Treatment of Mania

Antimanic Mood-Stabilizing Agents: Lithium

Lithium carbonate was introduced into psychiatry in 1949 for the treatment of mania (Cade, 1949; seeMitchell et al., 1999). However, it was not used for this purpose in the United States until 1970, in part due to concerns of American physicians about the safety of this treatment following reports of severe intoxication with lithium chloride from its uncontrolled use as a substitute for sodium chloride in patients with cardiac disease. Evidence for both the safety and the efficacy of lithium salts in the treatment of mania and the prevention of recurrent attacks of manic-depressive illness is both abundant and convincing (Davis et al., 1999; Mitchell et al., 1999). In recent years, the limitations and side effects of lithium salts have become increasingly well appreciated, and efforts to find alternative antimanic or mood-stabilizing agents have intensified (seeDavis et al., 1999; Goodwin and Jamison, 1990). The most successful alternatives or adjuncts to lithium to date are the anticonvulsants carbamazepine and valproic acid (Post, 2000).

History

Lithium urate is soluble, and lithium salts were used in the nineteenth century as a treatment of gout. Lithium bromide was employed in that era as a sedative (including its use in manic patients) and as a putative anticonvulsant. Thereafter, lithium salts were little used until the late 1940s, when lithium chloride was employed as a salt substitute for cardiac and other chronically ill patients. This ill-advised use led to several reports of severe intoxication and death and to considerable notoriety concerning lithium salts within the medical profession. Cade, in Australia, while looking for toxic nitrogenous substances in the urine of mental patients for testing in guinea pigs, administered lithium salts to the animals in an attempt to increase the solubility of urates. Lithium carbonate made the animals lethargic, and, in an inductive leap, Cade gave lithium carbonate to several agitated or manic psychiatric patients as early as 1948 (seeMitchell et al., 1999). In 1949, he reported that this treatment seemed to have a specific effect in mania (Cade, 1949).

Chemistry

Lithium is the lightest of the alkali metals (group Ia); the salts of this monovalent cation share some characteristics with those of Na⁺ and K⁺. Li⁺ is readily assayed in biological fluids by flame-photometric and atomic-absorption spectrophotometric methods, and it can be detected in brain tissue by magnetic resonance spectroscopy (Riedl et al., 1997). Traces of the ion occur normally in animal tissues, but it has no known physiological role. Lithium carbonate and lithium citrate currently are in therapeutic use in the United States.

Pharmacological Properties

Therapeutic concentrations of lithium ion (Li⁺) have almost no discernible psychotropic effects in normal individuals. It is not a sedative, depressant, or euphoriant, and this characteristic differentiates Li⁺ from other psychotropic agents. The general biology and pharmacology of Li⁺ have been reviewed in detail elsewhere (Jefferson et al., 1983). The precise mechanism of action of Li⁺ as a mood-stabilizing agent remains unknown, although many cellular actions of Li⁺ have been characterized (Manji et al., 1999b).

An important characteristic of Li⁺ is that it has a relatively small gradient of distribution across biological membranes, unlike Na⁺ and K⁺; although it can replace Na⁺ in supporting a single action potential in a nerve cell, it is not an adequate 'substrate' for the Na⁺ pump and it cannot, therefore, maintain membrane potentials. It is uncertain whether or not important interactions occur between Li⁺ (at therapeutic concentrations of about 1 mEq per liter) and the transport of other monovalent or divalent cations by nerve cells.

Central Nervous System

In addition to the possibility of altered distribution of cations in the CNS, much attention has centered on the effects of low concentrations of Li⁺ on the metabolism of the biogenic monoamines that have been implicated in the pathophysiology of mood disorders as well as on second-messenger and other intracellular molecular mechanisms involved in signal transduction and in cell and gene regulation (Jope, 1999; Lenox and Manji, 1998; Manji et al., 1999a,b).

In animal brain tissue, Li⁺ at concentrations of 1 to 10 mEq per liter inhibits the depolarization-provoked and Ca²⁺-dependent release of norepinephrine and dopamine, but not serotonin, from nerve terminals (Baldessarini and Vogt, 1988). Li⁺ may even enhance the release of serotonin, especially in the limbic system, at least transiently (Treiser et al., 1981; Manji et al., 1999a,b; Wang and Friedman, 1989). The ion has limited effects on catecholamine-sensitive adenylyl cyclase activity or on the binding of ligands to monoamine receptors in brain tissue (Manji et al., 1999b; Turkka et al., 1992), although there is some evidence that Li⁺ can inhibit the effects of receptor-blocking agents that cause supersensitivity in such systems (Bloom et al., 1983). Li⁺ can modify some hormonal responses mediated by adenylyl cyclase or phospholipase C in other tissues, including the actions of antidiuretic and thyroid-stimulating hormones on their peripheral target tissues (seeManji et al., 1999b; Urabe et al., 1991). In part, the actions of Li⁺ may reflect its ability to interfere with the activity of both stimulatory and inhibitory GTP-binding proteins (G_s and G_i) by keeping them in their less active trimer state (Jope, 1999; Manji et al., 1999b).

