Classic euphoric mania often presents as a social emergency and is preferably managed on an inpatient basis. Lithium works best in uncomplicated euphoric mania. After baseline laboratory tests (CBC, urinalysis, thyroxine, TSH, serum electrolytes, creatinine, and BUN) are performed, lithium carbonate 300 mg po bid or tid is given, and the dose is increased over 7 to 10 days until a blood level of 0.8 to 1.2 mEq/L is reached. Patients with acute mania have a high tolerance for lithium and preferentially retain it during the first 10 days while excreting Na+. A regular diet is recommended. Teenagers, whose glomerular function is excellent, need higher doses of lithium to achieve the same level; elderly patients need lower doses. Because lithium’s onset of action has a 4- to 10-day latency period, haloperidol 5 to 10 mg po or IM (up to 30 mg/day) or another antipsychotic is sometimes also necessary initially; it is given as needed until the manic stage is controlled. For extremely hyperactive psychotic patients with poor food and fluid intake, giving an antipsychotic IM with supportive care for a week before initiating lithium is preferable. Lorazepam or clonazepam 2 to 4 mg tid IM or po given early in acute management can boost the antipsychotic’s effects so that its dose can be reduced.
Lithium is a naturally occurring alkali metal. Its proposed therapeutic mechanisms include reducing neuronal Ca++ mobilization via activation of the membrane phosphoinositide signaling system; hyperpolarizing the neuronal membrane; increasing presynaptic deamination of norepinephrine and decreasing its release; blocking β-adrenergic receptor-stimulated adenylate cyclase; decreasing dopamine turnover; increasing tryptophan uptake and consequent stabilization of 5-HT synaptic dynamics; inhibiting the synthesis of prostaglandin E1; and slowing biologic rhythms. Although lithium attenuates bipolar mood swings, it has no effect on normal mood. It also appears to have an antiaggressive action, but whether this action occurs in persons without a bipolar disorder is unclear. Lithium does not directly produce sedation or, ordinarily, cognitive impairment; if the latter occurs, lithium-induced hypothyroidism must be ruled out.
Two thirds of patients with uncomplicated bipolar disorder respond to lithium. Predictors of a good response include a euphoric manic picture as part of a primary mood disorder,
< 2 episodes a yr, and a personal and family history of response to lithium. Lithium is less effective in patients with mixed states, rapid-cycling forms of bipolar disorder, comorbid anxiety, substance abuse, or a neurologic disorder.
Lithium, usually given as the carbonate, is rapidly and completely absorbed via the GI tract and peaks in serum in 90 min. It is not biotransformed; 95% is excreted via the kidneys, a process enhanced by a Na+ load. Thus, use of diuretics or disorders that lead to Na+ loss pose a risk of toxicity. The elimination half-life is 24 h, which tends to increase with age. Steady state is reached in 4 to 6 days, producing a delay in acute antimanic action. During a manic episode, the patient retains lithium and excretes Na+; oral dosage and the blood level need to be higher during acute treatment than during maintenance prophylaxis. Lithium has a narrow therapeutic index, and lithium blood levels must be strictly monitored.
The most common
acute, mild adverse effects of lithium are fine tremor, fasciculation, nausea, diarrhea, polyuria, thirst, polydipsia, and weight gain (partly attributed to drinking high-calorie beverages). These effects are usually transient and often respond to decreasing the dose slightly, dividing the dose (eg, tid), or using slow-release forms. Once dosage is established, the entire dose should be given after the evening meal. This dosing may improve compliance, and the troughs in blood levels are believed to protect the kidneys. A β-blocker, such as atenolol 25 mg po daily or bid, can control incapacitating tremor.
Toxic effects are manifested initially by gross tremor, increased deep tendon reflexes, persistent headache, vomiting, and mental confusion and may progress to stupor, seizures, and cardiac arrhythmias. Except for overdose, lithium toxicity is more likely in elderly patients and in patients with decreased creatinine clearance or with Na+ loss, which may result from fever, vomiting, diarrhea, or use of diuretics. NSAIDs other than aspirin may contribute to hyperlithemia. None of these situations is an absolute contraindication to lithium. However, renal function should be assessed at baseline and monitored frequently (measuring 24-h urine volume, urine concentration, and creatinine clearance), and blood lithium should be measured frequently. Doses may have to be decreased, and dietary sodium supplementation given. TSH response to TRH stimulation and other thyroid indexes should be checked when thyroid disease is suspected. In patients with relatively stable mood, blood lithium levels and weight should be measured quarterly, and creatinine and TSH should be measured biannually.
