The most important psychotropic medication in this group is lithium. Although lithium possesses some antidepressant properties, it is not, strictly speaking, an antidepressant. Lithium’s effectiveness in the treatment of patients with bipolar disorders and other disorders of mood has revolutionized the practice of psychiatry. Since lithium’s approval by the FDA in 1969, there has been an explosion of basic and clinical research focused on its pharmacologic mechanisms and clinical use.
Mechanism of action of lithium Considerable progress has been made in advancing our understanding of its clinical use, but the underlying mechanism by which lithium works is largely unknown. Lithium exerts effects on the brain’s monoaminergic neurotransmitter concentrations at the synapse, and there is agreement that, in part, this mediates its clinical effects. Lithium has strong effects on biologic membranes, and this has been offered as an additional mechanism of action in the CNS. Lithium is unique since it both attenuates the frenetic agitation of mania and controls depression in bipolar disorders. However, the central mechanisms by which lithium exerts its clinical effects on extremes of mood are not fully understood.
Conditions in which lithium is used Lithium is the drug of choice of acute manic/hypomanic episodes and for the prevention of recurrent episodes of mania and depression in bipolar depression. Although evidence exists that lithium is a low-grade antidepressant, especially in depressions seen in bipolar disorders, it is not a drug of choice for depression per se. Lithium may also be an effective agent in the prophylaxis of recurrent unipolar depressive disorders. It has been successfully used in conjunction with neuroleptics in schizoaffective schizophrenia; there may be a subpopulation of schizophrenics responsive to lithium, although most workers feel that lithium responders are atypical bipolar patients and not schizophrenics. Finally, there are reports that lithium may be useful in alcoholism; while this is of interest, it has not been established.
Clinical use of lithium Lithium is a very safe drug with an excellent risk/benefit ratio when it is used knowledgeably. The only genuine contraindication to lithium’s use is seriously compromised renal function. The following baseline studies should be obtained before prescribing lithium: CBC, routine urinalysis with a concentration test, total thyroxine (T4), serum creatinine, electrolytes, and (for those over 40) an ECG.
Serum lithium levels peak 1 to 3 h after an oral dose, and the biologic half-life is 24 h, but this varies with age. Elderly patients frequently have a drug half-life over 30 h (requiring lower doses) and adolescent patients less than 20 h (requiring higher doses). Lithium is monitored by serum levels, which are most informative approximately 10 h after the last dose. Therapeutic efficacy in acute mania is achieved at levels between 0.8 and 1.5 meq per liter. There is rarely a necessity for patients to be treated at serum levels above 1.5 meq per liter. Lithium is always administered orally, and the oral dose range is from 600 mg to 3000 mg qd. A general rule of thumb equates a 0.2 meq per liter rise in serum level with each additional 300-mg tablet of lithium. Unless sustained release tablets are used, lithium is usually administered in a two or three times daily regimen, allowing for smooth, sustained 24-h serum levels. There is a 7- to 10-day delay between starting lithium and achieving full therapeutic effects, which often necessitates the addition of antipsychotic medications during the early phase of treating a manic patient. Patients during acute manic episodes often tolerate relatively higher doses of lithium, but once the manic episode remits it is necessary to quickly reduce the dose to prevent toxicity. When an isolated acute manic/ hypomanic episode is being treated, it is common practice to maintain the patient on lithium for 6 to 8 months following symptom disappearance. The drug is tapered gradually over 3 to 4 weeks.
Because of medical complications, clinicians have become increasingly conservative about long-term maintenance on lithium unless it is clearly justified. Generally, for maintenance therapy, the patient should have had a total of three diagnosed and treated episodes of mania and/or depression, with two of the episodes occurring within a 2-year period and the next episode during the following 2 years. In other words, the clinician should be convinced that the patient is experiencing frequent, serious, and disruptive episodes. The current maintenance strategy is to seek the lowest possible serum levels that will prevent relapse. Previously, higher serum levels were used, but now maintenance levels range from 0.4 to 1.0 meq per liter with recent evidence indicating that the relapse rate is significantly increased only when serum levels fall below 0.4 meq per liter.
Lithium’s excretion rate is very stable within each patient; as a result patients can be maintained on the same dose day in and day out, with relative certainty that stable levels are present. Patients during maintenance are seen every 3 to 6 months, and serum lithium, sodium, potassium, T4, TSH, and creatinine are monitored along with urinalysis with a concentration test. The lithium excretion pattern psychiatry is altered by conditions which change sodium concentrations, and patients on thiazide diuretics or low-salt diets should be monitored more frequently.