A consistently reported, selective action of Li⁺ is to inhibit inositol monophosphatase (Berridge et al., 1989) and thus interfere with the phosphatidylinositol pathway (seeFigure 201). This effect can lead to decreases in cerebral inositol concentrations, which can be detected with magnetic resonance spectroscopy in human brain tissue (Manji et al., 1999a,b). However, the physiological consequences of this effect remain uncertain, including interference with neurotransmission mechanisms that are mediated by the phosphatidylinositol pathway (Lenox and Manji, 1998; Manji et al., 1999b).

Lithium treatment also leads to consistent decreases in the functioning of protein kinases in brain tissue, including calcium-activated, phospholipid-dependent protein kinase C (PKC) (Jope, 1999; Lenox and Manji, 1998), particularly subtypes and (Manji et al., 1999b). This effect also is shared with valproic acid (particularly for PKC) but not carbamazepine, among other proposed antimanic or mood-stabilizing agents (Manji et al., 1993). In turn, these effects may alter the release of amine neurotransmitters and hormones (Wang and Friedman, 1989; Zatz and Reisine, 1985) as well as the activity of tyrosine hydroxylase (Chen et al., 1998). A major substrate for cerebral PKC is the myristolated alanine-rich PKC-kinase substrate protein MARCKS, which has been implicated in synaptic and neuronal plasticity. Its expression is reduced by treatment with both Li⁺ and valproate, but not by carbamazepine or by antipsychotic, antidepressant, or sedative drugs (Watson and Lenox, 1996; Watson et al., 1998). Another important protein kinase that is inhibited by both Li⁺ and valproate treatment is glycogen synthase kinase-3 (GSK-3), which is involved in neuronal and nuclear regulatory processes, including limiting expression of the regulatory protein -catenin (Chen et al., 1999b; Manji et al., 1999b).

Li⁺ and valproic acid both interact with nuclear regulatory factors that affect gene expression. Such effects include increasing DNA binding of transcription-regulatory-factor-activator protein-1 (AP-1) as well as altered expression of other transcription regulatory factors, including AMI-1 or PEBP-2 (Chen et al., 1999a,c).

Finally, treatment with both Li⁺ and valproate has been associated with increased expression of the regulatory protein B-cell lymphocyte protein-2 (bcl-2), which is associated with protection against neuronal degeneration (Chen et al., 1999c, Manji et al., 1999c). The significance of these several interactions of mood-stabilizing agents with cell-regulatory factors remains to be clarified.

Absorption, Distribution, and Excretion

Li⁺ is absorbed readily and almost completely from the gastrointestinal tract. Complete absorption occurs in about 8 hours, with peak concentrations in plasma occurring 2 to 4 hours after an oral dose. Slow-release preparations of lithium carbonate provide a slower rate of absorption and thereby minimize early peaks in plasma concentrations of the ion. However, absorption can be variable, and the incidence of lower intestinal tract symptoms may be increased. Li⁺ initially is distributed in the extracellular fluid and then gradually accumulates in various tissues. The concentration gradient across plasma membranes is much smaller than those for Na⁺ and K⁺. The final volume of distribution (0.7 to 0.9 liter per kilogram) approaches that of total body water and is much lower than that of most other psychotropic agents, which are lipophilic and protein bound. Passage through the bloodbrain barrier is slow, and when a steady state is achieved, the concentration of Li⁺ in the cerebrospinal fluid is about 40% to 50% of the concentration in plasma. The ion does not bind appreciably to plasma proteins. The kinetics of Li⁺ can be monitored in human brain with magnetic resonance spectroscopy (Plenge et al., 1994).

Approximately 95% of a single dose of Li⁺ is eliminated in the urine. From one- to two-thirds of an acute dose is excreted during a 6- to 12-hour initial phase of excretion, followed by slow excretion over the next 10 to 14 days. The elimination half-life averages 20 to 24 hours. With repeated administration, Li⁺ excretion increases during the first 5 to 6 days until a steady state is reached between ingestion and excretion. When therapy with Li⁺ is stopped, there is a rapid phase of renal excretion followed by a slow 10- to 14-day phase. Since 80% of the filtered Li⁺ is reabsorbed by the proximal renal tubules, clearance of Li⁺ by the kidney is about 20% of that for creatinine, ranging between 15 and 30 ml per minute. This is somewhat lower in elderly patients (10 to 15 ml per minute). Loading with Na⁺ produces a small enhancement of Li⁺ excretion, but Na⁺ depletion promotes a clinically important degree of retention of Li⁺.

