Lithium acute manic episode

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). 

Combination therapy In combination with lithium or valproate for the short-term treatment of acute manic episodes associated with bipolar I disorder. 

For more than 40 years, Li+ has been used to treat mania. While it is relatively inert in individuals without a mood disorder, lithium carbonate is effective in 60 to 80% of all acute manic episodes within 5 to 21 days of beginning treatment. Because of its delayed onset of action in the manic patient, Li+ is often used in conjunction with low doses of high-potency anxiolytics (e.g., lo-razepam) and antipsychotics (e.g. haloperidol) to stabilize the behavior of the patient. Over time, increased therapeutic responses to Li+ allow for a gradual reduction in the amount of anxiolytic or neuroleptic required, so that eventually Li+ is the sole agent used to maintain control of the mood disturbance. 

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. 

It is well established that monotherapy with various antidepressants or mood stabilizers is relatively ineffective (i.e., they are necessary but not sufficient) for treating mood disorders with associated psychosis. Thus, psychotically depressed patients are best managed with a combination of antipsychotic-antidepressant or with electroconvulsive therapy. Although antipsychotics have a more rapid onset of action than lithium in an acute manic episode, we are unaware of clinical trials that examine the differential effect of antipsychotics or lithium for nonpsychotic versus psychotic mania. This topic is discussed further in... 

Clonazepam. Case reports and one small double-blind study indicate that oral clonazepam may be useful for psychotic agitation when combined with lithium or an antipsychotic (see also the section Management of an Acute Manic Episode in Chapter 10) ( j,7.0, 175). 

Paradoxically, ECT is equally useful in both the acute manic and depressive phases of bipolar disorder, constituting the only truly bimodal therapy presently available. For example, in their literature review, Mukherjee et al. ( 51) found that ECT was associated with marked clinical improvement or remission in 80% of patients undergoing treatment for an acute manic episode. This is not the case for lithium, valproate, or CBZ, which, at best, have relatively weak acute antidepressant effects. Drug therapies may also induce a switch from a depressed to a manic phase, whereas ECT can control both phases of the illness. 

Halman et al. (491) conducted a retrospective chart review on 11 patients who were HIV-positive and presented with an acute manic episode. Whereas the six patients with abnormal MRI findings demonstrated intolerance to standard drug treatment (i.e., lithium, conventional neuroleptics), all benefited from a trial with an anticonvulsant (e.g., valproate, CBZ, clonazepam). 

Lithium is readily absorbed from the gastrointestinal tract and completely distributed throughout all the tissues in the body. During an acute manic episode, achieving blood serum concentrations between 1.0 and 1.4 mEq/L is desirable. Maintenance doses are somewhat lower, and serum concentrations that range from 0.5 to 1.3 mEq/L are optimal. 

Mania can occur in any age group. Acute manic episodes in the elderly may best be managed with high potency neuroleptics. The use of lithium is not contraindicated in the elderly provided renal clearance is reasonably normal. The dose administered should be carefully monitored, as the half-life of the drug is increased in the elderly to 36-48 hours in comparison to about 24 hours in the young adult. The serum lithium concentration in the elderly should be maintained at about 0.5 mEq/litre. It is essential to ensure that the elderly patient is not on a salt-restricted diet before starting lithium therapy. The side effects and toxicity of lithium have been discussed in detail elsewhere (see p. 198 et seq.), and, apart from an increase in the frequency of confusional states in the elderly patient, the same adverse effects can be expected as in the younger patient. 

Patients with bipolar disorder frequently require multiple medications or changes in therapy. For example, antianxiety agents are helpful in reducing anxiety and agitation, especially in patients who refuse antimanic or antipsychotic agents. Likewise an added antipsychotic is more effective than lithium alone in acute manic episodes that include significant psychomotor activity and delusions or hallucinations. Ongoing treatment with antipsychotics after the manic episode is resolved is often not necessary. However, it is not uncommon for a refractory patient to require a combination of mood stabilizers, an antidepressant, and an antipsychotic. 

Quetiapine fumarate is a dibenzapine derivative that has antipsychotic effects, apparently caused by dopamine and serotonin receptor blockade in the CNS. It is indicated in the treatment of schizophrenia and as short-term treatment of acute manic episodes associated with bipolar 1 disorder, as either monotherapy or adjunct therapy to lithium or divalproex. 

Frequent lithium levels, normally drawn twice weekly, are required in the treatment of an acute manic episode because of the possibility of a rapid rise in lithium levels as the episode begins to resolve. 

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. 

