Update on Lithium Carbonate Therapy in Children and Adolescents

SPECIAL ARTICLE

Update on Lithium Carbonate Therapy in Children and Adolescents NORMAN ALESSI, M.D., MICHAEL W. NAYLOR, M.D., MOHAMMAD GHAZIUDDIN, M.D., AND JON KAR ZUBIETA, M.D.

ABSTRACT

The use of lithium to treat child and adolescent psychiatric disorders is becoming more common. Since the publication of the report of The Committee on Biological Aspects of Child Psychiatry of the American Academy of Child Psychiatry in 1978, a considerable body of literature has accumulated on the efficacy of lithium in treating adolescent bipolar disorders, childhood aggression, and behavioral disorders associated with mental retardation and developmental disorders. Efforts to understand lithium's mechanism(s) and refinements in psychiatric diagnosis have contributed to its growing use. J. Am. Acad. Child Ado/esc. Psychiatry, 1994,33, 3:291-304. Key Words: lithium carbonate, children, adolescents, psychopharmacology, psychopathology.

Since the introduction oflithium salts for the treatment of manic-depressive illness in adults more than 40 years ago, more than 16,000 articles have been published, with up to 1,000 new articles added annually (Baudhuin et al., 1987; Bunney and Carland-Bunney, 1987; Cade, 1949). In 1978, a review of the published literature on the use of lithium in children and adolescents suggested the efficacy of lithium in adolescent manic-depressive illness and its possible utility in aggression and hyperactivity, where there was an affective component (Youngerman and Canino, 1978). Also in 1978, The Committee on Biological Aspects of Child Psychiatry of the American Academy of Child Psychiatry offered a report on the status of lithium therapy in children and adolescents (Campbell et al., 1978). Their conclusions were that (1) lithium "... should be explored because of its potential therapeutic

Accepted January 27, 1993. Drs. Alessi and Ghaziuddin are with the University ofMichigan Medical Center, DepartmentofPsychiatry, Ann Arbor; Dr. Nayloris with Northwestern University, Chicago, IL; and Dr. Zubieta is with Johns Hopkins University, Baltimore, MD. Reprint requests to Dr. Alessi, Child and Adolescent Psychiatry, Department ofPsychiatry, University ofMichigan, RoomL5020, 200 East Hospital Drive, Ann Arbor, MI 48109-0290. 0890-8567/94/3303-0291$03.00/0©1994 by the American Academy of Child and Adolescent Psychiatry.

J.

value... " for manic-depressive illness, emotionally unstable character disorders, aggressiveness, and the highrisk offspring oflithium responders; (2) "lithium might be helpful" for childhood depression; and (3) "lithium is probably not helpful" for hyperkinetic syndrome and psychosis (p. 718). Fifteen years have passed since the publication of these overviews. There have been a number of reports substantiating these earlier conclusions and introducing possible new uses for lithium. With the veritable explosion in the neurosciences, in particular in our understanding of receptor and intracellular mechanisms of functioning, we have gained much greater understanding of not only lithium's mechanism(s) of action but also of its theoretical relationship to specific child and adolescent psychopathology. It is within this context that we reviewthe use oflithium in child and adolescent psychopathology and its purported mechanism(s) of action. LITERATURE SURVEY

The enthusiasm generated for lithium in the field of adult psychiatry has been paralleled in child and adolescent psychiatry, albeit on a far lesser scale. In fact, only 58 articles on the use of lithium in children and adolescents have been published, and these represent less than 0.5% of the lithium literature. Approximately 55% of the reports have been published since

AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 33:3, MARCH/APRIL 1994

291

ALESSI ET AL.

1978. These reports can be divided into three categories: (1) case reports; (2) case series (reports consisting of two or more than two cases, including open clinical trials); and (3) double-blind, placebo-controlled studies. Figure 1 shows the breakdown of these reports. Of the 58 reports, the majority, 26 (45%), are case series; 22 (39%) are case reports; and 9 (16%) are doubleblind, placebo-controlled studies. A total of 652 patients are represented in these reports. The largest proportion of patients, 483 (74%), were reported in case series; 152 (23%) in double-blind, placebo-controlled studies; and the remaining 24 (3%) in case reports. The diagnostic categories represented in these reports include bipolar disorders, manic-depressive illness, depressive disorders, aggression, conduct disorders, psychotic disorder, attention-deficit hyperactivity disorder (ADHD), emotionally disturbed offspring of lithium-responsive parents, after head trauma, eating disorders, "severe disturbances," and Kleine-Levin syndrome. Despite the increase in the number of reports on the use of lithium carbonate in this age group, most are case reports or case series.

9(15.8%) 22(38 .6%)

B. Percent of Patients

o Case Reports II Case Series •

Case Reports

Eighteen of the case reports concern the efficacy of lithium in children or adolescents with manic-depressive disorders (Adams et al., 1970; Berg et al., 1974; Carlson and Strober, 1978; ColI and Bland, 1979; Engstrom et al., 1978; Feinstein and Wolpert, 1973; Fisman et al., 1985; Ghadirian and Kusalic, 1990; Hall and Ries, 1983; Joshi et al., 1985; Kelley et al., 1976; Licamelle and Goldberg, 1989; Linter, 1987; Mattsson and Seltzer, 1981; Picker et al., 1990; Potter, 1983; Warneke, 1975; Youngerman and Canino, 1983). The youngest child treated for manicdepression was 5 years old (Feinstein and Wolpert, 1973). In three cases involving adolescents with manicdepressive disorder, the mania was presumed to . be medication induced (Ghadirian and Kusalic, 1990; Mattsson and Seltzer, 1981; Shafey, 1986). One case report involved the use of lithium in the treatment of aggression (Lena and O'Brian, 1975). In three single cases of adolescents with Kleine-Levin syndrome, a rare condition restricted almost exclusively to adolescent males and typified by hypersomnolence, behavioral disturbance, and hyperphagia, a reduction in symptoms was noted with lithium (Cawthorne, 1990; Goldberg, 1983; Jeffries and Lefebvre, 1973). The other two cases

292

A. Percent of Studies

J.