Because of the low therapeutic index for Li⁺ (as low as 2 or 3), concentrations in plasma or serum are determined to assure safe use of the drug. In the treatment of acutely manic patients, one can postpone treatment with Li⁺ until some degree of behavioral control and metabolic stability has been attained with antipsychotics, sedatives, or anticonvulsants. The concentration of Li⁺ in blood usually is measured at a trough of the oscillations that result from repetitive administration, but the peaks can be two or three times higher at steady state. When the peaks are reached, intoxication may result, even when concentrations in morning samples of plasma are in the acceptable range of around 1 mEq per liter. Single daily doses, with relatively large oscillations of the plasma concentration of Li⁺, may reduce the polyuria sometimes associated with this treatment, but the average reduction is quite small (Baldessarini et al., 1996b; Hetmar et al., 1991). Nevertheless, because of the low margin of safety of Li⁺ and because of its short half-life during initial distribution, divided daily doses often are used, and even slow-release formulations usually are given twice daily. Nonetheless, some physicians administer Li⁺ once per day and achieve good therapeutic responses safely.

Although the pharmacokinetics of Li⁺ vary considerably among subjects, the volume of distribution and clearance are relatively stable in an individual patient. However, a well-established regimen can be complicated by occasional periods of Na⁺ loss, as may occur with an intercurrent medical illness or with losses or restrictions of fluids and electrolytes; heavy sweating may be an exception due to a preferential secretion of Li⁺ over Na⁺ in sweat (Jefferson et al., 1982). Hence, patients taking Li⁺ should have plasma concentrations checked at least occasionally.

Most of the renal tubular reabsorption of Li⁺ seems to occur in the proximal tubule. Nevertheless, Li⁺ retention can be increased by any diuretic that leads to depletion of Na⁺, particularly the thiazides (Siegel et al., 1998). Renal excretion can be increased by administration of osmotic diuretics, acetazolamide, or aminophylline, although this is of little help in the management of Li⁺ intoxication. Triamterene may increase excretion of Li⁺, suggesting that some reabsorption of the ion may occur in the distal nephron; however, spironolactone does not increase the excretion of Li⁺. Some nonsteroidal antiinflammatory agents can facilitate renal proximal tubular resorption of Li⁺ and thereby increase concentrations in plasma to toxic levels; this interaction appears to be particularly strong with indomethacin; it may occur with ibuprofen and naproxen, and possibly less so with sulindac and aspirin (seeSiegel et al., 1998). Also a potential drugdrug interaction can occur between Li⁺ and angiotensin converting enzyme inhibitors (seeChapter 31: Renin and Angiotensin).

Less than 1% of ingested Li⁺ leaves the human body in the feces, and 4% to 5% is secreted in sweat. Li⁺ is secreted in saliva in concentrations about twice those in plasma, while its concentration in tears is about equal to that in plasma. Since the ion also is secreted in human milk, women receiving Li⁺ should not breast-feed infants.

Toxic Reactions and Side Effects

The occurrence of toxicity is related to the serum concentration of Li⁺ and its rate of rise following administration. Acute intoxication is characterized by vomiting, profuse diarrhea, coarse tremor, ataxia, coma, and convulsions. Symptoms of milder toxicity are most likely to occur at the absorptive peak of Li⁺ and include nausea, vomiting, abdominal pain, diarrhea, sedation, and fine tremor. The more serious effects involve the nervous system and include mental confusion, hyperreflexia, gross tremor, dysarthria, seizures, and cranial-nerve and focal neurological signs, progressing to coma and death; sometimes, neurological damage may be irreversible. Other toxic effects are cardiac arrhythmias, hypotension, and albuminuria. Side effects including nausea, diarrhea, daytime drowsiness, polyuria, polydipsia, weight gain, fine hand tremor, and dermatological reactions including acne are common even in therapeutic dose ranges (Baldessarini et al., 1996b).

Therapy with Li⁺ is associated initially with a transient increase in the excretion of 17-hydroxycorticosteroids, Na⁺, K⁺, and water. This effect usually is not sustained beyond 24 hours. In the subsequent 4 to 5 days, the excretion of K⁺ becomes normal, Na⁺ is retained, and in some cases pretibial edema forms. Na⁺ retention has been associated with increased aldosterone secretion and responds to administration of spironolactone; however, this maneuver incurs the risk of promoting the retention of Li⁺ and increasing its concentration in plasma. Edema and Na⁺ retention frequently disappear spontaneously after several days.