Common chronic adverse effects of lithium are exacerbation of acne and psoriasis, hypothyroidism, and nephrogenic diabetes insipidus (which may respond to dose reduction or temporary interruption of lithium). Patients with a history of parenchymal kidney disease may be at risk of structural damage to the distal tubule.
Acute manic psychosis is being increasingly managed with the atypical antipsychotics risperidone (usually 4 to 8 mg/day po) and olanzapine (usually 5 to 10 mg/day po), because of their minimal risk of extrapyramidal adverse effects.
Anticonvulsants, especially valproate and carbamazepine, are also widely used. Their precise therapeutic action in bipolar disorder is unknown but may involve GABAergic mechanisms and ultimately G-protein signaling systems. Their main advantages over lithium include a wider therapeutic margin and lack of renal toxicity. Valproate (especially as divalproex, which has good GI tolerability) is approved for acute mania. Unlike carbamazepine, divalproex does not suppress the bone marrow, but it may cause liver damage in children. Divalproex may cause weight gain, alopecia, and tremor in adults. Common adverse effects of carbamazepine include sedation, vertigo, ataxia, diplopia, and pruritic rashes. Carbamazepine induces its own catabolism, necessitating frequent increases in dose during the first months of treatment; divalproex does not.
Carbamazepine (up to about 28 mg/kg/day po) is useful for patients with mood-incongruent psychotic features. Divalproex (up to 60 mg/kg/day po) is preferred by many clinicians in the USA as a mood stabilizer for acute management, especially for hostile, irritable manic patients. “Depakotization” (escalation of dose in a few days) may work rapidly.
Although dysphoric mania can be managed with an antipsychotic, divalproex (up to 60 mg/kg/day po) is the treatment of choice, especially when psychotic features are present. The atypical antipsychotic clozapine can greatly benefit patients with refractory mixed-manic disorder but is associated with the risk of agranulocytosis; olanzapine may be an alternative without such risk. Electroconvulsive therapy is reserved for the most fulminant cases of mania and mixed states.
In patients with bipolar II disorder, any effective antidepressant may cause treatment-emergent hypomania, but bupropion and paroxetine appear least likely to cause it. Tranylcypromine is reserved for cases refractory to bupropion or paroxetine. These antidepressants can be used as monotherapy for patients who are relatively stable between episodes and who have infrequent relapses. For most other patients with bipolar II disorder, mood stabilizers are also needed. Lithium has a modest acute antidepressant effect in the depressive phase of bipolar disorder and can be given alone or with any antidepressant, but preferably with one that is least likely to induce cycling. Augmenting doses of lithium are 600 to 1200 mg/day. Antidepressants can also be augmented with divalproex 500 to 1000 mg/day. Some patients respond to a combination of lithium and divalproex.
Treatment of an isolated manic episode should continue for at least 6 mo. Most manias recur as part of a recurrent bipolar disorder. Maintenance therapy with lithium should be initiated after two classic bipolar episodes < 3 yr apart.
Levels should be maintained between 0.3 and 0.8 mEq/L, usually by giving two to five 300-mg capsules/day. Antidepressants should not be used during prophylaxis unless breakthrough depression is severe and, if used, should be given only for 4 to 12 wk. When disruptive psychomotor acceleration or mixed states supervene, thioridazine 50 to 300 mg/day po for 1 to 4 wk can restabilize the patient; olanzapine 5 to 10 mg/day may be a viable alternative.
In the noncompliant, cantankerous manic patient, a depot phenothiazine, such as fluphenazine decanoate 12.5 to 25 mg IM q 3 to 4 wk, is customarily given. In patients with bipolar disorder and mood-incongruent psychotic features beyond the usual boundaries of “pure” mood disorder, intermittent courses of depot antipsychotics are often necessary.
Anticonvulsants may be easier to use than lithium. Carbamazepine 400 to 2000 mg/day po (blood level: 6 to 12 mg/L) is effective. Because of the risk of agranulocytosis, clinical vigilance and periodic CBCs are prudent. Divalproex 400 to 2000 mg/day (blood level: 40 to 140 mg/L) does not cause hematologic abnormalities, but hepatic function should be checked periodically. Because divalproex is less likely to cause mental obtundation, it is often preferred for prophylaxis.
The anticonvulsant lamotrigine (up to 200 mg/day po) is particularly useful for the depressive phase of bipolar disorder and for severe affective storms in some patients with borderline personality. Treatment should begin with 25 mg; the dose is increased gradually to avoid pruritic rashes, which occur early in 5 to 10% of patients. Discontinuation as soon as a rash occurs averts the rare but grave Stevens-Johnson syndrome. Gabapentin appears to have few adverse effects but is reserved for refractory cases as an augmenting drug.