Double- Blind Placebo

Fig . 1 Review of lithium studies. A: Percentage of reports reflecting lithium efficacy. Total of 57 reportS; 22 (38%) case reports, 26 (46%) case series, and 9 (I 6%) double-blind studies. B: Percentage of patients within each group. Total of 657 patients; 22 (3%) case reporrs. 483 (74%) case series, and 152 (23%) double-blind studies. Cases were included only when the number of either children or adolescents was discernible from the number of adults. Also, these data represent only reportS and not instances of chapters or presentations, such as posters in which data may have been presented.

involved the treatment of children who either were psychotic or had a behavioral disturbance after head trauma (Cohn et al., 1977; Shafey, 1986). Case Series

The 26 case series involved a wide range of psychiatric disturbances, with 16 involving manic-depressive disorders (Annell, 1969; Brumback and Weinberg, 1977; Davis, 1979; Del.ong, 1978; DeLong and Aldershof, 1987; Hassanyehand Davison, 1980; Horowitz, 1977; Hsu and Srarzynski, 1986b; Kerbeshian and Burd, 1989; Kerbeshian et al., 1987; Rogeness et al., 1982; Steingard and Biederman, 1987; Strober et al., 1988, 1990; Sylvester et al., 1984; Varanka et al., 1988; Weinberg and Brumback, 1976), two depression

AM . ACAD . CHILD ADOLESC. PSYCHIATRY , 33:3 , MARCH/APRIL 19 94

LITHIUM THERAPY

(Ryan et al., 1988; Strober et al., 1992), four aggression (Siassi, 1982; Somogyi et al., 1988; Vetro et al., 1981, 1985), one ADHD (Whitehead and Clark, 1970), and one Kleine-Levin (Will et al., 1988). There was one case dealing with the response of children with lithiumresponsive parents (Dyson and Barcai, 1970). The age ranged from 3 to 19 years old, with several of the youngest children (4 and 5 years old) being mentally retarded or autistic and having bipolar disorders (Kerbeshian and Burd, 1989; Steingard and Biederman, 1987). Double-Blind, Placebo-Controlled Studies

Nine double-blind, placebo-controlled studies involving lithium have been published. Two involve the study of manic-depressive disorders (DeLong and Aldershof, 1987; McKnew et al., 1981), three aggression (Campbell et al., 1972; Campbell et al., 1984b; Sheard, 1975), one psychotic disorders (Gram and Rafaelsen; 1972), one ADHD (Greenhill et aI., 1973), and, the most recent, disruptive behavioral disorder and either bipolar or major depressive disorder (Carlson et al., 1992). For an extensive review of the earlier studies see Campbell et aI. (I 984a).

CLINICAL INDICATIONS

Newer reports, albeit case reports and case series, support earlier observations of the clinical utility of lithium. CHILDREN Disorders for Which Lithium Should Be Considered

Aggression. Aggression continues to be the most widely supported clinical diagnostic entity for which lithium is indicated. In a series of studies spanning more than 22 years, Campbell and coworkers demon strated in two double-blind, placebo-controlled studies that lithium is as efficacious as either chlorpromazine or haloperidol and more so than placebo in the management of impulsive aggression (Campbell et al., 1982; Campbell et al., 1984b). In addition, they observed far fewer side effects in subjects taking lithium. In the psychiatric and neuroscience literature, it is widely noted that lithium affects aggression (Eichelman, 1988; Mattes, 1986).

Although it is obvious that some patients with aggressionrespond favorably to lithium carbonate pharmacotherapy, it is very difficult to determine which children would benefit. As noted , "the lack of clear guidelines in determining the point at which normal aggression becomes pathological makes the management of childhood aggression very difficult" (Alessi and Wittekindt, 1989, p. 101). Bipolar Illness. Considerable controversy continues as to whether bipolar disorder presents in childhood, its prevalence, and the diagnostic criteria by which to establish the diagnosis. Bowring and Kovacs (I 992) suggest that low base rate of occurrence, variable presentation within and across episodes, symptomatic overlap with other more common childhood disorders, and variation of symptomatic expression resulting from the developmental stage of the child account for the difficulties in identifying bipolar illness in children . Despite these obvious difficulties, recent research suggests that scales such as the Mania Rating Scale might be used to differentiate children with bipolar disorders from thosewithADHD (Frisrad et al., 1992). Although these findings are promising, their replication is needed. Several diagnostic criteria have been proposed (Anthony and Scott, 1960;. Weinberg and Brumback, 1976); however, none have been adequately validated. One possible method is to identify those children or adolescents who have a lithium-responsive parent or parents with cyclical mood disturbances or cyclic psychosis (Dyson and Barcai, 1970). McKnew et al. (I 98 1) studied six children, aged 6 through 12 years, with incapacitating psychopathology whose parents (all of whom had bipolar illness) were lithium responders. Using a double-blind, crossover study of lithium carbonate treatment, the authors reported that two children had a clear-cut response. Those two appeared to have clear evidence of cyclothymia, whereas the four nonresponders did not. DeLong and Aldershof (I987) described the longterm treatment ofchildren with lithium, using a combination of double-blind placebo-controlled and open designs. They treated 196 children for periods up to 10 years and found that the usefulness of lithium was related to clinical diagnosis. Lithium was most useful in patients with bipolar disorder, in behaviorally disordered offspring of lithium-responsive parents, and in children with "emotionally unstable character disorder." It was not effective in children with attention

J. AM . ACAD. CHILD ADOLESC. PSYCHIATRY. 33:3. MARCH/APRIL 1994

293

ALESSI ET AL.

deficit disorder. Some children with a combination of affective and aggressivesymptoms, at times complicated by developmental disorders, also had a favorable response. Disorders for Which Lithium Might Be Considered When Other Medications Fail

Depression. The use of lithium in children as an augmenting agent has been reported only recently (Alessi, 1990). In this case report a 10-year-old girl demonstrated marked improvement after the addition of lithium to an antidepressant. ADOLESCENTS Disorder(s) for Which Lithium Should Be Considered

Manic-Depressive Illness. Bipolar affective disorder frequently has its onset during adolescence. Estimates of onset of bipolar affective disorder during adolescence vary widely from 0.075% (one of 1,334) to 20% (Loranger and Levine, 1978 ; Wiener and del Gaudio, 1976). Joyce (1984) found that 25% of patients with bipolar disorder dated its onset to between the ages of 15 and 19 years. One reason foe the wide range of estimated age of onset of bipolar disorder relates to the frequency of misdiagnosis in adolescents (Carlson and Strober, 1978; Gammon et al., 1983; Hsu and Starzynski, 1986a; Joyce, 1984). Horowitz (1977) found that all eight adolescents in his study eventually diagnosed with manic-depressive illness previously had been diagnosed with schizophrenia. Several studies demonstrate the effectiveness of lithium carbonate for adolescents with bipolar illness. The response is often dramatic, and remissions have been documented after 5 to 14 days of treatment. Most adolescents, however, may require up to 6 weeks (Hassanyeh and Davison, 1980; Horowitz, 1977; Hsu and Srarzynski, 1986a; Strober et al., 1988). In two reports , adolescents relapsed after discontinuation; in one case they responded to restarting of the medication, but in the other they did not. In an 18-month prospective , naturalistic follow-up study of 37 adolescents with bipolar affective disorder treated with lithium, Strober et al. (1990) found that noncompleters of an 18-month therapeutic trial relapsed nearly three times as often as did completers (92.3% versus 37.5%). Furthermore, completers who had episodes of mania or depression before the index 294

J.