A small number of patients treated with Li⁺ develop a benign, diffuse, nontender thyroid enlargement suggestive of compromised thyroid function. This effect may be associated with previous thyroiditis, particularly in middle-aged women. In patients treated with Li⁺, thyroid uptake of ¹³¹I is increased, plasma proteinbound iodine and free thyroxine tend to be slightly low, and thyroid-stimulating hormone (TSH) secretion may be moderately elevated. These effects appear to result from interference with the iodination of tyrosine and, therefore, the synthesis of thyroxine. However, patients usually remain euthyroid, and obvious hypothyroidism is rare. In patients who do develop goiter, discontinuation of Li⁺ or treatment with thyroid hormone results in shrinkage of the gland. Adding supplemental triiodothyronine (T₃) to bipolar disorder patients with low-normal thyroid hormone levels and continued depression or anergy may be useful clinically, but proposed use of high doses of thyroxin (T₄) to control rapid-cycling bipolar disorder is not established as a safe practice (Bauer and Whybrow, 1990; Baumgartner et al., 1994; Lasser and Baldessarini, 1997).

Polydipsia and polyuria occur in patients treated with Li⁺, occasionally to a disturbing degree. Acquired nephrogenic diabetes insipidus can occur in patients maintained at therapeutic plasma concentrations of the ion (Siegel et al., 1998). Typically, mild polyuria appears early in treatment and then disappears. Late-developing polyuria is an indication to evaluate renal function, lower the dose of Li⁺, or consider addition of a thiazide diuretic or a K⁺-sparing agent such as amiloride to counteract the polyuria (Batlle et al., 1985; Kosten and Forrest, 1986). The polyuria disappears with termination of Li⁺ therapy. The mechanism of this effect may involve inhibition of the action of antidiuretic hormone (ADH) on renal adenylyl cyclase as reflected in elevated circulating ADH and lack of responsiveness to exogenous antidiuretic peptides (Boton et al., 1987; Siegel et al., 1998). The result is decreased ADH stimulation of renal reabsorption of water. However, Li⁺ also may act at steps beyond cyclic AMP synthesis to alter renal function. The effect of Li⁺ on water metabolism is not sufficiently predictable to be therapeutically useful in treatment of the syndrome of inappropriate secretion of ADH. Evidence of chronic inflammatory changes in biopsied renal tissue has been found in a minority of patients given Li⁺ for prolonged periods. Since progressive, clinically significant impairment of renal function is rare, these are considered incidental findings by most experts; nevertheless, plasma creatinine and urine volume should be monitored during long-term use of Li⁺ (Boton et al., 1987; Hetmar et al., 1991).

Li⁺ also has a weak action on carbohydrate metabolism that resembles that of insulin. In rats, Li⁺ causes an increase in skeletal muscle glycogen accompanied by severe depletion of glycogen from the liver.

The prolonged use of Li⁺ causes a benign and reversible depression of the T wave of the ECG, an effect not related to depletion of Na⁺ or K⁺.

Li⁺ routinely causes EEG changes characterized by diffuse slowing, widened frequency spectrum, and potentiation with disorganization of background rhythm. Seizures have been reported in nonepileptic patients with plasma concentrations of Li⁺ in the therapeutic range. Myasthenia gravis may worsen during treatment with Li⁺ (Neil et al., 1976).

A benign, sustained increase in circulating polymorphonuclear leukocytes occurs during the chronic use of Li⁺ and is reversed within a week after termination of treatment.

Allergic reactions such as dermatitis and vasculitis can occur with Li⁺ administration. Worsening of acne vulgaris is a common problem, and some patients may experience mild alopecia.

In pregnancy, concomitant use of natriuretics and low-Na⁺ diets can contribute to maternal and neonatal Li⁺ intoxication, and during postpartum diuresis one can anticipate potentially toxic retention of Li⁺ by the mother. The use of Li⁺ in pregnancy has been associated with neonatal goiter, CNS depression, hypotonia, and cardiac murmur. All of these conditions reverse with time. The use of Li⁺ in early pregnancy may be associated with an increase in the incidence of cardiovascular anomalies of the newborn, especially Ebstein's malformation (Cohen et al., 1994). The basal risk of Ebstein's anomaly (malformed tricuspid valve, usually with a septal defect) of about 1 per 20,000 live births may rise severalfold, but probably not above 1 per 5000. Moreover, the defect typically is detectable in utero by ultrasonography and often is surgically correctable after birth. In contrast, the antimanic anticonvulsants valproic acid and perhaps carbamazepine have an associated risk of irreversible spina bifida that may exceed 1 per 100 and so do not represent a rational alternative (Viguera et al., 2000). In balancing the risk vs. benefit of using Li⁺ in pregnancy, it is important to evaluate the risk of untreated manic-depressive disorder and to consider conservative measures, such as deferring intervention until symptoms arise or using a safer treatment, such as a neuroleptic or ECT (seeCohen et al., 1994; Viguera et al., 2000).