Two studies have directly addressed the question of lithium s specificity for mania or affective psychosis, as it is sometimes called. In one of these studies a group of 78 patients admitted with an acute psychotic episode diagnosed as mania, schizophrenia or schizoaffective disorder were randomised to receive lithium or chlorpromazine. The authors hypothesised that patients diagnosed as manic would respond better to lithium and those diagnosed with schizophrenia would respond better to chlorpromazine. In contrast they found that there was no difference in the effects of the different drugs on people with different diagnostic labels and that the only discernible effect was the inferiority of lithium in severely disturbed patients (Braden et al. 1982). A similar study published in 1988 claimed to show that lithium had specificity for... 

The efficacy of adding olanzapine to either valproate or lithium alone in acute manic or mixed bipolar episodes has been studied in a 6-week, double-blind, randomized, placebo-controlled trial (110). Compared with valproate or lithium alone, the addition of olanzapine provided better efficacy. Olanzapine was associated with somnolence, dry mouth, weight gain, increased appetite, tremor, and slurred speech. 

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 has been proven effective for acute and prophylactic treatment of both manic and depressive episodes in patients with bipolar illness (American Psychiatric Association 2002). However, patients with rapid-cycling bipolar disorder (i.e., patients who experience four or more mood disorder episodes per year) have been reported to respond less well to lithium treatment (Dunner and Fieve 1974 Prien et al. 1984 Wehr et al. 1988). Lithium is also effective in preventing future depressive episodes in patients with recurrent unipolar depressive disorder (American Psychiatric Association 2002) and as an adjunct to antidepressant therapy in depressed patients whose illness is partially refractory to treatment with antidepressants alone (discussed in Chapter 2). Furthermore, hthium may be useful in maintaining remission of depressive disorders after electroconvulsive therapy (Coppen et al. 1981 Sackeim et al. 2001). Lithium also has been used effectively in some cases of aggression and behavioral dyscontrol. 

A limited body of evidence indicates that lithium helps atypical mania, schizoaffective disorder, or schizophreniform disorder, both as an acute treatment and for prevention of recurrence. There are younger patients who demonstrate both schizophrenic and manic features early in the course of their illness. When in doubt about the diagnosis, lithium may be preferable for an acute episode because, if successful, it will most likely be an effective prophylaxis as well. Clearly, some patients are so disturbed that the clinician cannot wait until lithium becomes fully effective, and an antipsychotic must be added, but often it can be discontinued after a brief period to determine whether lithium alone is sufficient. 

ECT is the only clearly established bimodal therapy in that it is equally effective for both the depressed and manic phases of the disorder. Although the primary indication for ECT is a severe, unremitting, or drug-nonresponsive depressive episode, data from as early as the 1940 s support its use for the treatment of acute mania, particularly manic delirium (242, 243 and 244). Based on clinical experience, we would expect mania to remit rapidly with ECT, whereas lithium can take weeks. Hence, there may be a superiority for E(3T over lithium in the early phases of treatment. What the final outcome would be is more problematic, but clearly, there is a need to further explore the efficacy of ECT in mania. In this light, Schnur and colleagues ( 245) reported on the relationship between various pretreatment symptoms and therapeutic outcome to ECT in 18 manic patients. They found that although severity of mania was not predictive, anger, irritability, and suspiciousness were more characteristic of nonresponders to ECT. 

FIGURE 7—35. Combination treatments for bipolar disorder (bipolar combos). Combination drug treatment is the rule rather than the exception for patients with bipolar disorder. It is best to attempt monotherapy, however, with first-line lithium or valproic acid, with second-line atypical antipsychotics, or with third-line anticonvulsant mood stabilizers. A very common situation in acute treatment of the manic phase of bipolar disorder is to treat with both a mood stabilizer and an atypical antipsychotic (atypical combo). Agitated patients may require intermittent doses of sedating benzodiazepines (benzo assault weapon), whereas patients out of control may require intermittent doses of tranquil-izing neuroleptics (neuroleptic nuclear weapon). For maintenance treatment, patients often require combinations of two mood stabilizers (mood stabilizer combo) or a mood stabilizer with an atypical antipsychotic (atypical combo). For patients who have depressive episodes despite mood stabilizer or atypical combos, antidepressants may be required (antidepressant combo). However, antidepressants may also decompensate patients into overt mania, rapid cycling states, or mixed states of mania and depression. Thus, antidepressant combos are used cautiously. 

Lithium was introduced into modern psychiatric practice in the 1950s and for decades it was the only drug that was thought to have a specific effect on the psychiatric condition known as manic depression. At first it was viewed as a specific treatment for an acute episode of mania and later it was proposed to have prophylactic properties against recurrence of future episodes. It continues to be recommended for the treatment of acute mania, although it is rarely used alone in such circumstances. It is most commonly prescribed for the prophylaxis, or prevention of recurrence, of manic-depressive episodes. 

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