hospitalization had a decreased frequency of affective illnesses while receiving lithium compared with baseline. Although not conclusive, these data suggest that lithium carbonate is an effective prophylactic agent , preventing or decreasing relapses. Despite the reported efficacy of lithium carbonate in the treatment of adolescent manic-depressive illness, not all adolescents with bipolar affective disorder respond. Factors thought to predict lithium nonresponsiveness include a greater genetic diathesis in younger patients, developmental immaturity, and neurological disorders (Himmelhoch and Garfinkel, 1986; Strober et al., 1988). Lithium resistance is particularly common in adolescents with mixed mania. Himmelhoch and Garfinkel (1986) reported on 46 lithium-resistant bipolar patients, 23 of whom were adolescents. Of these 23 , 17 had mixed mania and six had nonmixed mania. Aggression. Lithium carbonate is frequently effective in the treatment of aggressive adolescents as well as children. In two studies lithium carbonate was administered to institutionalized adolescents. Sheard (1975) found that lithium decreased the frequency and severity of aggression. In the study by Dostal (1972), lithium pharmacotherapy resulted in 65 % decrease in the incidence of aggression. Disorders for Which Lithium Might Be Considered When Other Medications Fail

Refractory Depression. Two recent studies have addressed the issue of lithium augmentation of tricyclic antidepressant (TCA) pharmacotherapy in TeA-refractory, depressed adolescents (Ryan et al., 1988; Strober et al., 1992). In Ryan and coworkers, retrospective study of 14 adolescents with un ipolar depression unresponsive to antidepressant therapy, augmentation with lithium carbonate led to a significant improvement in mood and psychosocial functioning in 6 (43%). In Strober and colleagues' group of 24 depressed adolescents who failed to respond to a 6-week open trial of imipramine, two pati ents (8.3%) had a dramatic response to lithium augmentation and eight patients (33%) had a partial response. Disorders with Limited Support for Consideration

Complicated Bipolar Cases. Lithium carbonate has been effective in the treatment of complicated cases of bipolar disorders in adolescents, especially rapidcycling bipolar disorder; comorbid T ourette's syndrome

AM. ACAD. CHILD ADOLESC . PSYCHIATRY. 33: 3 . MARCH/APRIL 1994

LITHIUM THERAPY

and bipolar disorder; organic mood disorder, manic type; and mild mental retardation associatedwith cyclic mood disturbance (Cohn et al., 1977; Kelly et al., 1976; Kerbeshian and Burd, 1989; Mattsson and Seltzer, 1981). Kleine-Levin Syndrome. Severalauthors have reported that lithium is effective in the acute treatment of Kleine-Levin syndrome, eliminating the attacks or decreasing their frequency and severity (Abe, 1977; Cawthorne, 1990; Goldberg, 1983; Ogura et al., 1976; Will et al., 1988). Eating Disorders. Very little research has been done on the use of lithium carbonate in the treatment of anorexia nervosa in adolescents (Stein et al., 1982). In a double-blind, placebo-controlled study of 16 hospitalized anorexic patients (aged 12 to 32 years), Gross and coworkers (1981) demonstrated that those receiving active medication showed a significantly greater weight gain than did those receiving placebo. .The use of lithium carbonate for the treatment of bulimia nervosa also has been studied. In the largest study to date, Hsu and associates (1991) found that lithium carbonate was no more effective than placebo in reducing binge/vomit frequency or abnormal eating attitudes. For the depressed bulimic subjects treated with lithium, however, those with higher plasma lithium levels tended to have a lower frequency of vomiting than did those with lower plasma levels. Extreme caution must be used when treating anorexia nervosa and bulimia nervosa with lithium. Lithium has been implicated in the death of "normal control" enrolled in a National Institute of Mental Health study who was later found to have an extensive history of anorexia nervosa with self-induced vomiting. Lithium may exacerbate the loss of intracellular potassium in patients who are hypokalemic, thereby enhancing cardiotoxicity of hypokalemia accompanying self-induced vomiting (Kolata, 1980). MentalRetardation and Developmental Disorders. Several reports have described the use oflithium in persons with mental retardation and developmental disorders. Most of these studies have been in adults. Those involving children and adolescents have been mainly in those with bipolar disorder, aggressive behavior, and self-injurious behavior. In some patients, the presence of a family history of bipolar disorder may be an acceptable indication for starting lithium therapy, especially when the behavioral problems show a cyclic

tendency (Chandler et aI., 1988). In a study of 14 patients with mental retardation, aged 19 to 58 years, Naylor et al. (1974) found that patients with affective symptoms responded to lithium. There are very few published reports of the use of lithium in children and adolescents with developmental disorders and comorbid bipolar disorder. Undoubtedly this reflects the difficulties inherent in the diagnosis ofpsychiatric disorders in this population. Nevertheless, severalcasereports have described the lithium treatment of "short-cycling manic-depressive illness" or "juvenile manic-depressive illness" (Fukuda et aI., 1986; Kelly et aI., 1976; Linter, 1987). Treatment of autistic children with atypical bipolar symptoms also has been described (Kerbeshian et al., 1987; Steingard and Biederman, 1987). Lithium pharmacotherapy also has been used to control aggressionin persons with developmental disorders. Tyrer and colleagues (1984) studied the effecJ{ oflithium on the aggressive behavior of26 institutionalized patients, aged 14 to 50 years, and found that certain variables differentiated the lithium responders from the nonresponders. These were female gender, overactivity, stereotypy, seizure disorder, and a low frequency of aggressive incidents « 1/week) before the start of the medication trial. Another study found that rage and aggressivity responded favorably to lithium treatment in behaviorally disordered children with neurological and medical conditions including mental retardation (DeLong and Aldershof, 1987). Campbell et al. (1972) conducted a double-blind study of the comparison of lithium and chlorpromazine in a group of 10 autistic children with a variety of disruptive behaviors. Two patients had an IQ less than 70. In general, neither drug was found to be effective,although in one child a decrease in self-mutilation and violent tantrums was observed with lithium. Self-injurious behavior in persons with mental retardation and developmental disorders may benefit from a trial of lithium carbonate (Winchel and Stanley, 1991). On the whole, experience with lithium in developmentally disabled populations is limited. Distinction has not often been made in the literature between aggression directed toward others and that directed toward self or between verbal and physical aggression. Apart from its use in some autistic children, there are no reports on its use in the various subtypes of mental

j. AM. ACAD. CHILD ADOLESC. PSYCHIATRY. 33:3, MARCH/APRIL 1994

295

ALESSI ET AL.

retardation, such as Down syndrome and fragile X syndrome.

