolar disorder with a history of mania. 403,404,405,407,410,412,421,422,424

Lithium salts also are used in the prophylaxis and treatment of major depressive disorder† (unipolar depression).410

Bipolar Disorder !!navigator!!

Diagnostic Considerations

Affective disorders currently are categorized as either bipolar (manic-depressive) or unipolar (depressive).402,410,422 A diagnosis of bipolar disorder is made if the patient has ever had a manic or hypomanic episode; otherwise, the criteria for bipolar depression and unipolar (major) depression are identical.402,410,422 According to DSM-IV-TR criteria, manic episodes are distinct periods lasting 1 week or longer (or less than 1 week if hospitalization is required) of abnormally and persistently elevated, expansive, or irritable mood accompanied by at least 3 (or 4 if the mood is only irritability) of the following 7 symptoms: inflated self-esteem or grandiosity, reduced need for sleep, pressure of speech, flight of ideas, distractibility, increased goal-directed activity (either socially, at work or school, or sexually) or psychomotor agitation, and engaging in high risk behavior (e.g., unrestrained buying sprees, sexual indiscretions, foolish business investments).401,402 In addition, to meet the criteria for manic episodes, the mood disturbances must be sufficiently severe that they cause marked impairment in occupational functioning, usual social activities, or relationships with others; they may necessitate hospitalization to prevent harm to self or others; and may be accompanied by psychotic features.401,402

According to DSM-IV-TR criteria, bipolar disorder can be classified as bipolar 1 disorder, bipolar 2 disorder, cyclothymia, or bipolar disorder not otherwise specified.401,402 Bipolar 1 disorder is characterized by the occurrence of one or more manic episodes or mixed episodes.401,402 In addition, patients with bipolar I disorder often have had previous depressive episodes and most patients will have subsequent episodes that can be either manic or depressive.401,402 Hypomanic and mixed episodes also may occur in bipolar I disorder as well as substantial subthreshold mood lability between episodes.401,402 Bipolar 1 disorder is further characterized according to whether the patient is experiencing a first manic episode (which is classified as single manic episode) or whether the most recent episode is manic, hypomanic, depressive, mixed (concurrent or rapidly alternating manic and depressive features), or unspecified.402,410

Patients meeting DSM-IV-TR criteria for bipolar 2 disorder have a history of one or more major depressive episodes accompanied by at least one hypomanic episode.401,402 However, patients with bipolar 2 disorder should not have had a previous manic or mixed episode.402

Some patients with bipolar disorder may exhibit evidence of mood lability, hypomania, and depressive symptoms but fail to meet the diagnostic criteria for any specific bipolar disorder.401,402 This condition is called bipolar disorder not otherwise specified according to DSM-IV-TR criteria.401,402

Cyclothymic disorder (cyclothymia) may be diagnosed in patients who have never experienced a manic, mixed, or major depressive episode but who have experienced numerous periods of depressive as well as hypomanic symptoms for at least 2 years in adults or 1 year in children, with no symptom-free period lasting longer than 2 months.401,402

Bipolar 1 or 2 disorder may be diagnosed as rapid-cycling if the patient has 4 or more mood disturbances within a single year that meet DSM-IV-TR criteria for a major depressive, mixed, manic, or hypomanic episode.401,402,422 These episodes are demarcated either by a partial or full remission for at least 2 months or a switch to an episode of the opposite nature (e.g., from a major depressive to a manic episode).401,402 Rapid-cycling bipolar disorder is sometimes associated with certain medical conditions (e.g., hypothyroidism) or drug or substance abuse.401 Certain drugs, such as antidepressants, also may contribute to rapid cycling, particularly in patients who are not receiving a mood-stabilizing agent (e.g., lithium, carbamazepine, valproic acid).401,402,422

Considerations in Choosing Therapy for Manic and Mixed Episodes

Although there presently is no cure for bipolar disorder, treatment may decrease the associated morbidity and mortality.402,403,422 The principal aim of acute treatment for patients with bipolar disorder experiencing a manic or mixed episode is to control the symptoms to allow a return to normal levels of psychosocial functioning.401,403,422 The rapid control of certain symptoms (e.g., agitation, aggression, impulsivity) may be particularly important for the safety of the patient and others.401,420,422

A variety of drugs currently are available for the treatment of acute manic and mixed episodes, including mood-stabilizing agents, olanzapine and other antipsychotics, and benzodiazepines.401,403,404,405,409,410,411,412,420,421,422,423,426 In bipolar disorder, drugs generally are considered mood stabilizers if they provide relief from acute episodes of mania or depression or prevent such episodes from recurring and they do not worsen depression or mania or lead to increased cycling.419,422 Lithium salts, valproic acid or divalproex, carbamazepine, and some other anticonvulsants (e.g., oxcarbazepine, lamotrigine, gabapentin) have been used clinically as mood stabilizers in bipolar disorder.401,403,404,405,409,410,411,412,420,421,422,425 However, the American Psychiatric Association (APA) states that there is no consensus on the definitions of “mood stabilizers” and does not use this term in its most recent guidelines for the treatment of bipolar disorder.401

For the initial management of less severe manic or mixed episodes in patients with bipolar disorder, monotherapy with lithium, valproate (e.g., sodium valproate, valproic acid, divalproex), or an antipsychotic agent such as olanzapine may be adequate.401,403,412,420,421,422 For more severe manic or mixed episodes, many experts recommend combination therapy involving lithium plus an antipsychotic or valproate plus an antipsychotic for first-line therapy.401,403,411,412,421,422 Some clinicians state that divalproex may be preferable to valproic acid in the treatment of bipolar disorder because of its more favorable adverse effect profile.403 Some experts recommend that carbamazepine or oxcarbazepine be used as alternatives to lithium or valproate therapy for patients who do not respond adequately to or who cannot tolerate other first-line therapies.401,421,422

Bipolar patients experiencing manic or mixed episodes with psychotic features or psychosis often require therapy with an antipsychotic agent.401,420,422 Antipsychotic agents also are commonly used in the treatment of manic or mixed episodes in patients with bipolar disorder to control psychotic symptoms and for sedation.403,422 Some evidence indicates that certain atypical antipsychotic agents also possess mood-stabilizing properties and may therefore help to control depressive and manic episodes.422,423 When an antipsychotic agent is clinically indicated in patients with bipolar disorder, some experts recommend the use of atypical antipsychotics (e.g., olanzapine, risperidone) over conventional antipsychotic agents (e.g., chlorpromazine, haloperidol) because of their more favorable adverse effect profile and possible mood-stabilizing activity.401,403,421,422,423,426

Short-term adjunctive therapy with a benzodiazepine (e.g., lorazepam, clonazepam) during manic episodes may be helpful for sedation and to help restore sleep in patients experiencing acute manic or mixed episodes.401,412,420,421,422 Some experts currently prefer high-potency benzodiazepines instead of antipsychotics in the management of acute manic episodes to avoid the risk of tardive dyskinesia and other adverse extrapyramidal effects associated with antipsychotic agents.421 However, benzodiazepines should be used with caution in bipolar patients with a history of substance abuse because of their addictive potential.420

In bipolar patients who experience an acute manic or mixed episode while receiving antidepressant therapy, many experts recommend that the antidepressant be tapered and discontinued, if possible.401 If psychosocial therapy is used, this treatment should be combined with pharmacotherapy.401

In patients with mixed episodes, many clinicians recommend valproate (valproic acid or divalproex) or carbamazepine rather than lithium as initial first-line therapy.403,420,422 In patients with dysphoric mania, combined divalproex and olanzapine currently is recommended by some clinicians.403,423

In patients who experience a manic or mixed episode (i.e., a “breakthrough” episode) while receiving maintenance therapy, some experts recommend that the dosage(s) of the current medication be optimized as an initial approach (e.g., ensuring that plasma drug concentrations are within the therapeutic range).401 In addition, an antipsychotic agent may be added or reinitiated.401,423,426 Severely ill or agitated patients also may require short-term therapy with a benzodiazepine.401,420 When first-line therapy given at optimal dosages fails to control the symptoms, another first-line drug may be added to the regimen.401,403,422 Alternatively, carbamazepine or oxcarbazepine may be added instead of a first-line agent and an antipsychotic agent may be added in patients not already receiving one.401,403,422,426 In addition, changing to a different antipsychotic agent occasionally may be helpful.401

In patients with refractory manic episodes, some experts recommend a trial of therapy with the antipsychotic clozapine.401,403,421 Electroconvulsive therapy (ECT) also may be considered in patients with particularly severe or treatment-resistant mania and in patients who prefer ECT in consultation with their clinician.401,403,412,421 ECT also has been recommended by some experts in patients experiencing mixed episodes or in patients who develop severe mania during pregnancy.401

Lithium Therapy for Acute Manic and Mixed Episodes

Extensive clinical experience and data from randomized, controlled studies have shown lithium to be effective in the treatment of acute mania and the acute manic phase of mixed bipolar disorder.401,403,404,405,411,412,413,414,415,416,417,421,422 Based on data from 5 controlled clinical trials, lithium appears to be more effective than placebo in the treatment of acute manic and mixed episodes.401,413,414,415,416,417 Data from these studies indicate that about 70% of patients receiving lithium display at least a partial reduction of manic symptoms.401,413,414,415,416,417

Based on data from several controlled clinical trials, lithium appears to be more effective than chlorpromazine in the treatment of acute mania. The percentage of patients achieving a complete or partial remission of a manic episode and the degree to which manic symptomatology is reduced are greater in patients treated with lithium than in those treated with chlorpromazine. Lithium is particularly effective in reducing affective and ideational signs and symptoms of mania, especially elation, grandiosity, feelings of persecution, flight of ideas, expansiveness, irritability, manipulativeness, anxiousness, and other manic behavior. Signs and symptoms of hyperactivity associated with mania, including sleep disturbances, pressured speech, increased motor activity, assaultive or threatening behavior, and distractability are reduced to a lesser extent. Because antipsychotic agents appear to be more effective than lithium in initially controlling the increased psychomotor activity of mania, many clinicians initiate treatment of acute mania with lithium or valproate (e.g., valproic acid, valproate sodium, divalproex) and an antipsychotic agent. Once psychomotor activity has been controlled (usually within 3-7 days), the antipsychotic agent usually is tapered and lithium or valproate therapy is continued to more specifically control disturbances of mood and ideation.