Treatment of Lithium Intoxication

There is no specific antidote for Li⁺ intoxication, and treatment is supportive. Vomiting induced by rapidly rising plasma Li⁺ may tend to limit absorption, but fatalities have occurred. Care must be taken to assure that the patient is not Na⁺- and water-depleted. Dialysis is the most effective means of removing the ion from the body and should be considered in severe poisonings, i.e., in patients exhibiting symptoms of toxicity or patients with serum Li⁺ concentrations greater than 4.0 mEq/l in acute overdoses or greater than 1.5 mEq/l in chronic overdoses.

Interactions with Other Drugs

Interactions between Li⁺ and diuretics and nonsteroidal antiinflammatory agents have been discussed above (seeSiegel et al., 1998). Thiazide diuretics as well as amiloride may correct the nephrogenic diabetes insipidus caused by Li⁺ (Boton et al., 1987). Retention of Li⁺ may be limited during administration of the weakly natriuretic agent amiloride as well as the loop diuretic furosemide, which also reduce the risk of toxic effects of hypokalemia with excessive circulating levels of Li⁺. Furosemide also may have lesser interactions with Li⁺ than do the thiazides. Amiloride and other diuretic agents (sometimes with reduced doses of Li⁺) have been used safely to reverse the syndrome of diabetes insipidus occasionally associated with Li⁺ therapy (Batlle et al., 1985; Boton et al., 1987; seeChapter 29: Diuretics). Li⁺ often is used in conjunction with antipsychotic, sedative, antidepressant, and anticonvulsant drugs. A few case reports have suggested a risk of increased CNS toxicity with Li⁺ when it is combined with haloperidol; however, this finding is at variance with many years of experience with this combination. Antipsychotic drugs may prevent nausea, which can be a sign of Li⁺ toxicity. There is, however, no absolute contraindication to the concurrent use of Li⁺ and psychotropic drugs. Finally, anticholinergic and other agents that alter gastrointestinal motility also may alter Li⁺ concentrations in blood over time.

Therapeutic Uses

The use of Li⁺ in bipolar disorder (manic-depressive illness) is discussed below. Treatment with Li⁺ is conducted ideally in cooperative patients with normal Na⁺ intake and with normal cardiac and renal function. Occasionally, patients with severe systemic illnesses can be treated with Li⁺, provided that the indications are sufficiently compelling. Treatment of acute mania and the prevention of recurrences of mania in otherwise-healthy adults or adolescents currently are the only uses approved by the United States Food and Drug Administration (FDA), even though the primary indication for Li⁺ treatment is for long-term prevention of recurrences of major affective illness, particularly both mania and depression in bipolar I or II disorders (seeBaldessarini et al., 1996b; Goodwin and Jamison, 1990; Shulman et al., 1996; Tondo et al., 1998a). In addition, on the basis of compelling evidence of efficacy, Li⁺ sometimes also is used as an alternative or adjunct to antidepressants in severe recurrent depression, as a supplement to antidepressant treatment in acute major depression, or as an adjunct when later response to an antidepressant alone is unsatisfactory (seeAustin et al., 1991; Bauer and Dpfmer, 1999).

These beneficial effects in major depression may be associated with the presence of clinical or biological features also found in bipolar affective disorder (seeGoodwin and Jamison, 1990; Baldessarini et al., 1996b). Growing clinical experience also suggests the utility of Li⁺ in the management of childhood disorders that are marked by adultlike manic-depression or by severe changes in mood and behavior, which are probable precursors to better known bipolar disorder in adults (seeBaldessarini et al., 1996b; Faedda et al., 1995).

Most preparations currently used in the United States are tablets or capsules of lithium carbonate. Slow-release preparations of lithium carbonate also are available, as is a liquid preparation of lithium citrate (with 8 mEq of Li⁺, equivalent to 300 mg of carbonate salt, per 5 ml or 1 teaspoonful of citrate liquid). Salts other than the carbonate have been used, but the carbonate salt is favored for tablets and capsules because it is relatively less hygroscopic and less irritating to the gut than other salts, especially the chloride salt.

