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. Currently, lithium salts are principally used in the treatment of bipolar disorder, particularly in the treatment of acute manic or mixed episodes in patients with bipolar 1 or bipolar 2 disorder. 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.
Lithium salts also are used in the prophylaxis and treatment of major depressive disorder (unipolar depression).
Affective disorders currently are categorized as either bipolar (manic-depressive) or unipolar (depressive). 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. 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). 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.
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. Bipolar 1 disorder is characterized by the occurrence of one or more manic episodes or mixed episodes. 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. Hypomanic and mixed episodes also may occur in bipolar I disorder as well as substantial subthreshold mood lability between episodes. 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.
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. However, patients with bipolar 2 disorder should not have had a previous manic or mixed episode.
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. This condition is called bipolar disorder not otherwise specified according to DSM-IV-TR criteria.
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.
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. 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). Rapid-cycling bipolar disorder is sometimes associated with certain medical conditions (e.g., hypothyroidism) or drug or substance abuse. 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).
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. 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. The rapid control of certain symptoms (e.g., agitation, aggression, impulsivity) may be particularly important for the safety of the patient and others.
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. 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. 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. 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.
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. 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. 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. 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.
Bipolar patients experiencing manic or mixed episodes with psychotic features or psychosis often require therapy with an antipsychotic agent. 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. Some evidence indicates that certain atypical antipsychotic agents also possess mood-stabilizing properties and may therefore help to control depressive and manic episodes. 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.
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. 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. However, benzodiazepines should be used with caution in bipolar patients with a history of substance abuse because of their addictive potential.
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. If psychosocial therapy is used, this treatment should be combined with pharmacotherapy.
In patients with mixed episodes, many clinicians recommend valproate (valproic acid or divalproex) or carbamazepine rather than lithium as initial first-line therapy. In patients with dysphoric mania, combined divalproex and olanzapine currently is recommended by some clinicians.
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). In addition, an antipsychotic agent may be added or reinitiated. Severely ill or agitated patients also may require short-term therapy with a benzodiazepine. When first-line therapy given at optimal dosages fails to control the symptoms, another first-line drug may be added to the regimen.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. In addition, changing to a different antipsychotic agent occasionally may be helpful.
In patients with refractory manic episodes, some experts recommend a trial of therapy with the antipsychotic clozapine. 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. ECT also has been recommended by some experts in patients experiencing mixed episodes or in patients who develop severe mania during pregnancy.
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. 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. Data from these studies indicate that about 70% of patients receiving lithium display at least a partial reduction of manic symptoms.
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. Antidepressant monotherapy and therapy with tricyclic antidepressants generally should be avoided in such cases because of the possibility of inducing rapid cycling of symptoms. Alternatively, some clinicians recommend initiation of combination therapy with lithium and an antidepressant, particularly in patients with more severe depressive episodes. Psychotherapy (interpersonal therapy and cognitive behavior therapy) may be useful as an adjunct to pharmacotherapy.In patients with life-threatening inanition, suicidality, or psychosis, ECT may be considered. ECT may also may be helpful for managing severe depressive episodes during pregnancy.
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. 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. When an antidepressant is indicated in patients with bipolar depression, nonsedating antidepressants (i.e., bupropion, selective serotonin-reuptake inhibitors, MAO inhibitors) usually are preferred. ECT should be considered in bipolar patients with severe or treatment-resistant depression or in those with depression accompanied by psychotic or catatonic features.
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. Depressive episodes accompanied by psychotic features usually require adjunctive antipsychotic therapy.
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. 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). 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.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. Therefore, the need for continued antidepressant therapy should be reassessed in rapid-cycling patients and antidepressant therapy should be gradually discontinued, if possible.
The initial therapy in bipolar patients who experience rapid cycling usually includes lithium or valproate (e.g., valproate sodium, valproic acid, divalproex). Alternatively, lamotrigine may be used. 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. 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.
Considerations in Choosing Maintenance Therapy
Following treatment of an acute episode, patients with bipolar disorder remain at high risk of relapse. Therefore, following a single manic episode, maintenance therapy is recommended by many experts. The principal goals of maintenance therapy are relapse prevention, reduction of subthreshold symptoms, and reduction of suicide risk. Other aims of maintenance therapy include reduction in cycling frequency, reduction of mood instability, and improvement in overall functioning.
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. 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. 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. Maintenance ECT therapy also should be considered in patients whose acute episode responded to ECT.
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. 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. 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. Patients with bipolar disorder are also likely to benefit from psychosocial interventions, including psychotherapy, during the maintenance phase.
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. Currently, data to support one combination over another are insufficient. Maintenance sessions of ECT also may be considered in patients whose acute episode responded to ECT.
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.
Patients with bipolar disorder are at high risk for suicide. 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. All patients with bipolar disorder should therefore be carefully evaluated to assess suicidal risk.
Long-term lithium therapy has been associated with a reduction in suicidal risk in patients with bipolar disorder. However, it has not been clearly established whether this reflects possible anti-impulsivity properties in addition to lithium's established mood-stabilizing activity. Lithium also may reduce the greater mortality risk observed among bipolar disorder patients from causes other than suicide. 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.
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
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. Earlier studies suggested that when added to antipsychotic agents in patients with schizophrenia, lithium increased overall efficacy and improved negative symptoms in particular. Other early studies indicated that lithium was beneficial in schizophrenic patients with prominent affective symptoms and in patients with schizoaffective disorder. 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. 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. 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. 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.
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. 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. 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. 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. For further information on the symptomatic management of schizophrenia, see .
Disorders of Impulse Control
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
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.
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. 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. 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. 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.
Neutropenia and Anemia
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/mm, 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.
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).