Lithium acute mania

Other agents are also used for the treatment of manic-depressive disorders based on preliminary clinical results (177). The antiepileptic carbamazepine [298-46-4] has been reported in some clinical studies to be therapeutically beneficial in mild-to-moderate manic depression. Carbamazepine treatment is used especially in bipolar patients intolerant to lithium or nonresponders. A majority of Hthium-resistant, rapidly cycling manic-depressive patients were reported in one study to improve on carbamazepine (178). Carbamazepine blocks noradrenaline reuptake and inhibits noradrenaline exocytosis. The main adverse events are those found commonly with antiepileptics, ie, vigilance problems, nystagmus, ataxia, and anemia, in addition to nausea, diarrhea, or constipation. Carbamazepine can be used in combination with lithium. Several clinical studies report that the calcium channel blocker verapamil [52-53-9] registered for angina pectoris and supraventricular arrhythmias, may also be effective in the treatment of acute mania. Its use as a mood stabilizer may be unrelated to its calcium-blocking properties. Verapamil also decreases the activity of several neurotransmitters. Severe manic depression is often treated with antipsychotics or benzodiazepine anxiolytics. 

The first mood stabilizer was lithium (its antimanic action being discovered in 1948) more recently the anticonvulsant drugs carbamazepine and valproate have been found to be effective in acute mania. Unfortunately these mood stabilizers are only successful in controlling mania to a limited extent and few patients are well enough to leave hospital at the end of 3 weeks of treatment using these drugs as monotherapy. It is increasingly common for combination treatment to be advocated, in which an antipsychotic dmg is combined with lithium or an anticonvulsant. 

Pharmacotherapy is the cornerstone of acute and maintenance treatment of bipolar disorder. Mood-stabilizing drugs are the usual first-choice treatments and include lithium, divalproex, carbamazepine, and lamotrigine. Atypical antipsychotics other than clozapine are also approved for treatment of acute mania. Lithium, lamotrigine, olanzapine, and aripiprazole are approved for maintenance therapy. Drugs used with less research support and without Food and Drug Administration (FDA) approval include topiramate and oxcarbazepine. Benzodiazepines are used adjunctively for mania. 

Introduced in clinical practice in the 1960s, lithium was the first mood stabilizer to be used in China. This was followed by carbamazepine and sodium valproate. For many years, these were the only treatment options available as mood stabilizers. Although lamotrigine was approved for maintenance treatment of bipolar I disorder in 2003 by FDA (Food and Drug Administration) in the USA, this indication has not yet been approved by the Chinese authorities. At present, only one atypical antipsychotic drug, risperidone, has been approved for treating acute mania (February 2005 by SFDA [State Food and Drug Administration]) in China (see Table 6.1). 

Lithium, divalproex sodium (valproate), aripiprazole, olanzapine, que-tiapine, risperidone, and ziprasidone are currently approved by the FDA for treatment of acute mania in bipolar disorder. Lithium, olanzapine, and lamotrigine are approved for maintenance treatment of bipolar disorder. Quetiapine is the only antipsychotic that is FDA approved for bipolar depression. 

Lithium was the first established mood stabilizer and is still considered a first-line agent for acute mania and maintenance treatment of both bipolar I and II disorders. It is the only bipolar medication approved for adults and children 12 years and older. Long-term use of lithium reduces suicide risk. Patients with rapid cycling or mixed states may not respond as well to lithium monotherapy as to some anticonvulsants. 

Ari pi prazole, olanzapine, quetiapine, risperidone, and ziprasidone are effective as monotherapy or as add-on therapy to lithium or valproate for acute mania. Prophylactic use of antipsychotics can be needed for some patients with recurrent mania or mixed states, but the risks versus benefits must be weighed in view of long-term side effects (e.g., obesity, type 2 diabetes, hyperlipidemia, hyperprolactinemia, cardiac disease, and tardive dyskinesia). 