Considerations in Choosing Therapy for Depressive Episodes

In patients with bipolar disorder experiencing a depressive episode, many experts recommend that therapy with either lithium or lamotrigine be initiated as first-line therapy.401,421 Antidepressant monotherapy and therapy with tricyclic antidepressants generally should be avoided in such cases because of the possibility of inducing rapid cycling of symptoms.401,420 Alternatively, some clinicians recommend initiation of combination therapy with lithium and an antidepressant, particularly in patients with more severe depressive episodes.401 Psychotherapy (interpersonal therapy and cognitive behavior therapy) may be useful as an adjunct to pharmacotherapy.401 In patients with life-threatening inanition, suicidality, or psychosis, ECT may be considered.401 ECT may also may be helpful for managing severe depressive episodes during pregnancy.401

In bipolar patients who suffer from a breakthrough depressive episode despite maintenance therapy, many experts recommend optimizing the dosages of the current medication as an initial step.401,403 For acute depressive episodes in bipolar disorder patients not responding adequately to first-line interventions at optimal dosages, some experts recommend the addition of a selective serotonin-reuptake inhibitor (e.g., paroxetine), bupropion, venlafaxine, lamotrigine, or a monoamine oxidase (MAO) inhibitor.401,403,420,421 When an antidepressant is indicated in patients with bipolar depression, nonsedating antidepressants (i.e., bupropion, selective serotonin-reuptake inhibitors, MAO inhibitors) usually are preferred.401,403,420,421 ECT should be considered in bipolar patients with severe or treatment-resistant depression or in those with depression accompanied by psychotic or catatonic features.401

Because the likelihood of antidepressant therapy precipitating a switch into a hypomanic or manic episode may be somewhat lower in patients with type 2 bipolar disorder than in patients with type 1 bipolar disorder, many clinicians choose to initiate antidepressant therapy earlier in patients with bipolar 2 disorder.401 Depressive episodes accompanied by psychotic features usually require adjunctive antipsychotic therapy.401

Considerations in Choosing Therapy for Rapid Cycling

According to DSM-IV-TR criteria, rapid cycling refers to the occurrence of 4 or more mood-related disturbances within a single year that meet criteria for a major depressive, mixed, manic, or hypomanic episode.401,402 These episodes are demarcated either by partial or full remission for at least 2 months or a switch to an episode of the opposite nature (e.g., from a major depressive to a manic episode).401,402 Initially, many experts advise that any concurrent medical condition that may contribute to rapid cycling, such as hypothyroidism or drug or alcohol abuse, be identified and treated.401 Certain drugs, such as antidepressants, also may contribute to rapid cycling in bipolar disorder, particularly in patients not receiving other therapy such as lithium, carbamazepine, or valproic acid.401,422,423 Therefore, the need for continued antidepressant therapy should be reassessed in rapid-cycling patients and antidepressant therapy should be gradually discontinued, if possible.401

The initial therapy in bipolar patients who experience rapid cycling usually includes lithium or valproate (e.g., valproate sodium, valproic acid, divalproex).401,403,420,422,423 Alternatively, lamotrigine may be used.401 In many patients, combination therapy (e.g., with 2 first-line agents or a combination of a first-line agent with an atypical antipsychotic) is required to adequately treat rapid cycling.401,423 Recent evidence suggests that atypical antipsychotic agents (e.g., olanzapine, clozapine) combined with mood stabilizers, such as valproic acid and/or lithium, may be effective in rapid cycling patients.423

Considerations in Choosing Maintenance Therapy

Following treatment of an acute episode, patients with bipolar disorder remain at high risk of relapse.401 Therefore, following a single manic episode, maintenance therapy is recommended by many experts.401,403,421 The principal goals of maintenance therapy are relapse prevention, reduction of subthreshold symptoms, and reduction of suicide risk.401 Other aims of maintenance therapy include reduction in cycling frequency, reduction of mood instability, and improvement in overall functioning.401

The choice of a maintenance regimen for initial therapy should be individualized and take into consideration illness severity, associated clinical features (e.g., rapid cycling, psychosis), and patient preference.401 Clinical experience to date indicates that either lithium or valproate (e.g., valproate sodium, valproic acid, divalproex) should be considered for first-line maintenance therapy in bipolar disorder; possible alternatives include lamotrigine, carbamazepine, or oxcarbazepine.401,421,424,425 If one of these agents was used to achieve remission from the most recent manic or depressive episode, many experts advise that it generally should be continued.401,403 Maintenance ECT therapy also should be considered in patients whose acute episode responded to ECT.401

In patients who received an antipsychotic agent during the preceding acute episode, the need for continued antipsychotic therapy should be reassessed during the maintenance phase of therapy.401 Many experts recommend that antipsychotic therapy be tapered and discontinued unless needed for control of persisting psychotic symptoms or to prevent recurrence of such symptoms.401 Although maintenance therapy with atypical antipsychotic agents also may be considered, their efficacy as maintenance therapy compared with lithium or valproate has yet to be fully established.401 Patients with bipolar disorder are also likely to benefit from psychosocial interventions, including psychotherapy, during the maintenance phase.401,422

Patients who continue to experience subthreshold symptoms or breakthrough episodes may require the addition of another mood-stabilizing maintenance agent (lithium or valproate), an atypical antipsychotic agent, or an antidepressant.401 Currently, data to support one combination over another are insufficient.401 Maintenance sessions of ECT also may be considered in patients whose acute episode responded to ECT.401

Maintenance Therapy with Lithium

Lithium is effective in preventing or attenuating recurrences of bipolar episodes when used for long-term maintenance treatment of bipolar affective disorder. In patients with bipolar disorder, the drug is more effective at preventing signs and symptoms of mania than those of depression.

Approximately 65-90% of patients with bipolar disorder will have relapses if left untreated. During long-term lithium therapy, less than 40% of patients with bipolar disorder relapse during the first 2 years of therapy. The decision to initiate long-term prophylaxis with lithium in such patients is based on the history of recurrence of signs and symptoms.

Suicide Considerations

Patients with bipolar disorder are at high risk for suicide.401,420 Among the phases of bipolar disorder, depression is associated with the highest risk of suicide, followed by mixed episodes and the presence of psychotic symptoms, with episodes of mania being the least frequently associated with suicide.401,420 All patients with bipolar disorder should therefore be carefully evaluated to assess suicidal risk.401,420

Long-term lithium therapy has been associated with a reduction in suicidal risk in patients with bipolar disorder.401 However, it has not been clearly established whether this reflects possible anti-impulsivity properties in addition to lithium's established mood-stabilizing activity.401 Lithium also may reduce the greater mortality risk observed among bipolar disorder patients from causes other than suicide.401 It remains to be established whether other drugs used as maintenance therapy such as valproic and carbamazepine also may prolong survival in patients with bipolar disorder.401

Major Depression !!navigator!!

Lithium appears to be an effective antidepressant in some acutely depressed patients†. Depressive symptomatology, including feelings of hopelessness, worthlessness, and guilt; psychomotor retardation; weight loss; early awakening; and suicidal ideation, often improves during treatment with lithium. The acute antidepressant effect of lithium is more likely to occur in patients with bipolar disorder than in patients with major depression. In acutely depressed patients, complete or partial response occurs in 60-80% of patients treated with the drug. In controlled studies in acutely depressed patients, the antidepressant effect of lithium was about equal to that of tricyclic antidepressants; however, in one study imipramine was more effective than lithium. Because the effectiveness of other antidepressants (e.g., tricyclic antidepressants) in the treatment of acute depression is better established, and because lithium may worsen depressive symptoms in some patients, most clinicians reserve a trial of lithium therapy for those depressed patients who fail to respond to other antidepressants.

Based on data from several controlled studies, lithium appears to be more effective than placebo at reducing the rate of relapse in patients with recurrent depression† (recurrent unipolar affective disorder). Lithium also appears to be at least as effective as tricyclic antidepressants at reducing the number of depressive episodes in such patients. Although lithium appears to be effective in the prophylactic treatment of recurrent depression, only a small number of patients have been studied. Some clinicians believe that these studies justify the long-term use of lithium in recurrent depression; however, most clinicians believe that additional comparative studies are needed to determine the efficacy of lithium in the prophylactic treatment of recurrent depression.

Schizoaffective and Schizophrenic Disorders !!navigator!!

In patients with schizoaffective disorder† or schizophrenia†, lithium has been used with varying results. In patients with mildly active schizoaffective disorder in which the affective component predominates, lithium appears to be as effective as chlorpromazine. Such patients often show improvement in mannerisms, posturing, excitement, cooperation, and thought disorders during lithium therapy. In the treatment of patients with highly active schizoaffective disorder in which the schizophrenic component predominates, lithium appears to be less effective than chlorpromazine. In these patients, lithium alone generally fails to adequately control hostile, excited behavior. In patients with schizophrenia, lithium has demonstrated limited effectiveness when given as monotherapy and has caused worsening of the disorder in some cases.

Most clinicians consider antipsychotic agents to be the treatment of choice in patients with schizoaffective disorder or schizophrenia. The addition of lithium to a regimen containing an antipsychotic agent may be beneficial in some patients such as those with predominantly affective signs and symptoms who fail to respond to an antipsychotic agent alone, especially when acute episodes are of recent onset (e.g., less than 6 months). The American Psychiatric Association (APA) states that lithium has limited efficacy when used alone in the treatment of schizophrenia and is less effective than antipsychotic agents when used as monotherapy in patients with this condition.439 Earlier studies suggested that when added to antipsychotic agents in patients with schizophrenia, lithium increased overall efficacy and improved negative symptoms in particular.439 Other early studies indicated that lithium was beneficial in schizophrenic patients with prominent affective symptoms and in patients with schizoaffective disorder.439 However, more recent studies evaluating combined antipsychotic agent and lithium therapy have not confirmed those earlier findings and suggest that adjunctive therapy with lithium is not more effective than antipsychotics used alone in schizophrenia.439 The addition of relatively low doses of lithium over an 8-week period to an existing antipsychotic regimen improved anxiety but did not improve other symptoms in one placebo-controlled study.439 In another placebo-controlled study, the addition of lithium did not result in clinical improvement in schizophrenic patients who had not responded to 6 months of fluphenazine decanoate therapy.439 Although controlled studies of lithium combined with atypical antipsychotic agents are lacking, some of the newer antipsychotic agents have demonstrated antidepressant, anxiolytic, and mood stabilizing activity; therefore, the potential value of combined therapy with these agents and lithium may be limited.439

When lithium and antipsychotic agents are used in combination, the APA states that lithium generally is added to the antipsychotic drug that the patient is already receiving after the patient has received an adequate trial but has reached a plateau in the level of clinical response and residual symptoms persist.439 The APA recommends that the dosage of lithium be adjusted so that serum lithium concentrations in the range of 0.8-1.2 mEq/L are achieved.439 Response to lithium therapy usually is evident soon after initiating therapy, and a trial of 3-4 weeks of lithium therapy usually is sufficient to determine effectiveness; however, clinical improvement may require 3 months or longer in some cases.439 In addition to monitoring for the usual adverse effects associated with lithium therapy, clinicians should carefully monitor patients for possible adverse drug interactions with the antipsychotic agent (e.g., adverse extrapyramidal effects, confusion, disorientation, and other signs of neuroleptic malignant syndrome), particularly during the early stage of combined therapy.439 For further information on the symptomatic management of schizophrenia, see Uses: Psychotic Disorders in the Phenothiazines General Statement 28:16.08.24.

Disorders of Impulse Control !!navigator!!

Lithium has been used successfully in the treatment of impulsive-aggressive behavior in a small number of adults with disorders of impulse control†. Lithium reduced temper outbursts, impulsive antisocial behavior, and the number of assaultive acts. Further studies are needed to confirm the usefulness of the drug in these patients.

Psychiatric Disorders in Children !!navigator!!

Lithium has been used to treat children with apparent mixed bipolar disorder symptomatology†, hyperactivity with psychotic or neurotic components†, or aggressive behavior† or aggressive outbursts† associated with attention-deficit hyperactivity disorder (ADHD). Although children with violent and aggressive behavior who do not have an underlying affective disorder may respond to lithium, children with a definite affective disorder are more likely to respond to the drug. Late-adolescent patients who have mixed bipolar disorder and a parent with a lithium-responsive mixed bipolar disorder are most likely to respond to lithium. Although lithium appears to be useful in children with mixed bipolar disorder†, emotionally unstable character disorder†, depression†, or aggressiveness†, data are too limited to support routine use of the drug in these children. When lithium is used in the treatment of these disorders after an adequate trial with more conservative therapy, the duration of lithium therapy should be short (i.e., not greater than 6 months) and continued only in the presence of unequivocal response to the drug.