MECHANISM(S) OF ACTION

Great advances in our understanding of the complexity of lithium's mechanism(s) of action have been made in the past 10 years. Lithium, an alkali metal, now is known to cause profound effects on a number of neurochemical systems including ion channels; neurotransmitters, including serotonin, dopamine, and norepinephrine (NE); and second-messenger systems, such as phosphoinositides (PIs) and cyclic AMP (cAMP). A limited reviewof the effectsoflithium on the secondmessenger systems and receptors will be offered, from molecular functioning (second messengers and transduction mechanisms) to receptor number and function (Table 1). SECOND-MESSENGER SYSTEMS Inositol Phosphate Metabolism

Phosphoinositides act as second messengers in a variety of neurotransmitter systems (for recent reviews see Baraban et al., 1989; Berridge et al., 1989; Hokin, 1985). Stimulation of PI-linked membrane receptors activates a phospholipase C enzyme. This enzyme metabolizes phosphatidylinositol-bis-phosphate to inositol trisphosphate and diacylglycerol. Both compounds act as intracellular second messengers (Fig. 2). Lithium initially was observed'to decrease the levels of free myoinositol in the rat brain (Allisonand Stewart, 1971). It was also shown that the levels of inositol phosphates were raised after lithium treatment (Allison et al., 1976). Lithium noncompetitively blocks the activity of inositol phosphatase enzymes (inositol polyphosphate l-phosphatase and inositol monophosphate phosphatase) that are involved in the recycling of free inositol from either the breakdown of inositol triphosphate or inositol monophosphates produced from glucose metabolism. The observation that lithium interferes with the function of PI systems has led to the theory that inositol depletion may underlie the therapeutic effectsoflithium by modulating the activity of neurotransmitter systems that use PI as second messengers depending on their overall activity: an overactive cycle would be more inhibited than a less active one by the rapid depletion of the precursor inositol

296

J.

(Berridge et al., 1989). This may partially explain the therapeutic effect of lithium in bipolar disorder or, in general, illnesses that may present with overactivity of PI-linked neurotransmitter systems, without causing decreases in presumably normal, functioning systems. Adenylate Cyclase Activity

The actions of lithium within this second-messenger system appear to be complex, involving several steps of the cascade that promotes or inhibits cAP formation (Bunney and Garland-Bunney, 1987). Although lithium directly inhibits adenylate cyclase by competing with magnesium (Mork and Geisler, 1987), it appears its most clinically relevant effects are mediated by inhibition of G proteins that stimulate (G,) or inhibit (G;) adenylate cyclase function (Mork and Geisler, 1989a, 1989b). By inhibiting the activity of the G proteins, lithium may cause adenylate cyclase-coupled receptors to remain in a low affinity state for agonists (Risby et al., 1991). Also, by reducing the functional activity of G j proteins adenylate cyclase will be more activated; the converse will be true for systems in which G, proteins are predominant. RECEPTOR NUMBER AND FUNCTION Serotonin Receptors and Function

Long-term treatment with lithium increases 5-hydroxytryptamine (5-HT) turnover and increases CNS tryptophan levels and the concentration of its principal metabolite, 5-hydroxyindoleacetic acid (seeBunney and Garland-Bunney, 1987; Manji et al., 1991). Presynaptic 5-HT receptors are subsensitive after long-term lithium administration, reducing their negative feedback on 5-HT release (Friedman and Wang, 1990). Hippocampal but not cortical 5-HT lA sites have been reported to down-regulate after long-term lithium treatment, without an effect on 5-HT2 receptors (Odagaki et al., 1990). The long-term administration oflithium induces regionally selective alterations in serotonin release. For example, lithium increases5-HT releasein the hippocampal formationwith a concomitant decrease in 5-HT receptors (Treiser et al., 1981). No similar changes have been described in the rat cortex. Similar findings have led to the theory that lithium-induced modifications in receptor number and function are due to increased, regionally selective, synaptic availability of

AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 33:3, MARCH/APRIL 1994

LITHIUM THERAPY

TABLE 1 Summary of Lithium's Mechanism(s) of Action

Neurosubstrate Second messengers Inositol phosphate

Adenyl cyclase

Receptor functioning Serotonergic

Postulated Psychopathology Effected by Action

Action Effected by Lithium

Result of Lithium's Action

• Blocks the activiry of inositol polyphosphare l-phosphatase and inositol monophosphate phosphatase • Directly inhibits adenyl cyclase by competing with magnesium • Inhibits G proteins (G, and G,)

• Leads to the depletion of inositol and dampens the function of the phosphoinositide cycle

• Manic-depressive illness • Aggression?

• Reduces or increases adenyl cyclase function depending on proportion of regional G, and G; populations

• Manic-depressive illness • Depression? • Aggression?

• Down-regulates some serotonergic receptor subtypes • Increases serotonin turnover

• Reduces negative feedback, thereby increasing the release of serotonin

• Aggression? • Depression? • Potentiation of antidepressant effects

• Increases the proportion of lowaffinity ~ receptors

• Reduces ~ receptor function

• Manic-depressive illness • Depression • Potentiation of antidepressant effects

• Induces subsensitivity of (Xz receptors • Blocks up-regulation of receptors when given concurrently with neuroleptics • Increases dopamine levels and turnover (regionally specific)

• Increases the release of norepinephrine • Prevents D z up-regulation • Augments the effects of indirect agonists

Adrenergic

~

Dopaminergic

the endogenous transmitter (Hotta et al., 1986), leading to variable enhancements in central 5-HT function. Adrenergic Receptors and Function

Adrenergic receptors have been implicated in the pathophysiology of affective and anxiety disorders and aggression. Both presynaptic and postsynaptic adrenergic receptors appear to be affected by lithium administration. The literature yields a complex picture of lithium's effects on both ex and ~ adrenoceptors. ~-Adrenoceptors

Lithium treatment has been reported to decrease total ~-receptor binding in rat brain homogenates (Rosenblatt et al., 1979; Treiser and Kellar, 1979).

• Manic-depressive illness

However, this finding has not been replicated by other authors (Gross et al., 1988; Maggi and Enna, 1980). Pretreatment with lithium has been shown to prevent the development of reserpine-induced ~-receptor supersensitivity (by depletion of NE stores), but this effect was not replicated after destruction ofNE neurons with the neurotoxin 6-hydroxydopamine and subsequent lithium administration (see Bunney and Garland-Bunney, 1987). It also appears that lithium does not prevent the down-regulation induced by either direct or indirect agonists (Belmaker, 1981; Rosenblatt et al., 1979). If lithium were to act preferentially by blocking the GTP binding to the G s protein linked to ~ receptors (Newman and Belmaker, 1987), it is possible these receptors would be locked in a low affinity state (Risby

]. AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 33:3, MARCH/APRIL 1994

297

ALESSI ET AL.

