Lithium acute effects

Matrila MJ, Aranko K, Seppala T Acute effects of huspirone and alcohol on psychomotor skills. J Clin Psychiatry 43 56-60, 1982 McMahon T, Andersen R, Merten P, et al Protein kinase C epsilon mediates upregu-lation ofN-type calcium channels by ethanol. Mol Pharmacol 37 33-58, 2000 Merry], Reynolds CM, Bailey], et al Prophylactic treatment of alcoholism by lithium carbonate. Lancet 2 481 82, 1976... 

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. 

If we dehne a mood stabilizer as a medication that is both an effective anti-manic and antidepressant, then lithium arguably remains to this day the prototypical mood stabilizer. Lithium not only reduces the symptoms of acute BPAD, it also prevents the recurrence of additional mood episodes. Despite the fact that lithium has revolutionized the treatment of BPAD and remains nearly 50 years after its introduction as the single best treatment for many patients with BPAD, there is still no consensus as to how it works. Lithium exerts effects on several neurotransmitter systems (e.g., serotonin, dopamine, norepinephrine, acetylcholine), on second messenger systems inside the nerve cell, and on nerve cell gene expression. Yet, precisely how these varied effects produce lithium s therapeutic benefit remains unclear. 

Lithium not only treats acute episodes of mania and hypomania but was the first psychotropic agent shown to prevent recurrent episodes of illness. Lithium may also be effective in treating and preventing episodes of depression in patients with bipolar disorder. It is least effective for rapid cycling or mixed episodes. Overall, lithium is effective in only 40 to 50% of patients. Furthermore, many patients are unable to tolerate it because of numerous side effects, including gastrointestinal symptoms... 

I In chnical trials lithium is effective in 60-80% of acutely ill patients. 

A study in 14 treatment-resistant depressed patients aged between 61 and 82 found that 7 showed eomplete improvement and 3 showed partial improvement, 3 to 21 days after lithium was added to treatment with the tricyclic or related antidepressants. Lithium adverse effects occurred in 6 patients 4 of whom stopped lithium as a result. One of them was successfully restarted at a lower dose. Tremor was the most frequent adverse effect, and reversible neurotoxicity with a stroke-like syndrome was the most severe. The antidepressants used were amitriptyline, doxepin, maprotiline and trazodone. A meta-analysis of 9 studies on the acute treatment of unipolar or bipolar depression indicated that the combined use of a mood stabiliser (lithium in 6 studies) and a tricyclic antidepressant was associated with an increased risk of switches into (hypo)mania, when compared with a mood stabiliser alone. It was suggested that monotherapy with a mood stabiliser should be tried to see if it is effective, before adding an antidepressant. Tricyclics were considered to be second-line antidepressants, with SSRIs the preferred choice. ... 

Treatment of Manic—Depressive Illness. Siace the 1960s, lithium carbonate [10377-37-4] and other lithium salts have represented the standard treatment of mild-to-moderate manic-depressive disorders (175). It is effective ia about 60—80% of all acute manic episodes within one to three weeks of adrninistration. Lithium ions can reduce the frequency of manic or depressive episodes ia bipolar patients providing a mood-stabilising effect. Patients ate maintained on low, stabilising doses of lithium salts indefinitely as a prophylaxis. However, the therapeutic iadex is low, thus requiring monitoring of semm concentration. Adverse effects iaclude tremor, diarrhea, problems with eyes (adaptation to darkness), hypothyroidism, and cardiac problems (bradycardia—tachycardia syndrome). 

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. 

Lamotrigine is effective for the maintenance treatment of bipolar disorder. It is more effective for depression relapse prevention than for mania relapse. Its primary limitation as an acute treatment is the time required for titration to an effective dosage. In addition to maintenance monotherapy, it is sometimes used in combination with lithium or divalproex, although combination with divalproex increases the risk of rash, and lamotrigine dosage adjustment is required.37... 

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). 

Carbamazepine is usually reserved for lithium-refractory patients, rapid cyclers, or mixed states. It has some acute antimanic effects, but its longterm effectiveness is unclear. 

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. 

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. 

Consequently, the choice for a primary mood stabilizer in acute therapy now includes lithium, valproate, carbamazepine, and the atypical antipsychotics. Among these, lithium and valproate remain first-line agents. Valproate and lithium are probably equally effective in the treatment of classic euphoric mania, but valproate and, for that matter, carbamazepine do not appear to provide the same degree of protec-... 

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. 

Antipsychotic drugs, such as flupentixol and haloperidol are the mainstay of treatment for acute attacks of mania. Lithium is not indicated as it may take a few days before the drug exerts an effect. Lithium may be given concomitantly with an antipsychotic drug. 

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