Alcohol Dependence !!navigator!!

Although early studies reported limited evidence of improved outcomes in patients with or without depression who received lithium for the management of alcohol dependence†, evidence from a large, randomized, double-blind, placebo-controlled study sponsored by the Department of Veterans Affairs indicated that lithium was not an effective treatment for alcohol dependence in either depressed or nondepressed alcoholics.429,430 In this study, clinical outcome measurements such as abstinence rates, number of days of drinking, number of alcohol-related hospitalizations, change in severity of alcoholism, and change in severity of depression in alcoholics who received lithium were comparable to those of alcoholics who received placebo.430 Unlike previous studies, the Department of Veterans Affairs Cooperative Study was large enough to have sufficient statistical power to detect a medium-effect size difference between the efficacy of lithium and placebo.429,430 This study also was controlled for comorbidity; alcoholics with antisocial personality disorder and major psychiatric illnesses other than nonpsychotic depression were excluded from the study.430

Neutropenia and Anemia !!navigator!!

Lithium has been used to treat neutropenia† or anemia† secondary to a variety of causes. Only in patients with antineoplastic drug-induced neutropenia have well-controlled studies of lithium therapy been reported.

In a limited number of patients with neutropenia secondary to myelosuppressive antineoplastic chemotherapy regimens, the addition of lithium to the regimen has decreased the number of days neutropenia is present, decreased the frequency of absolute neutrophil counts less than 500/mm3, and increased the neutrophil count at its nadir. The number of hospitalizations related to infection or fever and the number of infection-related deaths also have been reduced when lithium was added to a myelosuppressive antineoplastic chemotherapy regimen. There is no evidence to date that lithium increases the response of the underlying neoplastic disease to chemotherapy.

Patients receiving antineoplastic chemotherapy often are debilitated and generally are more susceptible to the adverse effects of lithium. Therefore, the benefit-to-risk ratio of lithium therapy in these patients remains to be established. Some clinicians recommend short-term lithium therapy when a patient has had severe neutropenic episodes during previous courses of chemotherapy or when a patient is undergoing treatment with combination chemotherapy known to be severely myelosuppressive.

Lithium has limited efficacy in the treatment of patients with congenital, idiopathic, or cyclic neutropenias†; Felty's syndrome†; or aplastic anemia†. In these patients, lithium has inconsistently increased leukocyte and/or erythrocyte counts. Most clinicians do not recommend routine use of lithium in these conditions since the efficacy of the drug has been limited and studies to date have not been adequately controlled.

Other Uses !!navigator!!

Lithium has been used in the treatment of hyperthyroidism†; however, because of its adverse effects, other treatments (e.g., radioactive iodine, surgery, propylthiouracil, methimazole) currently are preferred. Lithium also has been used to prolong the presence of radioactivity in the thyroid gland in patients receiving radioactive iodine†; however, use of the drug for this purpose requires further study.

Although lithium previously was considered one of the therapies of choice in the treatment of the syndrome of inappropriate secretion of antidiuretic hormone† (SIADH), it generally has been replaced with other more effective and/or less toxic therapies (e.g., demeclocycline).

Dosage and Administration ⬆ ⬇

[Section Outline]

General Dosage and Administration !!navigator!!

Lithium salts are administered orally, preferably with meals. Extended-release preparations should be swallowed intact and should not be chewed, crushed, or halved. Although there may be minor differences in bioavailability of commercially available lithium preparations, data do not support the use of one preparation over another. The choice of preparation usually is based on expense and patient preference. Lithium citrate oral solution may be useful in patients unable to swallow capsules or tablets; 5 mL of a commercially available solution contains about 8 mEq of lithium and is approximately equivalent to 300 mg of lithium carbonate.

Careful monitoring of serum lithium concentrations and clinical status of the patient is mandatory and patients should be carefully instructed in the safe use of the drug. The precautions and contraindications associated with lithium use should be reviewed carefully before initiating therapy. (See Cautions: Precautions and Contraindications.)

Serum lithium concentrations generally should be monitored twice weekly during initiation of the acute phase of therapy and until the serum concentration and clinical condition of the patient have been stabilized.404,405,428 Thereafter, serum concentrations should be monitored at least every 2 months in most patients.404,405,428 In patients whose affective disorder is not improving or in whom adverse effects are occurring, serum lithium concentrations should be monitored more frequently (e.g., weekly). There is wide interindividual variation in the dosage needed to achieve a given serum lithium concentration and in the serum lithium concentration needed to achieve therapeutic response. The established therapeutic range of serum lithium concentrations is based on correlations determined with monitoring of steady-state concentrations in the morning 12 hours after a dose in patients receiving a divided daily dosing regimen. Therefore, serum lithium concentrations should be determined at consistent times as close as possible to the twelfth hour after a dose. The manufacturers suggest that steady-state serum lithium concentrations be determined immediately before the next dose (i.e., 8-12 hours after the previous lithium dose).404,405,428 Total reliance must not be placed on serum lithium concentrations alone; accurate patient evaluation requires both careful clinical and laboratory evaluation.404,405,428 Dosage should be reduced and serum lithium concentration determined when a patient exhibits signs and symptoms of adverse nervous system, GI, or renal effects.

Although lithium has a long serum half-life and could be given in a single daily dose, the drug usually is given in divided doses because single daily doses often produce more frequent adverse effects (e.g., nausea, diarrhea). Several preliminary studies, however, indicate that the incidence of polyuria may be lower in patients receiving single daily doses rather than divided doses. Twice-daily dosing of conventional or extended-release preparations is sufficient for most patients. When adverse GI or nervous system effects occur, they may be minimized or prevented by giving the drug as conventional preparations in 3 or 4 divided doses. When lithium is used during pregnancy (see Cautions: Pregnancy, Fertility, and Lactation), some clinicians recommend dividing the total daily dose of conventional preparations into 3-5 doses to avoid exposing the fetus to high peak serum concentrations of the drug.

Dosage for Acute Episodes !!navigator!!

Serum lithium concentrations of 1-1.2 mEq/L are usually required during acute affective episodes.401,427 Although higher serum lithium concentrations may be required in some patients,427 the serum concentration should not exceed 1.5 mEq/L during the acute treatment phase. 401,427 If manifestations of lithium toxicity occur, the drug should be temporarily discontinued for 24-48 hours, then resumed at a lower dosage.405,405,428

Adult Dosage

During acute episodes of an affective disorder, the manufacturers recommend an initial lithium dosage of 1.8 g daily as conventional capsules or tablets of lithium carbonate, given in 3 or 4 divided doses, or 30 mL (about 48 mEq of lithium) of lithium citrate oral solution daily, given in 3 divided doses.404,428 Alternatively, the usual initial dosage of lithium carbonate of 1.8 g daily may be administered as extended-release tablets of lithium carbonate, given in 2 or 3 divided doses.404,405 However, because long-term compliance may be affected by a patient's initial experience with the drug, some clinicians recommend that lower initial dosages of lithium be used (e.g., 900 mg of lithium carbonate daily or less), especially in geriatric patients, in an attempt to minimize initial adverse effects, and then dosage be titrated slowly to achieve therapeutic serum lithium concentrations.401 Dosage must be individualized according to serum lithium concentrations, patient tolerance, and clinical response.404,405,428 The manufacturers state that serum lithium concentrations should be determined twice weekly during the acute phase of therapy and until the serum concentration and clinical condition of the patient have been stabilized.404,405,428 However, some clinicians recommend more frequent monitoring of serum lithium concentrations (e.g., before and after each dosage increase), particularly if a rapid dosage increase is necessary (e.g., in the treatment of acute mania) or if toxicity is suspected.401 Following resolution of acute manic signs and symptoms, many patients will not tolerate serum lithium concentrations of 1-1.2 mEq/L, and dosage reduction with appropriate patient monitoring is usually necessary.401,427

Pediatric Dosage

Although the usual dosage of lithium salts for acute episodes in children† has not been established, lithium carbonate dosages of 15-20 mg/kg (about 0.4-0.5 mEq/kg) daily or equivalent lithium citrate dosages have been given in 2 or 3 divided doses to children 11 years of age or younger.427 However, the usual adult dosage should not be exceeded. When lithium salts are used in children, dosage should be adjusted according to serum lithium concentrations, patient tolerance, and clinical response. Dosages for children 12 years of age and older usually are the same of those of adults.427

Maintenance Dosage !!navigator!!

Maintenance dosage of lithium should be based on serum lithium concentrations noted during the acute phase of therapy and on steady-state serum lithium concentrations determined 12 hours after a dose. Manufacturers recommend maintaining steady-state serum lithium concentrations at 0.6-1.2 mEq/L, using the minimum effective dosage that produces serum concentrations in this range, while avoiding excessive adverse effects.404,405,427,428 Geriatric patients often can be maintained with dosages that produce serum concentrations at the lower end of this range.401 During maintenance therapy, serum lithium concentrations are generally determined at least every 2 months in patients whose disease is well controlled.404,405,427,428

Adult Dosage

The usual adult maintenance dosage is 900 mg to 1.2 g daily of lithium carbonate as conventional tablets or capsules, given in 3 or 4 divided doses, or 15-20 mL of lithium citrate oral solution (about 24-32 mEq) daily, given in 3 or 4 divided doses. Alternatively, the usual maintenance dosage of lithium carbonate of 900 mg to 1.2 g daily may be administered as extended-release tablets, given in 2 or 3 divided doses.404,405 This dosage generally provides serum lithium concentrations of 0.6-1.2 mEq/L.404,405,427,428 Maintenance dosage usually should not exceed 2.4 g of lithium carbonate (65 mEq) daily.427

Pediatric Dosage

The usual maintenance dosage of lithium salts in children† has not been established. When lithium salts are used in children†, dosage should be adjusted according to serum lithium concentrations, patient tolerance, and clinical response.

Cautions ⬆ ⬇

[Section Outline]

Adverse reactions to lithium generally involve the CNS, GI tract, and kidneys. These adverse reactions usually are dose-dependent and generally occur at 12-hour steady-state serum lithium concentrations greater than 1-1.3 mEq/L; however, adverse CNS effects have occurred at serum concentrations less than 1 mEq/L, especially in children and geriatric patients. Other adverse effects, particularly GI effects, have been related to high peak serum concentrations of lithium.

Nervous System and Neuromuscular Effects !!navigator!!

Mild adverse CNS and neuromuscular effects initially occur in about 40-50% of patients receiving lithium. Lethargy, fatigue, muscle weakness, and tremor occur most frequently. As many as 40% of patients receiving lithium initially complain of headache, minor memory impairment and mental confusion, and/or a slightly decreased ability to concentrate.

Hand tremor occurs in about 45-50% of patients during initiation of lithium therapy and is usually benign. The tremor is a fine, rapid intention tremor, which generally resolves during continued therapy with the drug. After 1 year of lithium therapy, less than 10% of patients exhibit tremor. A coarsening of the tremor or its spread to other parts of the body may indicate lithium intoxication. Although hand tremor usually occurs early in the course of therapy, it can occur at any time and may be aggravated by anxiety, caffeine, or thyrotoxicosis. Most patients do not find lithium-induced tremor particularly troublesome. For those who do, a reduction in lithium dosage or low doses of a β-adrenergic blocking agent (e.g., propranolol) may be beneficial. The tremor is not responsive to antimuscarinic or other antiparkinsonian drugs.