Lamotrigine is effective for the maintenance treatment of bipolar I disorder in adults. It has both antidepressant and mood-stabilizing effects, and it may have augmenting properties when combined with lithium or valproate. It has low rates of switching patients to mania. Although it is less effective for acute mania compared to lithium and valproate, it may be beneficial for the maintenance therapy of treatment-resistant bipolar I and II disorders, rapidcycling, and mixed states. It is often used for bipolar II patients. 

Lithium is effective for acute mania, but it may require 6 to 8 weeks to show antidepressant efficacy. It may be more effective for elated mania and less effective for mania with psychotic features, mixed episodes, rapid cycling, and when alcohol and drug abuse is present. Maintenance therapy is more effective in patients with fewer episodes, good functioning between episodes, and when there is a family history of good response to lithium. It produces a prophylactic response in up to two-thirds of patients and reduces suicide risk by eight- to 10-fold. 

Lithium is usually initiated with low to moderate doses (600 mg/day divided into two to three doses) for prophylaxis, and higher doses (900 to 1,200 mg/day, divided into two to three doses) for acute mania. Immediate-release preparations should be given two to three times daily, whereas extended-release products can be given once or twice daily. After patients are stabilized, many patients can be switched to once-daily dosing. 

Valproate (Depakote, Depakene). Valproate is an anticonvnlsant that has been demonstrated in multiple controlled clinical trials to be an effective mood stabilizer and, in fact, has obtained FDA approval for the treatment of acute mania. It appears to be particularly effective in bipolar patients who experience mixed episodes or rapid cycling or who have not responded well in the past to lithium. 

The long-term toxic effects of lithium, such as nephrogenic diabetes insipidus, which has been calculated to occur in up to 5% of patients, and the rare possibility of lithium combined with neuroleptics being neurotoxic, has stimulated the research for other drug treatments. However, apart from the neuroleptics, these drugs have not been studied as extensively in the treatment of acute mania, but are worthy of consideration because of their reduced side effects. 

In CONCLUSION, lithium is universally accepted as a mood-stabilizing drug and an effective antimanic agent whose value is limited by its poor therapeutic index (i.e. its therapeutic to toxicity ratio). Neuroleptics are effective in attenuating the symptoms of acute mania but they too have serious adverse side effects. High potency typical neuroleptics appear to increase the likelihood of tardive dyskinesia. Of the less well-established treatments, carbamazepine would appear to have a role, particularly in the more advanced stages of the illness when lithium is less effective. 

Acute mania Optimal patient response is usually established and maintained with 600 mg 3 times/day or 900 mg twice/day for the slow release form. Such doses normally produce an effective serum lithium level ranging between 1 and 1.5 mEq/L. 

Lithium has numerous pharmacologic effects. It is able to cross through sodium channels, competing with monovalent and divalent cations in cell membranes (AHFS, 2000). Animal studies have shown that lithium at a serum level of 0.66 + — 0.08 mEq/L can increase the amphetamine-induced release of serotonin (5-hydroxytryptamine [5-HT]) and the concentrations of a serotonin metabolite (e.g., 5-hydroxyindoleacetic acid [5-HIAA]) in the perifornical hypothalamus (PFH) of rats before and after chronic lithium chloride administration (Baptista et ah, 1990), a mechanism possibly involved in lithium s antidepressant effect. The precise neurobiological mechanisms through which lithium reduces acute mania and protects against recurrence of illness remain uncertain (Lenox and Hahn,... 