Li⁺ is not prescribed merely by dose; instead, because of its low therapeutic index, determination of the concentration of the ion in blood is crucial. Li⁺ cannot be used with adequate safety in patients who cannot be tested regularly. Concentrations considered to be effective and acceptably safe are between 0.60 and 1.25 mEq per liter; the range of 0.9 to 1.1 mEq per liter is favored for treatment of acutely manic or hypomanic patients. Somewhat lower values (0.6 to 0.75 mEq per liter) are considered adequate and are safer for long-term use for prevention of recurrent manic-depressive illness; some patients may not relapse at concentrations as low as 0.5 to 0.6 mEq per liter, and lower levels usually are better tolerated (Maj et al., 1986; Tondo et al., 1998a). These concentrations refer to serum or plasma samples obtained at 10 to 12 hours after the last oral dose of the day. The recommended concentration usually is attained by doses of 900 to 1500 mg of lithium carbonate per day in outpatients and 1200 to 2400 mg per day in hospitalized manic patients; the optimal dose tends to be larger in younger and heavier individuals. Serum concentrations of Li⁺ have been found to follow a clear dose-effect relationship between 0.4 and 0.9 mEq per liter, with a corresponding dose-dependent rise in polyuria and tremor as indices of adverse effects, and little gain in benefit at levels above 0.75 mEq per liter (Maj et al., 1986). This pattern indicates the need for individualization of serum levels to obtain a favorable risk/benefit relationship.

Li⁺ has been evaluated in many additional disorders marked by an episodic course, including premenstrual dysphoria, episodic alcohol abuse, and episodic violence (seeBaldessarini et al., 1996b). Evidence of efficacy in most of these conditions has been unconvincing. The side effects of the Li⁺ ion have been exploited in the management of hyperthyroidism and the syndrome of inappropriate ADH secretion, as well as in the reversal of spontaneous or drug-induced leukopenias, but usually with limited benefit.

Drug Treatment of Mania

The modern treatment of the manic, depressive, and mixed-mood phases of bipolar disorder was revolutionized by the introduction of lithium in 1949, its gradual acceptance worldwide by the 1960s, and late official acceptance in the United States in 1970 for acute mania only and now primarily for prevention of recurrences of mania. Lithium is effective in acute mania but is now not often employed as a sole treatment due to its slow onset of action and potential difficulty in safe management in a highly agitated and uncooperative manic patient. Initially, an antipsychotic or potent sedative benzodiazepine (such as lorazepam or clonazepam) commonly is used to attain a degree of control of acute agitation (Licht, 1998; Tohen and Zarate, 1998). Alternatively, sodium valproate can bring about rapid antimanic effects (Pope et al., 1991; Bowden et al., 1994), particularly with doses as high as 30 mg/kg and later 20 mg/kg daily, with serum concentrations of 90 to 120 g/ml (Grunze et al., 1999; Hirschfeld et al., 1999).

Li⁺ then can be introduced more safely for longer-term mood stabilization, or the anticonvulsant may be continued alone. Li⁺ or an alternative antimanic agent usually is continued for at least several months after full recovery from a manic episode due to a high risk of relapse or of cycling into depression within 12 months (seeGoodwin and Jamison, 1990). The clinical decision to recommend more prolonged maintenance treatment is based on balancing the frequency and severity of past episodes of manic-depressive illness, the age and estimated reliability of the patient, and the risk of side effects (seeBaldessarini et al., 1996b; Zarin and Pass, 1987). Li⁺ remains by far the most securely established long-term treatment to prevent recurrences of mania and bipolar depression (Baldessarini and Tondo, 2000; Davis et al., 1999; Goodwin and Jamison, 1990). There also is compelling evidence of Li⁺ lowering risk of suicide substantially (Tondo and Baldessarini, 2000). The potential clinical utility of Li⁺ in conditions other than recurrences of mania or depression in bipolar I disorder was considered above. Applications include adjunctive use in patients who present clinically with major depression and have only mild mood elevations or hypomania (bipolar II disorder) and adjunctive use in severe, especially melancholic, apparently nonbipolar recurrent major depression.