Transient muscle weakness occurs in about 30% of lithium-treated patients; after 1 year of lithium therapy, about 1% of lithium-treated patients complain of muscle weakness. Similarly, fatigue, lethargy, dulled senses, and ataxia occur early in therapy but seem to resolve after 2-3 weeks of therapy. Dysarthria and aphasia also have been reported.

Muscle hyperirritability (including fasciculations, twitching, clonic movements of limbs), hyperactive deep tendon reflexes, hypertonia (hypertonicity), and choreoathetoid movements occur in less than 15% of patients receiving lithium. Cogwheel rigidity occurs in about 5% of patients. In one study, cogwheel rigidity reportedly occurred in 75% of patients receiving lithium; however, persistent concentrations of antipsychotic agents may have accounted for the higher incidence of cogwheel rigidity noted in these patients. Lithium-induced cogwheel rigidity generally is mild to moderate. Although it rarely may be associated with other extrapyramidal signs, lithium-induced cogwheel rigidity does not respond to antiparkinsonian agents.

Blackout spells, giddiness, dizziness, vertigo, disturbances in accommodation, somnolence and tendency to sleep, stupor, coma, restlessness, psychomotor retardation, acute dystonia, down-beat nystagmus, centrally mediated incontinence of urine and feces, and worsening of organic brain syndrome have occurred during lithium therapy. In one study, vertigo and disturbances in accommodation occurred in 15 and 10% of patients receiving the drug, respectively. Asterixis has occurred in at least one patient.

Pseudotumor cerebri (with increased intracranial pressure and papilledema) has occurred in patients receiving lithium. If undetected, this condition may result in enlargement of the blind spot, constriction of visual fields, and/or eventual blindness resulting from optic atrophy. If pseudotumor cerebri occurs during lithium therapy, the drug should be discontinued, if clinically possible. Papilledema with no evidence of increased intracranial pressure has also been reported.

Seizures and localizing neurologic findings have occurred in patients receiving lithium. Seizures generally are associated with toxic serum lithium concentrations and/or other signs of lithium neurotoxicity, but seizures also have occurred when lithium concentrations were within the therapeutic range. In one study, there was an increased frequency of lithium-induced seizures in patients with temporal-lobe epilepsy. Various EEG changes, including diffuse slowing, widening of frequency spectrum, and potentiation and disorganization of background rhythm, also have been reported. (See Pharmacology: Nervous System Effects.)

GI Effects !!navigator!!

Adverse GI effects occur frequently during initiation of lithium therapy but tend to be mild and reversible. Nausea, anorexia, epigastric bloating, diarrhea, vomiting, or abdominal pain occur in about 10-30% of patients. These adverse GI effects usually resolve during continued therapy and are present in 1-10% of patients after 1-2 years of therapy. These effects often are related to high peak serum lithium concentrations and are alleviated by taking the drug with meals, dividing dosage, or using an extended-release preparation. Some patients report a reduction in adverse GI effects when switched from one conventional capsule or tablet preparation to another.

Dry mouth occurs in about 20-50% of patients receiving lithium and is related to lithium-induced polyuria. Dysgeusia and sialorrhea also have been reported. An increased frequency of dental caries has been reported in patients treated with lithium, but this effect is probably related to increased consumption of sugar-containing fluids by patients with lithium-induced polydipsia. Contact stomatitis has occurred in at least one patient and was attributed to the formulation of the preparation.

Renal Effects !!navigator!!

Nephrogenic diabetes insipidus manifested as polyuria and polydipsia occurs in about 30-50% of lithium-treated patients, usually develops shortly after starting lithium therapy, and persists in about 10-25% of treated patients after 1-2 years of therapy. Polydipsia is largely a consequence of polyuria; both usually are well tolerated in most patients. Polyuria rarely is associated with serum electrolyte abnormalities, weight loss, or other signs and symptoms of dehydration; however, these effects may occur in patients who develop severe diabetes insipidus during lithium therapy. Many patients actually respond to polyuria with weight gain, probably because of increased consumption of high-calorie fluids. Although polyuria is a persistent and sometimes progressive finding in patients treated with lithium, it usually is reversible within 1 year after discontinuance of the drug; irreversible diabetes insipidus occurs rarely. Polyuria has been treated with lithium dosage reduction and/or with thiazide diuretics or amiloride (See Drug Interactions: Diuretics.)

Nonspecific nephron atrophy characterized by glomerular sclerosis, tubular atrophy, interstitial fibrosis, and urinary casts has been observed in patients treated with lithium. The tubular lesions are limited mainly to the distal convoluted tubule and collecting ducts. Sclerosis of 10-20% of glomeruli has been noted in some patients. These nonspecific changes have not been associated with a decrease in renal function. Although available data do not support a causal relationship between these findings and lithium therapy, studies of large numbers of patients receiving the drug for many years have not been conducted. In several trials using appropriate controls, there was no difference in the frequency of abnormal renal findings in pretreatment and posttreatment patients. However, cellular pleomorphism in the distal renal tubule has been associated with a decrease in renal-concentrating ability. Albuminuria and glycosuria also have occurred.

Modest decreases in glomerular filtration rate occasionally occur in patients receiving long-term lithium therapy; however, a causal relationship has not yet been established. Oliguric renal failure, reported in a few intoxicated patients, probably is not a direct renal effect of lithium but is related to circulatory collapse that may accompany lithium intoxication. (See Chronic Toxicity: Manifestations.)

Distal renal tubular acidosis of the incomplete type has occurred in some patients receiving lithium, but it does not appear to be clinically important unless these patients are stressed by an acid load. Most patients receiving lithium show a normal urine acidification response.

Endocrine Effects !!navigator!!

In therapeutic concentrations, lithium causes clinically evident hypothyroidism in about 1-4% of patients receiving the drug. These patients may require supplemental thyroid therapy. Symptoms of hypothyroidism may vary from mild to severe myxedema and may occur within weeks to years after initiating lithium therapy; rarely, hypothyroidism may persist after discontinuance of the drug. In addition, about 5% of lithium-treated patients develop goiters, resulting from stimulation of the thyroid gland by an indirect lithium-induced increase in thyrotropin release. Goiters may develop even in the absence of hypothyroidism in some patients receiving lithium. Lithium-induced goiters usually are diffuse and nontender and often so small as to be noticed only on palpation. Many patients have only laboratory evidence of hypothyroidism, including decreased serum concentrations of thyroxine (T4) and triiodothyronine (T3) and increased radioactive iodine uptake. Even in patients whose baseline serum thyrotropin concentrations are within normal limits, an exaggerated thyrotropin response to IV protirelin often occurs. Geriatric patients and patients with antithyroglobulin antibody, a prior history of Graves' disease or Hashimoto's thyroiditis, or those receiving iodine may be more likely to develop hypothyroidism during lithium therapy. Paradoxically, a few cases of hyperthyroidism have been reported.

Mild asymptomatic primary hyperparathyroidism has occurred during long-term lithium therapy and, rarely, may persist after discontinuance of the drug. (See Pharmacology: Endocrine Effects.)

Transient hyperglycemia has occurred rarely in patients receiving lithium.

Cardiovascular Effects !!navigator!!

Benign, reversible ECG T-wave depression occurs in 20-30% of patients receiving lithium. Isoelectricity or inversion of T waves also may occur. Reversible sinus node dysfunction (e.g., sinus bradycardia, sinoatrial block), atrioventricular (AV) node dissociation with AV block and junctional rhythms, and ventricular premature depolarizations occur rarely at therapeutic and toxic serum lithium concentrations. Syncope has occurred in patients with lithium-induced nodal dysfunction. In contrast, lithium also has been found to reduce the frequency of preexisting atrial premature depolarizations and supraventricular tachycardia.

Mild to moderate pretibial edema has occurred in a few patients during lithium therapy and appears to be associated with high sodium intake (more than 170 mEq/day). The edema has responded to spironolactone. Edematous swelling of the wrists also has occurred.

Other cardiovascular effects, including hypotension and cardiovascular collapse, have been noted during severe lithium intoxication and probably are not direct effects of the drug. Peripheral circulatory collapse also has been reported. Cardiomyopathy with associated myocardial and thyroid fibrosis was reported in one patient receiving lithium, amitriptyline, and potassium iodide.

Signs and symptoms resembling Raynaud's disease, which included painful discoloration of fingers and toes and coldness of the extremities, occurred in some patients within 1 day after initiating lithium therapy. The mechanism of this effect is not known; recovery occurred following discontinuance of the drug.

Dermatologic Effects !!navigator!!

Adverse dermatologic effects occur in about 1% of patients receiving lithium and rarely necessitate discontinuance of the drug. Acneiform eruptions and folliculitis appear to occur most frequently. Lithium-induced acneiform eruptions usually involve the face, neck, axilla, groin, and breast. The papules may become confluent or may subside spontaneously. Temporary discontinuance of the drug usually results in resolution of the eruption. Lithium-induced folliculitis resembles keratosis pilaris, is asymptomatic and usually limited to the extensor surfaces of the extremities, and often remits spontaneously. Pruritic maculopapular rashes occur rarely and usually remit with dosage reduction or discontinuance of lithium.

Lithium-induced or -exacerbated psoriasis has occurred occasionally; it is unclear whether a causal relationship to the drug exists. Alopecia, drying and thinning of the hair, xerosis cutis, anesthesia of the skin, cutaneous ulcers, exfoliative dermatitis, and lupus erythematosus-like rash also have occurred.

Hematologic Effects !!navigator!!

Most patients receiving lithium develop a reversible leukocytosis, with leukocyte counts of 10,000-15,000/mm3. Increases in erythrocyte and platelet counts are less frequently observed.

Lithium has been associated with the development of leukemia (see Cautions: Mutagenicity and Carcinogenicity), but a causal relationship to the drug has not been established. Aplastic anemia has been reported in at least one patient receiving lithium. Positive serum titers for antinuclear antibodies (ANA) have occurred during lithium therapy, but patients with positive serum ANA titers usually were receiving other drugs in addition to lithium.

Other Adverse Effects !!navigator!!

Other adverse effects associated with lithium therapy include weight loss or excessive weight gain (which may be associated with polyuria, see Cautions: Renal Effects), transient scotomata, exophthalmos, and generalized discomfort.

Precautions and Contraindications !!navigator!!

Since lithium toxicity is closely related to serum lithium concentrations and may occur at doses closely associated with therapeutic serum concentrations, monitoring of serum lithium concentrations and the clinical status of the patient is necessary in all patients receiving the drug. Lithium dosing should be monitored carefully when a patient's initial manic symptoms begin to subside, since the patient's ability to tolerate high serum lithium concentrations decreases as these symptoms resolve. (See Dosage and Administration: Dosage for Acute Episodes.)

Patients receiving lithium should be carefully instructed to avoid dehydration and to report polyuria and any prolonged vomiting, diarrhea, or fever to their physician. Patients should maintain their usual fluid (2.5-3 L/day) and sodium intake, and supplement these in the event of fever (e.g., during infections), vomiting, or diarrhea. A temporary reduction in dosage or discontinuance of the drug also may be required in these patients. Lithium should be used cautiously in patients whose sodium intake is restricted; in these patients, sodium intake should be stabilized and lithium dosage carefully titrated to avoid increased serum lithium concentrations that may occur with sodium depletion.