Adenylate Cyclase System

GDP~~ ~CGDP

8*

GTP

GTP

rr>. ATP

cAMP

Phosphoinositol Cycle

(Goodwin et al., 1986; Spengler et al., 1986) and clinical studies (Bambrilla et al., 1988; Garcia-Sevilla et al., 1986) and decreases the high-affinity binding of agonists (3H-clonidine) (Garcia-Sevilla et al., 1986). A decrease in the function of these receptors may in turn reduce their negative feedback over NE release, which indeed is increased after long-term lithium administration (Manji et al., 1991). Increases in the central activity of this system may be partially implicated in lithium's potentiation ofantidepressant effects.
I

INOSITOL-IP-IP2"IP3

/ GLUCOSE (de novo)

10

* *1 \::;: r;-;:-;;l

~

Fig. 2 Representation of adenylare cyclaseand phosphoinositide (secondmessenger) systems. Abbreviations: R = teceptor; R-S = stimulatory receptor; R-I = inhibitory receptor; G" G; = stimulatory and inhibitory G-proteins; A-C = adenylare cyclase enzyme; GTP = guanidine triphosphate; GDP = guanidine diphosphate; G = G protein, ATP = adenosine triphosphate; cAMP = cyclic adenosine monophosphate: CDP-DG = cytidine diphosphate: diacylglycerol; PI = phosphatidylinosirol; PIP = phosphatidylinositol phosphate; PIP 2 = phosphatidylinositol-bis-phosphate; IP = inositol phosphate; IP 2 = inositol-bis-phosphate; IP3 = inositol triphosphate; PKC = protein kinase C enzyme; IP3 -R = intracellular receptor for IP3; DAG = diacyglycerol. 'Postulated sites of lithium action.

et al., 1991), preventing the development of supersensitivity but not subsensitivity. Lithium's induction of a low affinity state for the ~ adrenoceptor may underlie its reported potentiation of antidepressant effects by stabilizing the down-regulation of ~ receptors induced by these agents. a-Adrenoceptors

These receptors, possibly located both presynaptically and postsynaptically, are linked, in their presynaptic location, to the modulation of NE release via inhibitory Gi-cAMP mechanisms. Lithium consistently induces subsensitivity of these receptors in both animal

298

Long-term lithium administration has been reported to increase dopamine levels and turnover in tuberoinfundibular pathways, whereas no changes (increases or decreases) have been reported for striatum, ponsmedulla, and midbrain regions in experimental animals (Bunney and Garland-Bunney, 1987). The concurrent administration of lithium with neuroleptics prevented the supersensitivity and/or upregulation of Dj-dopamine receptors induced by these agents. Dj-receptorstimulated cAMP formation does not appear to be altered by lithium pretreatment (Whitworth and Kendall, 1989). Although lithium might regionally increase the function of certain dopamine pathways, it again appears to prevent up-regulatory changes in D, receptors, which might contribute to its preventive effects on manic-depressive psychosis.

MANAGEMENT ISSUES Pharmacokinetics of Lithium in Children

In one study, nine children, mean age 10.9 years, were given 300 mg of lithium carbonate at 8 A.M. after an overnight fast; blood was drawn at fixed intervals up to 36 hours later (Vitiello et al., 1988). Peak serum lithium level was observed at 2.4 hours, with mean levels of 0.45 mEq/L. The elimination half-life from the body was approximately 17.9 hours, compared with approximately 21 hours in adults (Nielsen-Kudsk and Amdisen, 1979). The elimination rate was significantly higher in children than adults, 40.2 versus 27.6

]. AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 33:3, MARCH/APRIL \994

LITHIUM THERAPY

mL/kg per hour. This 20% difference in half-life may indicate that a child can reach a steady state sooner than an adult and that therapeutic levels can be instituted more quickly. There are no pharmacokinetic studies involving adolescents. Prediction of Lithium Dose

There are three methods (but no established standard) for the initiation and achievement of a therapeutic steady-state blood level of lithium (0.6 to 1.2 mEql L). The first requires the administration of the medication over a period of time with periodic blood draws and appropriate adjustments in the dosage of medication. The second requires the administration of a single test dose of lithium, obtaining a serum level 24 hours later and then using a nomogram to determine the dose to administer. This method has been successful in adults and effective in children (Cooper et al., 1973; Geller and Fetner, 1989). Six subjects received 600 mg of lithium carbonate at 9 A.M. on day 1. Serum lithium level, determined from blood drawn 24 hours later, was between 0.4 and 0.7 mEq/L in all subjects. The Cooper nomogram was used to determine dosage. Although four subjects required increases in dosage from 300 to 600 mg, none had excessive levels. The third uses a dosage guide with a starting dose of approximately 900/m 2 (Weller et al., 1986). By this method children would receive approximately 30 mgl kg day. In a study of 15 children, aged 6 to 12 years, the mean steady-state level of lithium, 0.95 ± 0.33 mEq/L, was achieved within 5 days. By this method two children had levels of 1.4 or above. Monitoring

Given the need to reach therapeutic levels and the absence of a dosage scale, monitoring of lithium level is mandatory. The two methods available are serum and saliva sampling. Despite the claims for the possible use of salivary levels, studies in children suggest that it should be considered only in extreme situations. This hesitancy is based on several factors: (1) there is greater variabiliry in saliva samples than in serum samples; (2) intrasubject variability necessitates the taking of a number of samples from a child to determine an individual ratio; and (3) children may not eat or drink for 12 hours before taking saliva samples (Lena and Bastable, 1978; Perry et al., 1984; Weller et al.,

J.

1987). Given these factors, monitoring serum levels is still the technique of choice. ADVERSE EFFECTS AND TOXICITY

For the most part, lithium pharmacotherapy in children and adolescents is well tolerated. Side effects are infrequent and generally mild (Gross et al., 1981; Hsu et al., 1986a; Siassi, 1982; Varanka et al., 1988). Indeed, various investigators state that the frequency and severity of adverse reactions to lithium in children is lower than in adults (Lena, 1989; Siassi, 1982). Frequently reported side effects in children and adolescents include weight gain, stomach upset, nausea, vomiting, tremor, polydipsia, polyuria, diarrhea, and fatigue (Campbell et al., 1991; Carlson, 1979; Gross et al., 1981; Sheard, 1975; Siassi, 1982; Varanka et al., 1988). Campbell et al. (1991) found that younger children had a greater incidence of side effects than did older children, even after weight, lithium dosage, serum lithium levels, and duration of the optimal dose of lithium carbonate were controlled. Patient diagnosis may also affect the frequency and severity of adverse effects of lithium. In the previously described study, Campbell et al. (1991) reported that autistic children had more side effects than did patients with conduct disorder, even when they accounted for age. Strayhorn and Nash (1977) indict a seizure diathesis and the diagnosis ofschizophrenia as conditions that predispose a patient to severe neurotoxicity despite "therapeutic" serum lithium levels. It appears that certain diagnoses and certain types of encephalopathy may place a patient at risk for developing adverse effects, even at "subtherapeutic" dosages. Central Nervous System