Side effects and interactions with other drugs Lithium’s side effects are listed in a continuum ranging from those seen relatively commonly to those which indicate lithium toxicity. Many of these are minor side effects, which appear early and disappear as time passes, but some may persist throughout treatment. As a general rule the rapid escalation of serum levels often induces side effects, especially those involving the gastrointestinal tract, and therefore smoother, more gradual serum lithium increases are desirable.
Usually the first signs of lithium toxicity are increases in the deep tendon reflexes and muscle fasciculations. Unusual degrees of sedation and cognitive disruption also may herald lithium toxicity. Lithium toxicity mimics barbiturate intoxication, and when death occurs it is secondary to respiratory depression and its complications. The treatment involves good supportive care and excellent hydration; and since lithium’s half-life is 24 h, this treatment sustains the patient while awaiting the kidney’s elimination of lithium at the predictable rate. Various methods have been tried to improve the treatment of lithium toxicity, such as increasing lithium excretion by aminophylline or alkalinizing the urine, but all have been disappointing. For life-threatening cases, the last resort is renal dialysis, but toxicity rarely progresses to the point where this intervention is needed.
Lithium’s interactions with other drugs primarily involve its reciprocal relationship with the sodium ion. Diuretics, which increase sodium excretion, can increase lithium toxicity. There have also been reports that combined neuroleptic and lithium therapy has resulted in a reversible neurotoxicity in a small number of middle-aged and older patients. Clinical observations indicate that this combination is safe and effective provided that the antipsychotic drug and lithium are used in low to moderate doses and are carefully monitored, and that the combination treatment is discontinued as soon as the lithium effect is sufficiently present for the patient to be managed without it.
Medical sequelae of lithium’s use Several medical complications can develop during lithium treatment. Because of its effect on adenylate cyclase activity, lithium inhibits the secretory function of the thyroid gland; nontoxic goiters and hypothyroidism can develop, which can be readily corrected during lithium therapy by thyroid supplement. Lithium may induce the following ECG changes especially in older patients: T-wave depression, sinus node dysfunctions, and very rarely sinoatrial block and ventricular irritability.
The most important sequelae are the renal complications. About 25 percent of patients develop some degree of antidiuretic hormone-resistant nephrogenic diabetes insipidus with polyuria and polydipsia. The lithium inhibition of adenylate cyclase activity is responsible for the disruption of renal tubular transport. These symptoms are usually completely reversible by lithium withdrawal and often can be ameliorated by reduction in serum level. The most economic and accurate method of monitoring changes in renal function during lithium treatment is by the urine concentration test and serum creatinine level. Urine concentration levels below a specific gravity of 1.025 indicate an early renal effect, and a creatinine clearance test should be obtained. If creatinine clearance is abnormal, the patient’s clinical condition is reevaluated and termination of the lithium treatment should be considered. There have been reports of renal focal necrosis and interstitial fibrosis in a few long-term lithium patients, and there is evidence, by biopsy, for an increased basal rate of renal pathology among patients with affective disorders. Nonetheless, this nonspecific renal lesion does appear with a higher degree of frequency in patients receiving long-term lithium. Therefore, many experienced clinicians do not maintain patients on lithium for more than 5 years without a drug-free trial.
Evidence has emerged linking the more serious renal complications to increased episodes of lithium toxicity and possibly to prolonged combined use of lithium and neuroleptics. While good clinical practice should obviate lithium toxicity, it may be equally important to avoid extremes of high and low serum lithium levels during the day. Despite these concerns, lithium remains one of the most important and effective psychotropic agents with an excellent risk/benefit ratio.
Carbamazepine and other mood-stabilizing medications The anticonvulsant carbamazepine has, in controlled trials, been used successfully in the treatment of manic and, to a lesser extent, depressive episodes in bipolar patients. There is also growing evidence that a significant number of bipolar patients who do not respond to lithium benefit from carbamazepine treatment, and that the combination of lithium and carbamazepine may be therapeutically additive. The drug regimen for bipolar disorders is initated beginning with 200 mg bid administered orally increasing to 600 to 1600 mg daily in divided doses with the therapeutic blood levels ranging from 8 to 12 mg/dL. Carbamazepine is not a completely benign drug; side effects include nausea, blurred vision, and ataxia, and more importantly there have been cases of aplastic anemia reported. Patients treated with carbamazepine must be monitored for renal, liver, and bone marrow functions during the time they are on the medication. There are also reports of reversible CNS toxicity when this drug is combined with lithium, therefore patients on this combination should be monitored carefully. Valproic acid, the drug of choice in certain seizure disorders, has also been reported to prevent recurrence of manic episodes in a small number of bipolar patients. The development of this new class of psychotropic compounds is very promising and may herald the future development of a new and useful group of medications.