Outpatients and their families should be warned that the patient must discontinue lithium therapy immediately and consult a physician if signs of lithium intoxication such as muscle twitching, tremor, mild ataxia, drowsiness, muscle weakness, diarrhea, or vomiting occur. Patients also should be warned that lithium may impair their ability to perform activities requiring mental alertness or physical coordination (e.g., operating machinery, driving a motor vehicle).

Because nonspecific nephron atrophy has occurred in patients receiving lithium, many clinicians recommend a thorough assessment of renal function before initiating therapy. Many clinicians recommend that measurement of 24-hour creatinine clearance, renal-concentrating ability, and a urinalysis should ideally be performed in all patients prior to initiating therapy. Many clinicians also recommend that renal function be evaluated every 2-3 months for the first 6 months, then every 6-12 months during therapy or whenever clinically indicated.401,420 If progressive or sudden changes in renal function, even within the normal range, occur during lithium therapy, the need for therapy with the drug should be reevaluated.

Lithium should be used cautiously in patients with preexisting cardiovascular or thyroid disease. Patients with underlying cardiovascular disease should be observed carefully for signs and symptoms of arrhythmia (including periodic ECG determinations), and serum lithium concentrations should be kept within the therapeutic range since nodal arrhythmias may occur. Patients with underlying hypothyroidism should have thyroid function (T3, T4, and TSH concentrations) evaluated yearly and be given supplemental thyroid therapy when needed.

Lithium should be used with caution in geriatric patients since they appear to be more susceptible to adverse effects of the drug (e.g., adverse nervous system and neuromuscular effects), even at therapeutic serum concentrations. Because geriatric patients are more prone than younger patients to developing lithium-induced goiter and clinical hypothyroidism, some clinicians recommend that thyroid function tests be performed every 6-12 months in these patients. In addition, because of decreased renal function, geriatric patients are more likely to develop lithium intoxication subsequent to accumulation of the drug.

Although most patients receiving lithium and an antipsychotic agent (e.g., haloperidol, phenothiazines) concurrently do not develop unusual adverse effects, an acute encephalopathic syndrome (consisting of confusion, disorientation, adverse extrapyramidal effects, and possibly neuroleptic malignant syndrome) occasionally has occurred, especially when high serum lithium concentrations were present and associated with dehydration. Patients receiving such combined therapy should be observed for evidence of adverse neurologic effects; treatment should be promptly discontinued if such signs or symptoms appear. (See Drug Interactions: Antipsychotic Agents.)

Lithium generally should not be used in patients with severe renal or cardiovascular disease or severe dehydration, sodium depletion, or debilitation since the risk of toxicity is increased in these patients. If the psychiatric indication is life-threatening and other forms of therapy are contraindicated or ineffective, lithium may be used with extreme caution in these patients; if lithium therapy is initiated in these patients, the patient should be hospitalized, serum lithium concentration should be monitored carefully, and dosage should be adjusted as necessary. Although the manufacturers caution against the concurrent use of lithium and a diuretic, when combined therapy is necessary, some clinicians recommend that the usual dosage of lithium initially be reduced by about 50%, the patient and serum lithium concentrations be monitored carefully, and lithium dosage be adjusted as necessary. (See Drug Interactions: Diuretics.)

Pediatric Precautions !!navigator!!

Safety and efficacy of lithium therapy in children younger than 12 years of age have not been established; however, the drug has been used in this age group when benefits were thought to outweigh risks. Transient acute dystonia and hyperreflexia occurred in a 15-kg child who ingested 300 mg of lithium carbonate.404,405,428

Geriatric Precautions !!navigator!!

Clinical studies of lithium carbonate as extended-release tablets did not include sufficient numbers of patients 65 years of age and older to determine whether geriatric patients respond differently than younger patients.405 While clinical experience with lithium therapy generally has not revealed age-related differences in response to the drug, care should be taken in dosage selection of lithium.405 Because of the greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy in geriatric patients, patients in this age group should receive initial dosages of the drug in the lower end of the usual range.405 Lithium is substantially excreted by the kidneys and the risk of severe adverse reactions to the drug may be increased in patients with impaired renal function.405 Because geriatric patients may have decreased renal function, renal function should be monitored and dosage adjusted accordingly.405

Mutagenicity and Carcinogenicity !!navigator!!

It is not known if lithium is mutagenic or carcinogenic.

An increased number of chromosomal breaks, gaps, and satellite associations, as well as a reduced percentage of replicating cells were found in one study of lithium-containing leukocyte cultures. Similar findings were not found in 2 other in vitro studies. Mice inoculated with viable sarcoma cells have shown an earlier incidence of tumor development but no change in tumor size when treated with lithium. The number and growth of induced mammary tumors in rats have not been increased by lithium.

There have been occasional reports of lithium-induced hematologic neoplasms (e.g., acute leukemia), but a causal relationship to the drug has not been established. Studies have shown no changes in blast and mature neutrophil counts in patients with various blood dyscrasias who were receiving lithium. One study found the incidence of leukemia not to be increased in a group of manic-depressive patients receiving chronic lithium therapy.

Pregnancy, Fertility, and Lactation !!navigator!!

Pregnancy

Lithium can cause fetal toxicity when administered to pregnant women, but potential benefits may be acceptable in certain conditions despite the possible risks to the fetus. Lithium should be used during pregnancy only in life-threatening situations or severe disease for which safer drugs cannot be used or are ineffective. When lithium is administered during pregnancy or if the patient becomes pregnant while receiving the drug, the patient should be informed of the potential hazard to the fetus. When possible, lithium should be withdrawn for at least the first trimester unless it is determined that this would seriously endanger the mother. Women of childbearing age receiving lithium should be counseled about methods of birth control.

When lithium is used during pregnancy, serum lithium concentrations should be carefully monitored and dosage adjusted if necessary since renal clearance of the drug and distribution of the drug into erythrocytes may be increased during pregnancy. Pregnant women receiving lithium may have subtherapeutic serum lithium concentrations if dosage of the drug is not increased during pregnancy. Immediately postpartum, renal clearance of lithium may decrease to pre-pregnancy levels; therefore, to decrease the risk of postpartum lithium intoxication, dosage of the drug should be reduced 1 week before parturition or when labor begins.

Lithium has caused various teratogenic effects in submammalian species and cleft palates in mice. Studies in rats, rabbits, and monkeys have shown no evidence of lithium-induced teratology.

Data from lithium birth registries suggest that the drug may increase the incidence of cardiac and other anomalies, especially Ebstein's anomaly (distorted tricuspid valve with secondary dilation of the right ventricular outflow tract). Atrial septal defect, patent foramen ovale, and right ventricular conduction delay also have occurred. Other reported fetal cardiovascular abnormalities included mitral atresia, coarctation of the aorta, ventricular septal defect, tricuspid atresia, patent ductus arteriosus, and dextrocardia. Down's syndrome, clubfoot, meningomyelocele, transient hypothyroidism with goiter, and transient nephrogenic diabetes insipidus also have been reported. Lithium-exposed neonates also have presented briefly with muscular hypotonia (floppy infant syndrome) and apneic spells. A 5-year follow-up study of children without apparent congenital abnormalities who were born to women treated with lithium found no increase in the frequency of physical or mental abnormalities in these children compared with matched controls (i.e., siblings during whose pregnancy the mother did not take lithium).

Fertility

The effect of lithium on fertility in humans is not known. Erective impotence has been noted by a few men receiving the drug. Lithium has had adverse effects on nidation in rats and on embryo viability in mice. In vitro metabolism of rat testes and human spermatozoa also have been observed.

Lactation

Lithium is distributed into milk. (See Pharmacokinetics: Distribution.) Because of the potential for serious adverse reactions from lithium in nursing infants, a decision generally should be made to discontinue nursing or the drug, taking into account the importance of the drug to the woman.

Drug Interactions ⬆ ⬇

[Section Outline]

Diuretics !!navigator!!

In general, the concomitant use of lithium and diuretics should be avoided.405 In those cases where concomitant use is necessary, extreme caution is advised because diuretic-induced sodium loss may reduce the renal clearance of lithium and increase the risk of lithium toxicity.404,405 When such combinations are used, the lithium dosage may need to be decreased and more frequent monitoring of serum lithium concentrations is recommended.404,405

Thiazide diuretics, sometimes used in combination with lithium to reduce lithium-induced polyuria, will reduce renal lithium clearance within several days. The reduced lithium clearance has resulted in increased serum lithium concentrations and several cases of lithium intoxication. When thiazide diuretics are used to treat lithium-induced polyuria, most clinicians recommend reducing lithium dosage by about 50% and carefully monitoring serum lithium concentrations. Other diuretics that enhance sodium excretion (e.g., furosemide, spironolactone) also may reduce renal clearance of lithium; however, this effect does not occur consistently and lithium clearance often is increased initially. Urea also has increased renal clearance of lithium. Amiloride does not appear to substantially affect lithium pharmacokinetics in most patients. (See Drug Interactions: Lithium, in Amiloride Hydrochloride 40:28.10.)

Antipsychotic Agents !!navigator!!

Numerous pharmacokinetic and clinical interactions have been reported between phenothiazines and lithium. Phenothiazines have been shown to increase erythrocyte lithium concentrations and to increase renal clearance of lithium. Lithium has been reported to decrease serum chlorpromazine concentrations. The clinical result of these pharmacokinetic interactions is unpredictable; therefore, patients receiving lithium and a phenothiazine should be monitored for altered response to either drug. In addition, an acute encephalopathic syndrome (toxic-confusional state) consisting of confusion, disorientation, extrapyramidal adverse effects, and possibly neuroleptic malignant syndrome occasionally has been reported in patients receiving lithium and antipsychotic agents concurrently, particularly in dehydrated patients with high serum lithium concentrations. Therefore, patients receiving combined therapy should be observed for evidence of adverse neurologic effects (e.g., adverse extrapyramidal effects, confusion, disorientation, and other signs of neuroleptic malignant syndrome), particularly during the early stage of combined therapy. Nausea and vomiting, which are occasionally signs of lithium intoxication, may be masked by the antiemetic effect of some phenothiazines when used concurrently.

Occasionally, patients have developed acute encephalopathic syndromes or extrapyramidal reactions when concurrently using lithium and an antipsychotic agent (e.g., haloperidol, phenothiazines). Irreversible brain damage, parkinsonian movements, and dyskinesias have resulted. Although a causal relationship has not been established and most patients can receive the drugs concurrently without adverse effect, caution is advised. Patients receiving such combined therapy should be monitored for adverse neurologic effects, especially when large dosages of lithium and an antipsychotic agent are used; combined therapy should be promptly discontinued if such signs or symptoms appear.

Nonsteroidal Anti-inflammatory Agents !!navigator!!

Indomethacin, mefenamic acid, phenylbutazone, piroxicam, and ibuprofen have been reported to increase serum lithium concentrations by 30-60%, resulting in lithium toxicity in some cases. These nonsteroidal anti-inflammatory agents (NSAIAs) appear to decrease renal clearance of lithium. There is evidence that other NSAIAs, including selective inhibitors of cyclooxygenase-2 (COX-2), have the same effect.404,405 In one clinical study, mean steady-state plasma lithium concentrations increased approximately 17% in healthy individuals who received lithium (450 mg twice daily) in conjunction with celecoxib (200 mg twice daily) compared with those who received lithium alone.404,405 When these agents are started or discontinued in a patient receiving lithium, serum lithium concentrations should be closely monitored and the patient should be observed for signs and symptoms of lithium intoxication. Appropriate adjustment in lithium dosage may be required when therapy with the NSAIA is discontinued.