Adverse effects involving the CNS are often the most dramatic and serious of all complications resulting from lithium pharmacotherapy. Factors predisposing to neurotoxicity, even in the faceof "therapeutic" serum lithium levels, include combination pharmacotherapy (such as haloperidol and lithium), increasing age, seizure diathesis, schizophrenia, intercurrent medical illness, and tissue retention (Strayhorn and Nash, 1977). It is not uncommon for patients treated for an acute bout of mania to develop lithium toxicity after remission. As reviewed by the authors, patients with acute mania tend to sequester more lithium than do normal

AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 33:3, MARCH/APRIL 1994

299

ALESSI ET AL.

subjects or patients with well-controlled bipolar disorder. Resolution of the mania leads to "normalization" of lithium metabolism, and toxic lithium levelsmay result. Lithium also has been reported to alter EEG patterns in the pediatric age group. Bennett et al. (1983) found that 58% of the patients who had baseline EEGs subsequently developed EEG abnormalities, including paroxysmal discharges and focal slowing. Brumback and Weinberg (1977) reported that one of their six prepubescent patients with mania developed epileptiform activity on the EEG and four of the six demonstrated EEG slowing with increased () and e activity compared with baseline. Contradictory findings have been reported, however. Other reported CNS abnormalities include increased frequency of migraine headaches (Peatfield and Rose, 1981) and altered cognitive processes. Platt et al. (1981) found that performance in qualitative scores on the Portteus Mazes test decreased, with no change in reaction time or on the Matching Familiar Figures test. Neuromuscular

Neil et al. (1976) described the case of an 18-yearold woman in whom myasthenia gravis-like symptoms developed during the course of a lithium trial. The symptoms remitted with discontinuation of lithium only to return when the lithium was reinstated. Brust et al. (1979) reported the case of an 18-year-old in whom acute generalized polyneuropathy developed after lithium poisoning. Clinically, the neuropathy resembled the Landry-Cuillain-Barre syndrome. In both cases, however, haloperidol was prescribed concurrently, so it is not certain lithium was the offending agent. Cardiovascular

Rarely, cardiovascular side effects have been reported. Campbell et al. (1972) reported that two 5-year-old boys treated with lithium carbonate developed reversible conduction defects, including mild right ventricular conduction delay, and an atrioventricular nodal rhythm. Renal

One of the most commonly reported abnormalities is polyuria due to inhibition of the action ofantidiuretic

300

hormone on renal adenylate cyclase at the distal tubule and collecting ducts, resulting in decreased renal reabsorption of water (Forrest et al., 1974). Usually reversible, this nephrogenic diabetes insipidus may persist. Few studies have addressed the issue of renal functioning in children receiving long-term lithium treatment. Khandelwal et al. (1984) studied four children who had been treated with lithium carbonate for at least 2 years and reported no change in renal function compared with baseline. There are two separate reports of 14-year-old girls who developed proteinuria during a trial of lithium therapy (Lena et al., 1978; Wood et al., 1989). Although proteinuria typically resolves with discontinuation of the offending agent, sustained proteinuria has been described. Treatment with corticosteroids may be necessary in these cases. Endocrinological

Perhaps the most widely studied and widely reported adverse effects in adults involve thyroid function. Commonly reported abnormalities include hypothyroidism, goiter formation, the presence of thyroid autoantibodies, and an abnormal thyroid-stimulating hormone response to thyrotropin-releasing hormone. In children and adolescents, biochemical evidence of hypothyroidism (elevated thyroid-stimulating hormone and decreased T4) was reported in two brothers hospitalized for bipolar affective disorder (9 year old) or explosive aggression (7 year old), leading the authors to conclude that the effect of lithium on the thyroid is genetically determined (Picker et al., 1990). In Campbell and coworkers' series (1972), two children demonstrated decreased thyroxine compared with baseline. DeLong and Aldershof (1987) described a case of an l l-yearold boy who developed a goiter and hypothyroidism after 4 years of treatment. Finally, Vetro et al. (1985) reported two cases of lithium-induced goiter out of 17 children treated with lithium. Miscellaneous

Neutrophilia is such a consistent finding in patients treated with lithium that lithium is often used therapeutically in medical conditions associated with neutropenia. Finally, Cohen and Cohen (1991) published a case report of a 17-year-old boy with Gilbert's disease who developed hyperbilirubinemia in the midst of a lithium trial. The hyperbilirubinemia resolved with

]. AM . ACAD . CHILD ADOLESC. PSYClllt\TRY . .\ .\ :.\. :-"l:\Rl'II\I '\,11

' ,h '

LITHIUM THERAPY

discontinuation of the lithium but returned when the patient was rechallenged with lithium. Lithium in Combination with Other Medications

Lithium in combination with a neuroleptic has been reported to cause somnambulism, seizures, increased incidence of extrapyramidal side effects, and neurotoxicity (Addonizio et al., 1988; Charney et al., 1979; Miller and Menninger, 1987). Development of neurotoxicity was dependent on neuroleptic dosage but was not correlated with serum lithium level (Miller and Menninger, 1987). Parmelee and O'Shanick (1988) published a case series of four adolescents with encephalopathy (three with traumatic brain injury, one with Lennox-Gastault syndrome) who became lethargic, neurotoxic, and aggressive while receiving the combination of lithium carbonate and carbamazepine. Seizure frequency increased. The symptoms resolved within 3 to 8 days of discontinuing the medications.

COMMENT Lithium has proved to be a useful drug in the management of a variety of psychiatric disorders. Although its use in children and adolescents is not as well documented as in adults and is mainly confined to uncontrolled reports, there is increasing evidence to suggest that it can play an important role in the psychopharmacologic treatment of child and adolescent psychiatric disorders. It has been used mainly in the treatment of mood disorders of adolescents, aggressive and disruptive disorders of childhood, and behavioral disorders coexistent with mental retardation and developmental disabilities. It does not appear to be associated with specific side effects in children and adolescents, nor is there any firm evidence to suggest that its side effects are increased in this population. However, its narrow margin of safety calls for close monitoring and supervision. It is hoped that insights into its basic mechanism of action, coupled with greater sophistication in the assessment of psychopathology, will stimulate controlled and prospective research on its use in children and adolescents.