Owing to the limited tolerability of Li⁺ and its imperfect protection from recurrences of bipolar illness, antimanic anticonvulsants, particularly carbamazepine and valproic acid or its sodium salt, also are increasingly employed prophylactically in bipolar disorder on an empirical basis. However, their long-term research support remains limited and inconclusive (Calabrese et al., 1992, 1995; Davis et al., 1999; Bowden et al., 2000; Davis et al., 2000). There is even growing evidence for the inferiority of carbamazepine to lithium (Dardennes et al., 1995; Davis et al., 1999; Denicoff et al., 1997; Greil et al., 1997; Post et al., 1998; Post, 2000). The relevant pharmacology and dosing guidelines for these agents in the treatment of epilepsy are provided in Chapter 21: Drugs Effective in the Therapy of the Epilepsies. Doses established for their anticonvulsant effects are assumed to be appropriate for the treatment of manic-depressive patients, although formal doseresponse studies in psychiatric patients are lacking. Thus, dosing usually is adjusted to provide plasma concentrations of 6 to 12 g/ml for carbamazepine and 60 to 120 g/ml for valproic acid. It also is common to combine Li⁺ with an anticonvulsant, particularly valproate, when patients fail to be fully protected from recurrences of bipolar illness by monotherapy (Freeman and Stoll, 1998).

Antipsychotic drugs commonly are employed empirically to manage psychotic features or failures of prophylaxis against mania in manic-depressive illness (Sernyak et al., 1994), and they have short-term antimanic effects (Segal et al., 1998; Tohen and Zarate, 1998; Tohen et al., 1999). However, there is no credible scientific support for the long-term efficacy of these agents in mood disorders, and the risk of tardive dyskinesia in these syndromes may be even higher than in schizophrenia (Kane, 1999). The empirical use of antimanic-antipsychotic agents in bipolar disorder (particularly in mania and psychosis) is widespread, despite a lack of research demonstrating their long-term benefits. However, the recent availability of atypical antipsychotic agents with a lower risk of tardive dyskinesia and other neurological side effects, clinical experience suggesting a mood-stabilizing action of clozapine, and evidence of antimanic actions of risperidone and olanzapine all suggest that better-tolerated and safer antipsychotic agents now in development should be considered for treatment of bipolar disorder (Tohen et al., 1999; Keck and Licht, 2000). Other alternatives to lithium and the anticonvulsants have been less well evaluated.

Discontinuation of maintenance treatment with Li⁺ carries a high risk of early recurrences and of suicidal behavior over a period of several months, even if the treatment has been successful for several years; recurrence is much more rapid than is predicted by the natural history of untreated bipolar disorder, in which cycle lengths average about one year (Baldessarini et al., 1996b, 1999; Tondo et al., 1998b). This risk probably can be moderated by slowing the gradual removal of Li⁺ when that is medically feasible (Faedda et al., 1993). Significant risk also is suspected after the rapid discontinuation or even sharp dosage reduction during maintenance treatment with other agents, including antipsychotic, antidepressant, and antianxiety drugs at least (seeBaldessarini et al., 1996b, 1999). This phenomenon affects the design and interpretation of many studies in experimental therapeutics in which an ongoing maintenance treatment is interrupted to compare higher vs. lower doses, an alternative agent, or a placebo.

Prospectus

Novel Treatments for Psychotic Disorders

Acceptance of clozapine for general use stimulated renewed interest in discovering other antipsychotic agents with a low risk of extrapyramidal neurological side effects and high efficacy and without the several potentially serious adverse effects of clozapine discussed above (Baldessarini and Frankenburg, 1991). Several benzepine analogs have been introduced and approved by the FDA for clinical use, including olanzapine and quetiapine. These compounds do not induce seizures and lack the hematological toxicity of clozapine, although olanzapine has a higher incidence of motor side effects than does clozapine, as well as a high risk of weight gain and associated metabolic adverse effects. Other compounds currently in development include several substituted-benzamide analogs of sulpiride, the indole derivatives sertindole and ziprasidone, and the dibenzothiepine analog of clozapine, zotepine (Daniel et al., 1999; Waddington and Casey, 2000). Most of these agents have a complex neuropharmacology resembling that of clozapine, with interactions at several classes of cerebral neurotransmitter receptors.

A specific approach stimulated by clozapine is to test agents with antidopaminergic plus other actions, particularly antagonism of central 5-HT_2A-serotonin receptors. A lead compound of this type is the benzisoxazole risperidone, discussed above. Other compounds that have a risperidone-like binding profile and potential antipsychotic efficacy include ziprasidone (Daniel et al., 1999), sertindole (recently removed from clinical trials due to cardiac depressant actions; seeWaddington and Casey, 2000), iloperidone (Sainati et al., 1995), and ORG-5222 (Andree et al., 1997).

Compounds selective for dopamine receptors other than the D₂ subtype have been considered, but so far have shown little evidence of antipsychotic activity. Substituted enantiomeric R(+)-benzazepines show high selectivity for D₁-dopamine receptors; these include the experimental compounds SKF-83566 and SCH-23390 (Kebabian et al., 1997). A modified, longer-acting tetracyclic analog, ecopipam (SCH-39166), reached clinical trials as a potential atypical antipsychotic agent, but lacked evidence of efficacy (Karlsson et al., 1995).