Anticonvulsants !!navigator!!

Adverse neurologic effects have occurred in patients receiving lithium concurrently with carbamazepine or phenytoin. Concurrent use of lithium and phenytoin also has resulted in increased serum lithium concentrations in at least one patient; however, the clinical importance of this effect has not been determined and further substantiation of this interaction is required.

Angiotensin-converting Enzyme Inhibitors !!navigator!!

Concomitant administration of lithium and an ACE inhibitor (e.g., captopril, enalapril, lisinopril) may result in elevated plasma lithium concentrations and has resulted in several cases of lithium intoxication.404,405 Consequently, at least one manufacturer of lithium and some clinicians recommend that such concomitant use of these agents be avoided, particularly in geriatric patients or in those with congestive heart failure, renal insufficiency, or volume depletion. The mechanism of this interaction is not known, but it has been postulated that dehydration and loss of sodium may decrease excretion of lithium. Moderate renal insufficiency (serum creatinine of 2.2 mg/dL) or acute renal failure also has occurred in some patients receiving an ACE inhibitor concomitantly with lithium. (See Drug Interactions: Lithium, in Enalapril 24:32.04.) If lithium is used with an ACE inhibitor, the dosage of lithium may need to be reduced and serum lithium concentrations should be carefully monitored.

Calcium-channel Blocking Agents !!navigator!!

Serum lithium concentrations may decrease following initiation of verapamil in patients stabilized on lithium therapy. In a patient with bipolar disorder whose lithium dosage had been stabilized for several years, manic symptoms emerged and serum lithium concentrations decreased to subtherapeutic levels within 1 month after initiating 320 mg of verapamil hydrochloride daily, requiring an increase in lithium carbonate dosage from 900-1200 mg daily to 1800-2100 mg daily. Serum lithium concentrations also decreased in another patient and urinary excretion of the cation increased.

Although the mechanism of this interaction currently is not known, serum lithium concentrations and the patient should be monitored closely and lithium dosage adjusted accordingly when verapamil is initiated or discontinued in patients receiving lithium therapy.

There also is some evidence that calcium-channel blocking agents may potentiate the toxic effects of lithium; neurotoxicity (e.g., ataxia, choreoathetosis, tremors, tinnitus), adverse GI effects (e.g., nausea, vomiting, diarrhea), and bradycardia have been reported in patients receiving lithium concomitantly with a calcium-channel blocking agent. When 240 mg of verapamil hydrochloride daily was initiated for potential antimanic effects in a patient whose bipolar disorder was inadequately controlled with a therapeutic dosage of lithium, bipolar disorder was controlled within 1 week after initiating combined therapy, but manifestations of neurotoxicity occurred 2 days later despite therapeutic serum lithium concentrations. Neurotoxicity subsided within 2 days following discontinuance of verapamil but recurred when the patient was rechallenged with verapamil in an attempt to regain control of the bipolar disorder. Verapamil did not appear to affect the pharmacokinetics of lithium in this patient. The mechanism of this interaction is not known, but a similar interaction has been described in a patient receiving lithium and diltiazem concomitantly. Calcium-channel blocking agents appear to share some of the neuropharmacologic effects of lithium, and combined therapy with the drugs may potentiate neurotoxicity. Pending further accumulation of data, verapamil and possibly other calcium-channel blocking agents should be used concomitantly with lithium cautiously.

Selective Serotonin-Reuptake Inhibitors !!navigator!!

Adverse effects possibly associated with increased serum lithium concentrations, lithium toxicity, and/or serotonin syndrome (e.g., absence seizures, agitation, ataxia, confusion, diarrhea, dizziness, dysarthria, stiffness of the extremities, tremor) have been reported in patients receiving lithium concomitantly with selective serotonin-reuptake inhibitors (SSRIs). In addition, concomitant use of lithium and fluoxetine has resulted in both increased and decreased serum lithium concentrations; therefore, patients receiving such combined therapy should be monitored closely.405 Lithium appears to have some serotonergic activity and serotonin syndrome has been reported following initiation of lithium therapy in patients receiving SSRIs such as fluoxetine or paroxetine. For further information on serotonin syndrome, including manifestations and treatment, see Serotonin Syndrome under Drug Interactions: Drugs Associated with Serotonin Syndrome, in Fluoxetine Hydrochloride 28:16.04.20. The clinical importance of this potential interaction remains to be determined and further substantiation is required; however, caution should be exercised when lithium and serotonin reuptake-inhibitors are used concurrently.

Neuromuscular Blocking Agents !!navigator!!

Lithium has been reported to prolong the latency of neuromuscular blockade induced by succinylcholine or pancuronium. In limited clinical studies, however, no prolongation of neuromuscular blockade was noted in patients receiving electroconvulsive therapy, succinylcholine, and lithium concurrently. Patients receiving neuromuscular blocking agents should have lithium temporarily withdrawn during their use or should be carefully monitored if lithium is continued.

Iodides !!navigator!!

Concurrent use of lithium salts and iodides may result in an additive or synergistic hypothyroid effect. Lithium carbonate and potassium iodide have produced hypothyroidism in several patients when used concurrently. A lithium salt and potassium iodide generally should not be used concomitantly; when the drugs are used together, the patient should be monitored closely for signs and symptoms of hypothyroidism.

Sodium !!navigator!!

Changes in sodium intake in patients receiving lithium may alter the renal elimination of lithium. The renal clearance of lithium may be increased or decreased by as much as 30-50% by increased or decreased sodium intake, respectively. Patients should be advised to avoid substantial changes in their sodium intake. (See Cautions: Precautions and Contraindications.) When drugs with a high sodium content (e.g., antacids) are used concomitantly with lithium, serum lithium concentrations should be monitored.

Electroconvulsive Therapy !!navigator!!

Acute neurotoxicity with prominent delirium has occurred in patients receiving lithium and electroconvulsive therapy (ECT) concurrently. Some clinicians recommend decreasing lithium dosage or withdrawing the drug 2 days prior to ECT.

Metronidazole !!navigator!!

Initiation of short-term metronidazole therapy in patients stabilized on a relatively high dosage of lithium has been reported to increase serum lithium concentrations, resulting in signs of lithium toxicity in several patients; in some cases, signs of renal damage (e.g., persistent elevations in serum creatinine concentration, hypernatremia, abnormally dilute urine) were present. Pending further accumulation of data, caution should be exercised and frequent monitoring of serum lithium concentrations should be performed when metronidazole and lithium are administered concurrently.

Beta-Adrenergic Blocking Agents !!navigator!!

Although β-adrenergic blocking agents have been used to suppress lithium-induced tremor, the absence of tremor may make lithium intoxication more difficult to diagnose. Therefore, patients should be monitored for other signs and symptoms of lithium intoxication when the drugs are used concomitantly.

Alkalinizing Agents !!navigator!!

Urinary alkalinizing agents such as sodium bicarbonate may increase renal excretion of lithium, and a higher dosage of lithium may be required in patients receiving these agents concomitantly.

Methyldopa !!navigator!!

Symptoms of lithium intoxication, including confusion, disorientation, hand tremor, and slurred speech, have been reported occasionally when methyldopa was administered in patients already receiving lithium.432,433,434,435 Although plasma lithium concentrations were reported to be within the therapeutic range in some of the published cases, increased lithium concentrations have also been reported during concurrent administration of methyldopa.432,433,434,435 The possible mechanism for this interaction remains to be established.432,435 Pending further experience with this combination, some clinicians recommend that patients receiving lithium and methyldopa should be closely monitored for signs of lithium toxicity and that consideration should be given to the use of alternative antihypertensive agents in patients receiving lithium.432,433,434

Tetracycline !!navigator!!

Tetracycline reportedly increased serum lithium concentrations when the 2 drugs were used concurrently in one patient; however, the clinical importance of this effect has not been determined.

Diazepam !!navigator!!

Profound hypothermia has been reported in one patient taking lithium and diazepam concurrently; however, widespread use of this combination without unusual adverse effects indicates that it is safe in most patients.

Opiate Analgesics !!navigator!!

Lithium reportedly interferes with opiate-induced euphoria and diminishes the analgesic effect of opiates (narcotic analgesics).

Other Drugs !!navigator!!

Decreased serum lithium concentrations as a result of increased urinary lithium excretion may occur when lithium is used concomitantly with acetazolamide or xanthine derivatives (e.g., aminophylline).404,405

Hyperkinetic movements and tardive dyskinesia have been reported when lithium was used concomitantly with baclofen or a monoamine oxidase (MAO) inhibitor, respectively.

Other Information ⬆ ⬇

[Section Outline]

Acute Toxicity

Since the pathophysiology, manifestations, and treatment of acute lithium intoxication are similar to those of chronic lithium intoxication, the Chronic Toxicity section should be consulted for additional information.

Pathogenesis !!navigator!!

Acute lithium intoxication occurs as the result of ingestion of a single toxic dose. The acute lethal dose of lithium varies but is generally associated with a dose that produces serum lithium concentrations greater than 3.5 mEq/L 12 hours after ingestion.

Manifestations !!navigator!!

In individuals not previously receiving the drug, acute ingestion of a single massive dose of lithium may produce only vomiting and diarrhea usually within 1 hour of ingestion. Manifestations associated with chronic lithium intoxication also may occur. A transient syndrome of acute dystonia and hyperreflexia has been reported in a 15-kg child following ingestion of 300 mg of lithium carbonate. Death has occurred in adults who ingested single 10- to 60-g doses of lithium. However, some patients who ingested a single 6-g dose of lithium have had no signs of lithium intoxication.

Treatment !!navigator!!

In acute overdosage, the stomach should be emptied immediately by inducing emesis or by gastric lavage. If the patient is comatose, having seizures, or lacks the gag reflex, gastric lavage may be performed if an endotracheal tube with cuff inflated is in place to prevent aspiration of gastric contents. Following induction of emesis or gastric lavage, the treatment described for chronic intoxication generally should be followed. (See Chronic Toxicity: Treatment.)

Chronic Toxicity

Pathogenesis !!navigator!!

Chronic lithium intoxication, when it occurs, generally results from high dosages, prolonged therapy with high dosages, or changes in lithium pharmacokinetics. The main contributing factor to the development of chronic intoxication often is water loss, which may result from fever, decreased fluid or food intake during acute manic or depressive episodes, diuretics, abnormal GI conditions (e.g., nausea, diarrhea, vomiting), or pyelonephritis. Geriatric patients also are more prone to develop chronic lithium intoxication.

Although there is no clearly defined relationship between serum lithium concentration and severity of intoxication, the serum concentration 12 hours after the last dose may roughly predict severity of intoxication. Serum lithium concentrations of 1.5-2.5 mEq/L often indicate slight to moderate intoxication; concentrations of 2.5-3.5 mEq/L often indicate severe intoxication; and concentrations greater than 3.5 mEq/L often indicate potentially lethal intoxication. In addition to the serum lithium concentration, the severity of lithium intoxication depends on the length of time the serum concentration remains in the toxic range. It is important to promptly recognize the signs and symptoms of lithium intoxication and to initiate treatment if necessary.