REFERENCES Abe K (1977), Lithium prophylaxis of periodic hypersomnia. Br] Psychia-

try 130:312-316

Adams GL, Kivowitz J, Ziskind E (1970), Manic depressive psychosis, mental retardation, and chromosomal rearrangement. ArchGenPsychia-

try 23:305-309 Addonizio G, Roth SO, Stokes PE, Stoll PM (1988), Increased extrapyramidal symptoms with addition of lithium to neuroleptics. ] Nerv Ment

Dis 176:682-685 AlessiNE (1990), Refractorychildhood depressivedisorders from a pharmacotherapeutic perspective. In: Refractory Depression: Frontiers in Research & Treatment, Amsterdam J, ed. New York: Raven Press Alessi NE, Wittekindt J (1989), Childhood aggressive behavior. Pediatr

Ann 18:94-101 Allison JH, Blisner ME, Holland WH, Hipps PP, Sherman WR (1976), Increased brain myo-inosirol l-phosphare in lithium-treated rats. Bio-

chem Biophys Res Commun 71:664-670 Allison JH, Stewart MA (1971), Reduced brain inositol in lithium treated rats. Nature New BioI 233:267-268 Annell A (1969), Manic-depressiveillnessin children and effect of treatment with lithium carbonate. Acta Paedopsychiatr 36:292-301 Anthony J, Scott P (1960), Manic-depressive psychosis in childhood. ] Child Psychol Psychiatry 1:53-72 Bambrilla F, Catalano M, Lucca A, Smeraldi E (1988), Effect of lithium treatment on the GH-clonidine test in affective disorders. Eur ] Clin

PsychopharmacoI35:601-605 Baraban JM, Worley PF, Snyder SH (1989), Second messenger systems and psychoactive drug action: focus on the phosphoinositide system and lithium. Am] Psychiatry 146:1251-1260 Baudhuin MG, Carroll JA, Jefferson JW, Greist JH, Hartley BL (1987), Information and education about lithium: the Lithium Information Center. In: Depression and Mania: Modern Lithium Therapy, Johnson FN ed. Washington, DC: IRL Press Belmaker RH (1981), Receptors, adenylare cyclase, depression and lithium.

BioIPsychiatry 16:333-350 Bennett WG, Korein J, Kalmijn M, Grega OM, Campbell M (1983), Electroencephalogram and treatment of hospitalized aggressive children with haloperidol and lithium. Biol Psychiatry 18:1427-1440 Berg I, Hullin R, Allsopp M, O'Brien P, MacDonald R (1974), Bipolar manic-depressive psychosis in early adolescence: a case report. Br ]

Psychiatry 125:416-417 Berridge MJ, Downes CP, Hanley MR (1989), Neural and developmental actions of lithium: a unifying hypothesis. Cell 59:411-419 Bowring MA, KovacsM (1992), Difficulties in diagnosing manic disorders among children and adolescents. ] Am Acad Child Adolesc Psychiatry 31:611-614 Brumback RA, Weinberg WA (1977), Mania in childhood, II: therapeutic trial of lithium carbonate and further description of manic-depressive illness in children. Am] Dis Child 131:1122-1126 Brust JCM, Hammer JS, Challenor Y, Healton EB, Lesser RP (1979), Acute generalized polyneuropathy accompany lithium poisoning. Ann

Neurol6:360-362 Bunney WE, Garland-Bunney BL (1987), Mechanisms of action of lithium in affectiveillness: basic and clinical implications. In: Psychopharmacology: The Third Generation of Progress, Meltzer HY, ed. New York: Raven Press, pp 553-565 Cade JFJ (1949), Lithium salts in the treatment of psychotic excitement.

Med] Aust 2:349-352 Campbell M, Cohe1 IL, Small AM (1982), Drugs in aggressive behavior. I Am Acad Child Psychiatry 21: 107-117 Campbell M, Fish B, Shapiro T, Collins P, Koh C (1972), Lithium and chlorpromazine: a controlled crossover study of hyperactive severely disturbed children. ] Autism Child Schizophr 2:234-263 Campbell M, Perry R, Green WH (1984a), Use of lithium in children and adolescents. Psychosomatics 25:95-106 Campbell M, Schulman D, Rapport J (1978), The current status of lithium therapy in child and adolescent psychiatry. ] Am Acad Child

Psychiatry 17:717-719 Campbell M, Silva RR, Kafantaris V et al. (1991), Predictors of side effects associated with lithium administration in children. Psychopharmacol Bull 27:373-380

]. AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 33:3, MARCH/APRIL 1994

301

ALESSI ET AL. Campbell M, Small AM, Green WH, Jennings WG, Anderson L (l984b), Behavioral efficacy of haloperidol and lithium carbonate.

Arch Gen Psychiatry 41:650-656 Carlson GA (l979), Lithium use in adolescents: clinical indications and management. Adolesc Psychiatry 7:410-418 Carlson GA, Rapport MD, Kelly KL, Pataki CS (l992), The effects of methylphenidate and lithium on attention and activity level. J Am Acad Child Adolesc Psychiatry 31:262-270 Carlson GA, Strober M (l978), Affective disorders in adolescence: issues in misdiagnosis. J Clin Psychiatry 39:59-66 Cawthorne P (l990), A disorder unique to adolescence? The KleineLevin syndrome. J Adolesc 13:401-406 Chandler M, Gualtieri CT, Fahs J (1988), Other psychotropic drugs: stimulants, antidepressants, and lithium carbonate. In: Psychopharmacology ofthe Developmental Disabilities. Aman MG, Singh NN. New York: Springer-Verlag Charney DS, KalesA, Soldatos CR, Nelson JC (l979), Somnambalisticlike episodes secondary to combined lithium-neuroleptic treatment.

Br J Psychiatry 135:418-424 Cohen LS, Cohen DE (l991), Lithium-induced hyperbilirubinemia in an adolescent (letter). J Clin Psychopharmacol11:274-275 Cohn CK, DeVaul RA, Wright JR (l977), Post head trauma syndrome in an adolescent treated with lithium carbonate: case report. Dis

Nero Sys 38:630-631 Coli P, Bland R (l979), Manic depressive illness in adolescence and childhood: review and case report. CanJ Psychiatry 24:255-263 Cooper TB, Bergner PE, Simpson GM (1973), The 24-hour lithium level as a prognostication of dosage requirements. Am J Psychiatry 130:601-603 Davis RE (l979), Manic-depressive variant syndrome of childhood: a preliminary report. Am J Psychiatry 136:702-706 Delong GR (1978), Lithium treatment of select behavior disorders in children suggesting manic-depressive illness. J Pediatr 93:689-694 Delong GR, Aldershof AL (l987), Long-term experience with lithium treatment in childhood: correlation with clinical diagnosis. J Am

Acad Child Adolesc Psychiatry 26:389-394 Dostal T (l972), Antiaggressive effect of lithium salts in mentally retarded adolescents. In: Depressive States in ChildhoodandAdolescence. Annell A, ed. Stockholm: Almquist & Wiskell, pp 491-498 Dyson WL, Barcai A (l970), Treatment of children of lithiumresponding parents. Current Therapeutic Research 12:286-290 Eichelman B (l988), Toward a rational pharmacotherapy for aggressive and violent behavior. Hosp Community Psychiatry 39:31-39 Engstrom FW, Robbins DR, May JG (1978), Manic-depressive illness in adolescence. JAm Acad Child Psychiatry 17:514-520 Feinstein S, Wolpert E (l973), Juvenile manic-depressive illness. JAm