There are no randomized, double-blind, controlled studies of hospitalized children and adolescents with acute mania. Two systematic, albeit open, studies of lithium in hospitalized, acutely manic adolescents had response rates of 67%-80% in classic manic adolescents, and 33%-40% in manic adolescents with prior ADHD (Strober et al., 1988 1998). In a discontinuation study in which manic adolescents stabilized on lithium were subsequently assigned double-blind to placebo or continuation treatment, the response rate was 53.5%, and the presence of prior ADHD made no difference in outcome (Kafantaris et al., 1998). However, the presence of psychosis decreased the likelihood of lithium response and antipsychotic medication was necessary for stabilization. Naturalistic discontinuation of lithium (because of noncompliance) after stabilization resulted in relapse rates of 90% vs. 37.5% for those remaining on lithium (Strober et al., 1990). A NIMH multisite study is currently examining this issue more systematically. 

More common are case series and open trials of mood stabilizers for acute mania (see Davanzo and McCracken, 2000 for review). These studies, some of which were done in the 1970s and 1980s with classical adolescent manic patients, showed promise for the use of lithium in the treatment of mania. In some early studies, response to lithium was a requirement for diagnosis, a circular criterion that would undoubtedly have increased the response rate. 

There are several controlled trials of young outpatients with bipolar and bipolar spectrum conditions. Geller et al. (1998) studied 25 adolescents in a 6-week, doubleblind, placebo-controlled study. Twelve received lithium, of whom 4 had BP-I (presumably acute mania), 4 had BP-II (presumably hypomania), and 4 had major depression with bipolar predictors. All had concurrent substance abuse. There were no significant differences in outcome between active and placebo groups, except in... 

These data suggest that there is more available information for use of lithium than for other mood stabilizers, and that adolescents hospitalized with adolescent-onset, acute mania have rates of response between 50% and 80%. Supplementation with sedating medication appears to be common but not systematically evaluated. Children hospitalized with mania also respond to lithium, but their comorbid disorders often need separate attention. Open trials with DVP in hospitalized adolescents are also supported. There is much less information on CBZ and there are no data on newer anticonvulsants such as lamotrigine, topiramate, or gabapentin. These data are largely consistent with data from studies of hospitalized adults with classic mania. 

According to the Expert Consensus Panel for Mental Retardation Rush and Frances, (2000), the mainstays of the pharmacological treatment of acute mania or bipolar disorder in adults are anticonvulsant medications (divalproex, valproic acid, or carbamazepine) or lithium. Both divalproex or valproic acid and lithium were preferred treatments for classic, euphoric manic episodes. Divalproex or valproic acid was preferred over lithium and carbamazepine for mixed or dysphoric manic episodes and rapid-cycling mania. For depressive episodes associated with bipolar disorder, the addition of an antidepressant (SSRI, bupropion, or venlafaxine) was recommended. According to the Expert Consensus Panel, the presence of MR does not affect the choice of medication for these psychiatric disorders in adults. 

Brunet et al. (1990), in an open study, reported positive antimanic effects of nimodipine in six patients with acute mania. Our results showed a much lower response rate, ffowever, our patients were much more refractory by history, were treated in a tertiary referral research center, and generally showed a higher incidence of rapid, ultrarapid, and ultradian cycling patterns than in more traditional studies. Our results, however, are consistent with those of Manna (1991), who reported equal long-term efficacy of nimodipine and lithium monotherapy and greater efficacy on a combination of the two drugs than on either drug alone. 

In total, 61 (54%) of 113 patients with acute mania treated with valproate in controlled clinical trials showed moderate or better improvement. In those trials comparing it with placebo, valproate demonstrated significant efficacy. Further, when compared with lithium, no significant differences in response rates were observed. In summary, valproate has demonstrated considerable efficacy in the treatment of acute mania, although, as with lithium, 25%-50% of the patients in these trials did not respond. 

In contrast with studies of the treatment of acute mania, studies of lithium in bipolar depression are less common. Initially, Cade (1949) reported that lithium had no efficacy in the treatment of depression, although this opinion was reversed by the results of several open trials and finally a controlled study by Fieve et al. in 1968. Subsequently, eight placebo-controlled trials have been... 