Manifestations !!navigator!!

Initial manifestations of lithium intoxication often involve the nervous system and include drowsiness, confusion, giddiness, apathy, coarse hand tremor, and dysarthria. Occasionally, GI symptoms are seen (e.g., decreased appetite, nausea, vomiting, diarrhea). Muscle rigidity or fasciculations, slight ataxia, tinnitus, increased lethargy, increased deep tendon reflexes, blurred vision, and vertical nystagmus usually follow; photophobia also has occurred. Lithium intoxication can progress to impaired consciousness, increasing fasciculations and ataxia, coarse and irregular limb tremors, choreoathetoid movements, cogwheel rigidity, and other focal neurologic signs. Coma, twitching, coarse contractions of muscles, generalized tonic-clonic seizures, cardiovascular collapse with oliguria and anuria, and death may ensue. Arrhythmias, electrocardiographic widening of the QRS interval, inverted T waves, and myocardial infarction also have occurred. The clinical course of lithium intoxication is quite variable; patients may present with any of the above signs and symptoms.

Approximately 70-80% of lithium-intoxicated patients fully recover. Persistent sequelae, including dementia, ataxia, polyuria, dysarthria, spasticity, nystagmus, and tremor, have occurred in about 10% of intoxications. Death has occurred in 10-25% of reported lithium intoxications.

Treatment !!navigator!!

There is no specific antidote for lithium intoxication.404,405 Treatment of lithium intoxication is principally supportive and depends on the patient's clinical condition and serum lithium concentration.404,405,431 Early symptoms of milder lithium intoxication (e.g., diarrhea, vomiting, drowsiness, muscular weakness, lack of coordination) usually respond to dosage reduction or temporary discontinuance of the drug and correction of fluid and electrolyte abnormalities.404,405,431 When intoxication is more severe, the patient generally should be hospitalized and provided intensive, supportive care, including infection prophylaxis and regular chest X-rays. Discontinuance of lithium and any concurrently administered diuretic is essential.

IV infusion of 0.9% sodium chloride injection is begun when lithium intoxication is thought to be secondary to total body depletion of sodium. Rapid administration of large volumes of IV solutions, or IV administration of potassium or a diuretic apparently provides no additional benefit. Although diuretics (e.g., furosemide, mannitol, urea), carbonic anhydrase inhibitors, and xanthine derivatives (e.g., aminophylline) may increase lithium clearance.404,405,431 The increased clearance is insufficient to be useful in treating intoxication.431 Because dehydration resulting in sodium and lithium retention may also occur when these agents are used, these agents are not recommended for the treatment of lithium intoxication.431

Hemodialysis is the only reliable method of rapidly removing excess lithium in patients who manifest lithium intoxication and/or who cannot excrete lithium.431 Because lithium is not metabolized and is only excreted renally, patients with chronic renal failure should undergo hemodialysis following potentially toxic exposures to lithium.431 In addition, patients with acute lithium intoxication who were not previously receiving the drug should undergo hemodialysis regardless of their clinical status if their serum lithium concentration equals or exceeds 4 mEq/L.431 These patients will not be able to excrete lithium in time to prevent a clinically important amount from entering the CNS and causing severe and potentially permanent neurologic toxicity.431 Because patients with an acute on chronic overdosage or chronic overdosage of lithium already have a body burden of the drug, a serum lithium concentration of 2.5 mEq/L or greater and moderate-to-severe neurologic toxicity are reasonable indications for hemodialysis.431 Hemodialysis for 8-12 hours is also recommended when fluid or electrolyte abnormalities are unresponsive to supportive treatment; when creatinine clearance or urine output decreases substantially; or when serum lithium concentration is not reduced by at least 20% in 6 hours. Serum lithium concentrations usually rebound within 5-8 hours after hemodialysis because of redistribution of the drug, often necessitating repeated courses of hemodialysis. The goal of hemodialysis is to produce a serum lithium concentration less than 1 mEq/L 8 hours after hemodialysis is completed. Although intermittent hemodialysis usually is performed in severe cases of lithum intoxication, continuous venovenous hemodialysis has also been successfully used in several patients in order to more slowly remove lithium from the body in hemodynamically unstable patients and to avoid postdialysis rebound elevations in lithium levels.436,437,438 Peritoneal dialysis is less effective at removing lithium and is used only when hemodialysis is not possible.

Pharmacology

Lithium has numerous pharmacologic effects. Although traces of lithium are found in animal tissues, lithium has no known physiologic function. Although the mechanisms of action have not been fully elucidated, lithium, as a monovalent cation, competes with other monovalent and divalent cations (potassium, sodium, calcium, magnesium) at cellular sites in body tissues, including the following: at cell membranes, where lithium passes readily through sodium channels and, at high concentrations, blocks potassium channels; at cellular binding sites sensitive to changes in cation concentration; at the level of cellular proteins sensitive to usual cation concentrations; and at cellular carrier-binding and transport sites for monovalent and divalent cations.

Lithium also interacts with a number of cyclic adenosine monophosphate (AMP) second-messenger cellular processes, including those regulated by polypeptide hormones. By inhibiting adenylate cyclase, lithium reduces intracellular concentrations of cyclic AMP. To a lesser extent, lithium also reduces plasma concentrations of cyclic guanosine monophosphate (cGMP).

Nervous System Effects !!navigator!!

Lithium has antimanic and antidepressant effects. Because of the complexity of the CNS, the exact mechanism(s) of these effects is unknown. Univalent and divalent cations appear to be critical to the synthesis, storage, release, and reuptake of central monoamine neurotransmitters, including indoleamines (e.g., serotonin) and catecholamines. These neurotransmitters appear to be involved in the pathogenesis of mania and depression.

Evidence suggests that dopamine and norepinephrine may be involved in the pathogenesis of mania. In animals, brain tissue lithium concentrations of 1-10 mEq/L inhibit depolarization-provoked and calcium-dependent release of norepinephrine, dopamine, and serotonin from nerve terminals and synapses. Lithium only minimally affects catecholamine-sensitive adenylate cyclase activity or the binding of ligands to adrenergic receptors in the CNS. Turnover of norepinephrine in the CNS is initially increased with lithium therapy, but the increased turnover does not persist with prolonged administration. Lithium may block the development of supersensitive dopamine receptors in the CNS of manic patients. Lithium blocks some of the behavioral manifestations of mania (e.g., euphoria, hyperactivity, talkativeness, decrease in sleep, increase in libido) induced by drugs (e.g., amphetamines, cocaine) that produce functional increases in CNS dopamine concentrations.

Serotonin may play a role in the pathogenesis of depressive episodes. Serotonin is present in low concentrations in the CNS of some patients with bipolar affective disorders. Animal studies have shown that lithium increases the concentrations of serotonin metabolites (e.g., 5-hydroxyindoleacetic acid) and decreases hemispheric asymmetry of serotonin and other indoleamines. Lithium is thought to increase neuronal tryptophan uptake and serotonin synthesis by decreasing the affinity of tryptophan hydroxylase for tryptophan at low tryptophan concentrations.

In healthy individuals, lithium has been shown to increase lethargy and lassitude, decrease clearheadedness, and cause deficits in cognitive motor tasks. Lithium also produces small but consistent delays in sleep-wake circadian rhythm and decreases rapid eye movement (REM) sleep, increases delta-wave sleep, and normalizes the sleep of some depressed patients. Lithium may cause benign EEG changes, including diffuse slowing and increased amplitude of alpha waves with an increase in beta-wave activity as alpha rhythm diminishes. In some patients, lithium has produced changes similar to those induced by electroconvulsive therapy (ECT), including marked epileptiform dischar these effects generally are associated with toxic serum lithium concentrations and/or other signs of lithium neurotoxicity, but also have occurred when lithium concentrations were within the therapeutic range.

Hematologic Effects !!navigator!!

Lithium produces neutrophilia and may also increase erythrocyte and platelet counts and decrease lymphocyte counts; however, the latter 3 effects appear to occur less consistently than neutrophilia.

The hematologic effects of lithium appear to be related to its effect on the pluripotent stem cell of the myeloid series. Although there probably are many modifiers of stem-cell production, the monocyte appears to be the key modifier involved in the effect of lithium on the stem cell. Lithium stimulates the production of colony-stimulating factor by monocytes. Colony-stimulating factor in turn stimulates production of neutrophils by the pluripotent stem cell and, to a lesser extent, production of erythrocytes, platelets, and macrophages. The increase in colony-stimulating factor is related to the action of lithium on cyclic nucleotides.

Lithium causes a true increase in neutrophil production and survival time and in granulocyte marrow reserve; neutrophilia does not result from demargination. Neutrophilia is seen generally within 3-7 days after lithium therapy is initiated and occurs at serum lithium concentrations of 0.5-1 mEq/L; the effect rapidly reverses (within 1-2 weeks) when the drug is discontinued. Data from one in vitro study indicate that the effect of lithium on neutrophil production is apparently transient when stem cells are severely depleted, since increases in neutrophil counts were not seen after 4 weeks. Although some studies indicate that lithium produces neutrophilia at the expense of neutrophil function, most studies have shown no effect of the drug on phagocytosis, chemotaxis, adherence, or bactericidal activity of neutrophils. Although not clearly established, lithium may enhance lymphocyte activity.

Renal Effects !!navigator!!

Lithium causes alterations in renal function and often produces a mild nephrogenic diabetes insipidus manifested as polyuria. The drug decreases renal-concentrating ability and water reabsorption and initially increases sodium and potassium excretion. Some of these effects are overcome by counteracting physiologic mechanisms, while others may persist. Glomerular filtration rate may be slightly decreased in patients receiving prolonged lithium therapy.

A decrease in renal-concentrating ability occurs in 30-50% of patients shortly after starting lithium therapy and persists in about 25% of treated patients after 1-2 years of lithium therapy. The decrease in renal-concentrating ability is usually reversible following discontinuance of the drug; however, in one study, this effect persisted in more than 50% of patients 1 year after discontinuing lithium therapy. Lithium-induced polyuria results from a major disturbance in the water conservation system and a minor disturbance in the thirst regulatory system. Although a central mechanism for lithium-induced diabetes insipidus has been described in one patient, most evidence indicates that the impairment of renal-concentrating ability is nephrogenic, since lithium inhibits vasopressin-induced adenylate cyclase activity. In most patients with lithium-induced nephrogenic diabetes insipidus, plasma vasopressin concentrations usually are elevated and urine osmolality is reduced. Lithium-induced diabetes insipidus has been inhibited by increased urinary potassium or hydrogen ion concentrations, and by thiazide diuretics, triamterene, or amiloride.

The effects of lithium on serum and urinary electrolytes are variable and time and dose related. Lithium initially increases sodium and potassium excretion and urine volume; after 2-3 days, excretion of these electrolytes is reduced, probably because of a feedback increase in aldosterone. Sodium and potassium excretion return to pretreatment levels within 1 week of continuous therapy. Overall, lithium generally does not affect sodium reabsorption in the ascending limb of the loop of Henle or in the distal renal tubule; free water clearance is unchanged even in the presence of lithium-induced polyuria. However, high serum concentrations of lithium have been associated with increased renin release and resultant inhibition of sodium reabsorption in the proximal and distal renal tubules and collecting ducts.

Endocrine Effects !!navigator!!