Discovery of several gene products that appear to represent new dopamine receptor subtypes also has encouraged a search for agents selective for them. Agents partially selective for the D₃-dopamine receptor include several hydroxyaminotetralins [particularly R(+)-7-hydroxy-N, N-dipropylaminotetralin, and the tricyclic analog PD-128,907], hexahydrobenzophenanthridines, nafadotride and BP-897, and others in development (Baldessarini et al., 1993; Watts et al., 1993; Sautel et al., 1995; Kebabian et al., 1997; Pilla et al., 1999). The subtle and atypical functional activities of cerebral D₃ receptors suggest that D₃ agonists rather than antagonists may have useful psychotropic effects (Shafer and Levant, 1998; Pilla et al., 1999).

D₄-dopamine receptors also are of interest because of their very low prevalence in the extrapyramidal basal ganglia and their moderate selectivity for clozapine (Van Tol et al., 1991). Selective D₄ antagonists or mixed D₄/5HT₂ antagonists, so far, have proved ineffective in treating the psychotic symptoms of schizophrenia (Kramer et al., 1997; Truffinet et al., 1999). However, D₄-selective compounds may emerge as clinically innovative treatments for other neuropsychiatric disorders genetically associated with dopamine D₄ receptors, including attention deficithyperactivity disorder (Tarazi and Baldessarini, 1999).

In general, the rate of development of novel antipsychotic agents has again slowed following a burst of innovation that led to several new drugs currently in clinical use or advanced clinical trials. Novel principles are needed, particularly involving targets other than dopamine receptors, which have dominated antipsychotic drug development for a half-century.

Novel Treatments for Bipolar Disorder

The clinical success of valproate and carbamazepine as antimanic agents has strongly encouraged further exploration of other anticonvulsant agents, including older agents such as primidone and those that may act by enhancing the function of GABA as a key central inhibitory transmitter (Keck and McElroy, 1998; Manji et al., 2000; Post et al., 1998; Post, 2000). A growing number of such compounds are being introduced into neurological practice (seeChapter 21: Drugs Effective in the Therapy of the Epilepsies). Several also are in postmarketing evaluation for potential psychiatric applications, including gabapentin, lamotrigine, oxcarbazepine, tiagabine, and topiramate (seeFerrier and Calabrese, 2000; Post, 2000). For bipolar disorder, a critical challenge is to develop effective antidepressants that do not induce mania as well as mood-stabilizing agents that consistently outperform lithium and with greater safety (seeBaldessarini et al., 1996b; Stoll et al., 1994). Lamotrigine has been found effective in bipolar depression with minimal risk of inducing mania (Calabrese et al., 1999).

Because the sedative-anticonvulsant benzodiazepine clonazepam has useful short-term antimanic or sedative effects, it and lorazepam commonly are used adjunctively in the immediate control of manic excitement (Baldessarini et al., 1996b). Whether or not the anticonvulsant properties of clonazepam actually are greater than those of other potent benzodiazepines and whether or not such agents have a potential for providing a long-term mood-stabilizing action remain uncertain (seeChapter 21: Drugs Effective in the Therapy of the Epilepsies; Bradwejn et al., 1990).

Despite their theoretical plausibility, central antiadrenergic drugs have not been considered seriously for the treatment of mania, perhaps due to expectations of excessive sedation or hypotension. In addition to agents acting on central adrenergic receptors, other antihypertensive agentsnotably certain lipophilic, highly centrally active L-type Ca²⁺-channel blockers including nimodipine and other dihydropyridinesdeserve further exploration as mood-stabilizing agents (seeDubovsky, 1998; Pazzaglia et al., 1998).

Given the several shared actions of lithium and valproate, it may be possible to develop novel antimanic agents that act directly on effector mechanisms that mediate the actions of adrenergic and other neurotransmitter receptors (Manji et al., 1999b). These include drugs that affect protein kinase C, such as the antiestrogen tamoxifen (Bebchuk et al., 2000) as well as other novel kinase-inhibiting agents that are under experimental development.

Finally, among natural products, long-chain, unsaturated, omega-3 fatty acids (including docosohexaenoic and linoleic acids) found in seed oils and particularly concentrated in fish flesh oils may have at least moderate mood-stabilizing effects and seem to be particularly helpful in bipolar depression. At least one controlled trial supports this approach (Stoll et al., 1999).

For further discussion of psychiatric disorders, seeChapter 371 in Harrison's Principles of Internal Medicine, 16th ed., McGraw-Hill, New York, 2005.