Although studies reviewed thus far support the efficacy of lithium treatment for acute mania, the presence of concurrent depression or depressive symptoms during mania, the so-called mixed state, has been associated with poor lithium response. In 1976, Himmelhoch et al. observed that patients with mixed states were significantly less likely to demonstrate a good treatment response than were manic patients [42% vs. 81%] in a retrospective chart review of 84 consecutively referred patients with bipolar disorder. Secunda et al. [1985] reported on 18 patients with mania studied as part of the Collaborative Study of the Psychobiology of Depression and found that patients with concomitant depression and mania [n = 8] had a significantly lower rate of... 

Other factors associated with poor lithium response in mania include a history of prior lithium failure and a diagnosis of schizoaffective disorder. Bowden et al. [1994b] observed in a double-blind, placebo-controlled trial of patients with acute mania that those with a history of lithium response improved on lithium in this trial, whereas those with a history of prior lithium failure did not. Patients with a diagnosis of schizoaffective disorder may respond less well to lithium than patients with bipolar disorder, although this has not been extensively studied [Keck et al. 1994, for review]. 

From the above discussion, it appears that both lithium and valproate are equally effective pharmacological treatments for acute mania. Lithium is also established as an effective prophylactic agent, particularly for prevention of... 

Freeman TW, Clothier JL, Pazzaglia P, et al A double-blind comparison of valproate and lithium in the treatment of acute mania. Am J Psychiatry 149 108-111,1992 Frenchman IB, Prince T Clinical experience with risperidone, haloperidol, and thioridazine for dementia-associated behavioral disturbances. Int Psychogeriatr 9 431-435, 1997... 

Garza-Trevino ES Verapamil versus lithium in acute mania (NR27), in 1990 New Research Program and Abstracts, American Psychiatric Association 143rd Annual Meeting, New York, NY, May 12-17, 1990. Washington, DC, American Psychiatric Association, 1990... 

Garza-Trevino ES, Overall JE, Hollister LE Verapamil versus lithium in acute mania. Am J Psychiatry 149 121-122, 1992... 

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Lithium carbonate is completely absorbed by the gastrointestinal tract and reaches peak plasma levels in 1-2 hours. The elimination half-life is approximately 24 hours. Steady-state lithium levels are achieved in approximately 5 days. Therapeutic plasma levels range from 0.5 to 1.2 mEq/L. Lower plasma levels are associated with less troubling side effects, but levels of at least 0.8 mEq/L are often required in the treatment of acute manic episodes. Therefore, when intolerable side effects have not intervened, treatment of acute mania with lithium should not be considered a failure until plasma levels of 1.0-1.2 mEq/L have been reached and have been maintained for 2 weeks. As discussed at the end of this chapter (see Treatment of Mania or Mixed Episodes ), more severely ill patients may require combination treatment. 

Oxcarbazepine is a keto derivative of carbamazepine but offers several advantages over carbamazepine. Oxcarbazepine does not require blood cell count, hepatic, or serum drug level monitoring. It causes less cytochrome P450 enzyme induction than does carbamazepine (but may decrease effectiveness of oral contraceptives containing ethinyl estradiol and levonorgestrel). As opposed to carbamazepine, oxcarbazepine does not induce its own metabolism. These properties, combined with its similarity to carbamazepine, led many clinicians to use this medication for the treatment of bipolar disorder. Randomized controlled trials suggested efficacy in the treatment of acute mania compared with lithium and haloperidol, but these trials were quite small and did not include a placebo control (Emrich 1990). 

Dunner DL, Eieve RR Clinical factors in lithium carbonate prophylaxis failure. Arch Gen Psychiatry 30 229-233, 1974 Edmonds LD, Oakley GP Ebstein s anomaly and maternal lithium exposure during pregnancy. Teratology 41 551-552, 1990 Emrich HM Studies with oxcarbazepine (Trileptal) in acute mania. Int Clin Psychopharmacol 5 83-88, 1990... 

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