Lithium has various effects on the thyroid gland, but its principal effect is to block the release of thyroxine (T4) and triiodothyronine (T3) mediated by thyrotropin. This results in a decrease in circulating T4 and T3 concentrations and a feedback increase in serum thyrotropin concentration. Lithium also inhibits thyrotropin-stimulated adenylate cyclase activity and thyrotropin-induced release of thyroidal iodine 131, decreases intrathyroidal iodothyronine-iodotyrosine ratios, and inhibits colloid droplet formation.

Long-term lithium therapy may alter calcium, magnesium, and parathyroid hormone homeostasis; these alterations may cause a mild asymptomatic primary hyperparathyroidism. Lithium may cause slight increases in serum calcium (total), magnesium, and parathyroid hormone concentrations and a decrease in serum phosphate concentration. Lithium may also cause slight alterations in bone mineral metabolism.

Lithium has varying effects on carbohydrate metabolism. Increased and decreased glucose tolerance and decreased sensitivity to insulin have been observed. It is unclear whether these are direct effects of lithium or are related to changes in the course of the underlying psychiatric disorder.

In animals, lithium decreases hepatic cholesterol and fatty acid synthesis.

Cardiovascular Effects !!navigator!!

In patients with therapeutic serum lithium concentrations, reversible ECG T-wave depression occurs frequently. T-wave inversion occurs rarely. Resting or exercise-induced ST-segment abnormalities have not been observed. Arrhythmias have occurred rarely. (See Cautions: Cardiovascular Effects.)

The cardiac effects of lithium may result partly from displacement of potassium from intracellular myocardial sites by lithium; this displacement may result in a slow, partial depletion of intracellular potassium.

GI Effects !!navigator!!

Lithium reduces intestinal absorption of glucose and water, probably by incompletely substituting for sodium in a sodium-dependent transport mechanism at the intestinal mucosa. These actions may be responsible for the osmotic diarrhea and other adverse GI effects that frequently occur during initiation of lithium therapy.

Pharmacokinetics

Absorption !!navigator!!

Lithium is readily absorbed from the GI tract. Food does not appear to affect the bioavailability of lithium. Although lithium carbonate capsules show a slightly longer dissolution time than do tablets, differences in the disintegration and dissolution properties of various preparations do not appear to be clinically important. Conventional lithium carbonate capsules and tablets are 95-100% absorbed. Extended-release lithium carbonate tablets are 60-90% absorbed, and lithium citrate oral solutions are essentially 100% absorbed.

Absorption from conventional lithium carbonate tablets and capsules is usually complete within 1-6 hours with peak serum lithium concentrations usually occurring within 0.5-3 hours. Following oral administration of a single 300-mg dose of lithium carbonate to fasting adults, peak serum lithium concentrations of 0.4-0.5 and 0.4-0.9 mEq/L have been reported for conventional tablets and capsules, respectively. Absorption of lithium carbonate from extended-release tablets is both delayed and prolonged, with peak serum lithium concentrations occurring within 4-12 hours. Oral solutions of lithium citrate are the most rapidly absorbed, with peak serum lithium concentrations usually occurring within 15-60 minutes. Following oral administration to fasting patients of single doses of lithium citrate solution equivalent in lithium content to 600 mg and 0.9-1 g of lithium carbonate, peak serum lithium concentrations of about 0.7 and 1 mEq/L, respectively, have been reported.

During the first 6-10 hours after dosing, serum lithium concentrations fluctuate depending on the absorption of the drug and tissue distribution. Therefore, the 12-hour steady-state serum lithium concentration is used by most clinicians for monitoring serum concentrations; this concentration shows a high intraindividual (but not interindividual) reproducibility. Steady-state serum lithium concentrations of 0.4-1.3 mEq/L are considered necessary for therapeutic effect in the treatment of affective and schizoaffective disorders. At 12- to 16-hour steady-state serum concentrations of less than 0.4 mEq/L, about 60% of lithium-responsive patients with bipolar disorder relapse, compared with about 15% relapse at concentrations of 0.4-0.59 mEq/L and about 20% relapse at concentrations of 0.6-1 mEq/L. Steady-state serum lithium concentrations of 1-1.4 mEq/L usually are required for an acute antimanic effect. Onset of the acute antimanic effect of lithium usually occurs within 5-7 days; full therapeutic effect often requires 10-21 days. The likelihood of toxicity increases substantially at steady-state serum lithium concentrations of 1.5 mEq/L or greater, but some patients who are sensitive to the effects of lithium may develop toxicity at serum concentrations less than 1 mEq/L. Salivary lithium concentrations have been used by some clinicians to monitor lithium therapy, but most clinicians have not found this method practical. (See Pharmacokinetics: Distribution.)

Distribution !!navigator!!

Lithium is widely distributed into most body tissues and fluids. Lithium is initially distributed into extracellular fluid and then gradually accumulates in varying degrees in tissues. The drug is rapidly distributed into thyroid, bone, and brain tissue; concentrations in these tissues often are 50% greater than simultaneous serum concentrations. Lithium is distributed more slowly and less completely into heart, lung, kidney, and muscle; concentrations in these tissues approximate those in serum. Lithium concentrations in CSF and liver usually are 30-50% of simultaneous serum concentrations.

Lithium also distributes into saliva. The ratio of serum-to-mixed saliva lithium concentrations shows considerable interindividual variation, but once steady-state is achieved there is little intraindividual variation. Steady-state mixed saliva lithium concentrations are generally 2- to 3-fold greater than concurrent serum concentrations.

Lithium distributes into erythrocytes against an electrochemical potential gradient, drawn by an oppositely directed sodium ion gradient. The ratio of the lithium concentration in erythrocytes to that in serum shows wide interindividual variation but less intraindividual variation. Steady-state lithium concentrations in erythrocytes may range from 30-90% of concurrent serum concentrations but usually are 50% or less. The ratio has been shown to be slightly higher in women (especially during pregnancy), in patients with bipolar illness compared with patients with unipolar illness, and in patients with affective illness in remission compared with those in acute stages; however, the clinical importance of these findings is unknown. Distribution of lithium into erythrocytes also may depend partially on genetic factors.

Lithium initially distributes into an apparent volume that is about 25-40% of body weight, and later into a volume that is equal to that of total body water. Steady-state and initial apparent distribution volumes of about 0.7-1 L/kg and 0.3-0.4 L/kg, respectively, have been reported. Geriatric patients may have slightly smaller volumes of distribution, while individuals younger than 30 years of age may have slightly larger volumes of distribution. Lithium is not bound to plasma proteins.

Lithium freely crosses the placenta; maternal and fetal serum concentrations are approximately equal. The milk of nursing women contains lithium concentrations that are approximately 33-50% of those in serum.

Elimination !!navigator!!

Serum concentrations of lithium appear to decline in a biphasic manner. In patients with normal renal function, an initial half-life (t½α) of 0.8-1.2 hours and a terminal half-life (t½β) of 20-27 hours have been observed following single-dose administration of lithium. Patients receiving lithium for more than 1 year had terminal half-lives of 2.4 days in one study. In geriatric patients and patients with impaired renal function, serum half-lives of 36 and 40-50 hours, respectively, have been reported.

Lithium is not metabolized; it is excreted almost entirely in the urine. About 80% of the lithium that is filtered by the renal glomeruli is reabsorbed in the proximal renal tubules. Thus, renal plasma clearance of lithium is about 20% of the glomerular filtration rate or about 20-40 mL/minute. Geriatric patients may have lower, and younger patients and pregnant women may have higher, renal clearances. Proximal tubular reabsorption of lithium occurs against electrical and concentration gradients that do not distinguish between sodium and lithium. Lithium clearance can be increased or decreased by as much as 30-50% by sodium loading or depletion, respectively. Sodium depletion generally has a greater effect than does sodium loading. Several drugs (e.g., thiazide diuretics, aminophylline, urea) have been shown to increase or decrease renal clearance of lithium. Polyuria and potassium chloride administration do not increase renal clearance of lithium. Beyond the proximal tubule, lithium reabsorption is minimal. For this reason, most diuretics do not enhance renal lithium clearance. (See Drug Interactions: Diuretics.)

Approximately 95-99% of a single dose of lithium is excreted in urine. Small amounts may be excreted in feces as unabsorbed drug or in sweat. In patients with normal renal function, about 30-70% of a single dose is excreted in urine within 6-12 hours and 50-80% within 24 hours; the remainder is excreted slowly over 10-14 days. Lithium is readily removed by hemodialysis with reported clearances of about 50-90 mL/minute; however, the amount of lithium removed during hemodialysis depends of several factors (e.g., type of coil used, dialysis flow-rate). The drug is removed less readily by peritoneal dialysis, with reported clearances of 13-15 mL/minute. Because of slow equilibration between intracellular and extracellular fluid compartments, rebound increases in serum lithium concentration frequently occur 5-8 hours after dialysis.

Chemistry and Stability

Chemistry !!navigator!!

Lithium salts are antimanic agents. Lithium is a monovalent cation belonging to the group of alkali metals, but it also shares some of the chemical properties of calcium and magnesium. Lithium is commercially available as the carbonate and citrate salts.

Lithium Carbonate

Lithium carbonate occurs as a white, granular powder that has a slight saline taste. The drug is sparingly soluble in water, very slightly soluble in alcohol, and dissolves, with effervescence, in dilute mineral acids. Each gram of lithium carbonate contains 27 mEq of lithium.

Lithium Citrate

Lithium citrate occurs as a tetrahydrate, white, somewhat deliquescent, crystalline powder that has a slight saline taste. The drug is very soluble in water and practically insoluble in alcohol. Each gram of anhydrous lithium citrate contains approximately 14.3 mEq of lithium. Lithium citrate oral solution is prepared from lithium citrate or lithium hydroxide to which an excess of citric acid has been added. The oral solution has a pH of 4-5.

Stability !!navigator!!

Lithium Carbonate

Lithium carbonate conventional tablets, extended-release tablets, and capsules should be stored in well-closed containers at 15-30°C. When stored as directed, commercially available lithium carbonate extended-release tablets (Lithobid®) have an expiration date of 18 months following the date of manufacture.

Lithium Citrate

Lithium citrate oral solution should be stored in tight containers at 15-30°C.

Preparations ⬆ ⬇

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Lithium Carbonate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules

150 mg (4.06 mEq of lithium)*

Lithium Carbonate Capsules

300 mg (8.12 mEq of lithium)*

Eskalith®

GlaxoSmithKline

Lithium Carbonate Capsules

600 mg (16.24 mEq of lithium)*

Lithium Carbonate Capsules

Roxane

Tablets

300 mg (8.12 mEq of lithium)

Lithium Carbonate Tablets (scored)

Tablets, extended-release

450 mg (12.18 mEq of lithium)*

Eskalith CR® (scored)

GlaxoSmithKline

Lithium Carbonate Extended-release Tablets

Tablets, extended-release, film-coated

300 mg (8.12 mEq of lithium)*

Lithobid® Slow-release

JDS Pharma

Lithium Carbonate Extended-release Film-coated Tablets

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Lithium Citrate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Solution

8 mEq (of lithium) per 5 mL

Lithium Citrate Syrup

Copyright ⬆ ⬇

AHFS® Drug Information. © Copyright, 1959-2024, Selected Revisions January 1, 2006. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References ⬆

Only references cited for selected revisions after 1984 are available electronically.

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