Acad Child Psychiatry 12:123-136 Fisman S, Max P, Woodside DB (1985), Affective disorder in an adolescent. Can J Psychiatry 30:530-534 Forrest IN, Cohen AD, Torretti J, Himmelhoch JM, Epstein FH (l974), On the mechanism of lithium-induced diabetes insipidus in man and the rat. J Clin Invest 53:1115-1123 Friedman E, Wang HY (l990), Effect of chronic lithium treatment on 5-hydroxyttyptamine autoreceptors and release of5-[3H] hydroxytryptamine from rat brain cortical, hippocampal, and hypothalamic slices. J Neurochem 50:195-201 Fristad MA, Weller EB, Weller RA (1992), The Mania Rating Scale: can it be used in children? A preliminary report. J Am Acad Child Adolesc Psychiatry 31:252-257 Fukuda K, Etoh T, Okuma T (1986), Affective disorders in mentally retarded adolescents: report of two caseswith lithium treatment. [pn

J Psychiatry NeuroI40:551-557 Gammon GD, John K, Rothblum ED, Mullen K, Tischler GL, Weissman MM (l983), Use of structured diagnostic interview to identify bipolar disorder in adolescentinpatients: frequency and manifestations of the disorder. Am J Psychiatry 140:543-547

302

Garcia-Sevilla JA, Guimon J, Garcia-Vallejo P, Fuster MJ (1986), Biochemical and functional evidence of supersensitive platelet alpha2-adrenoceptors in major affective disorder: effectoflong term lithium carbonate treatment. Arch Gen Psychiatry 43:51-57 Geller B, Fetner HH (l989), Children's 24-hour serum lithium level after a single dose predicts initial dose at steady-state plasma intervals. J Clin Psychopharmacol9: 155 . Ghadirian AM, Kusalic M (l990), Rapid cycling following antidepressant in an adolescent. Bioi Psychiatry 27:1184 Goldberg MA (l983), The treatment of Kleine-Levin syndrome with lithium. CanJ Psychiatry 28:491-493 Goodwin GM, DeSouza RJ, Wood AJ, Green AR (l986), Lithium decreases 5-HT, and 5-HTz receptor and alpha-2-adrenoceptor mediated function in mice. Psychopharmacology 90:482-487 Gram LF, Rafaelsen OJ (l972), Lithium treatment of psychotic children and adolescents. Acta Psychiatr Scand48:253-260 Greenhill LL, Rieder RO, Wender PH, Buchsbaum M, Zahn TP (l973), Lithium carbonate in the treatment of hyperactive children.

Arch Gen Psychiatry 28:636-640 Gross G, Dodt C, Hanft G (1988), Effect of chronic lithium administration on adrenoceptor binding and adrenoceptor regulation in rat cerebral cortex. Naunyn Schmiedebergs Arch PharmacoI337:267-272 Gross HA, Ebert MH, Faden VB, Goldberg SC, Nee LE, Kaye WH (1981), A double-blind controlled trial of lithium carbonate in primary anorexia nervosa. J Clin Psychopharmacol1:376-381 Hall DC, Ries RK (l983), Bipolar illness,catatonia, and the dexamethasone suppression test in adolescence: case report. J Clin Psychiatry 44:222-224 Hassanyeh F, Davison K (l980), Bipolar affective psychosis with onset before age 16 years: report of 10 cases. BrJ Psychiatry 137:530-539 Himmelhoch JM, Garfinkel ME (l986), Mixed mania: diagnosis and treatment. Psychopharmacol Bull 22:613-620 Hokin LE (l985), Receptors and phosphoinositide generated second messengers. Annu Rev Biochem 54:205-235 Horowitz HA (l977), Lithium and the treatment of adolescent manic depressive illness. Dis Nero Syst 38:480-483 Horta I, Yamawaki S, Segawa T (1986), Long-term lithium treatment causesserotonin receptor down-regulation viaserotonergic presynapses in rat brain. Neuropsychobiology 16:19-26 Hsu LKG, Starzynski J (1986a), Mania in adolescence. J Clin Psychia-

try 47:596-599 Hsu LKG, StarzynskiJ (1986b), Case reports: lithium-resistant adolescent mania. JAm Acad Child Adolesc Psychiatry 25:280-283 Hsu LKG, Starzynski J, [u ESY (1991), Treatment of bulimia nervosa with lithium carbonate: a controlled study. J Neru Mens Dis 179:351-355 Lefebvre A (l973), Depression and mania associated with Jeffries Kleine-Levin-Critchley syndrome. Can Psychiatr Assoc J 18:439-444 Joshi P, CapozzoliJ, Coyle J (1985), Effectivemanagement with lithium of a persistent, post-rraumatic hypomania in a 10-year-old child. J

n,

Dev Behav Pediatr 6:352-354 Joyce PR (1984), Age of onset in bipolar affective disorder and misdiagnosis as schizophrenia. Psychol Med 14:145-149 Kelly J, Kock M, Buegel D (l976), Lithium carbonate in juvenile manic depressive illness. Dis Nero Syst 37:90-92 Kerbeshian J, Burd L (1989), Tourerte disorder and bipolar symptomatology in childhood and adolescence. CanJ Psychiatry 34:230-233 Kerbeshian J, Burd L, Fisher W (1987), Lithium carbonate in the treatment of two patients with infantile autism and atypical bipolar symptomatology. J Clin PsychopharmacoI7:401-405 Khandelwal SK, Varma VK, Murthy RS (1984), Renal function in children receiving long-term lithium prophylaxis. Am J Psychiatry 141:278-279 Kolara GB (1980), NIH shaken by death of research volunteer. Science 209:475-476, 478-479 Lena B (1979), Lithium in child and adolescent psychiatry. Arch Gen

Psychiatry 36:854-855 Lena B, Bastable MD (l978), The reliability of salivarylithium estimations in children. IRCSJ Med Sci 6:208

j, AM. ACAD. CHILD ADOLESC. PSYCHIATRY. 33:3. MARCH/APRIL 1994

LITHIUM THERAPY

Lena B, O'Brian EMD (1975), Success with lithium in a disturbed child (letter) Lancet 2:1307-1308 Lena B, Surtees SJ, Maggs R (1978), The efficacy of lithium in the treatment of emotional disturbance in children and adolescents. In: Lithium in Medical Practice, Johnson FN, Johnson S, eds. Lancaster, England: MTP Press Ltd, pp 79-83 Licamelle WL, Goldberg RL (1989), The concurrent uses of lithium and methylphenidate in a child. J Am Acad Child Adolesc Psychiatry 28:785-787 Linter CM (1987), Short-cycle manic-depressive psychosisin a mentally handicapped child without family history: a case report. BrJ Psychiatry 151:554-555 Loranger AW, Levine PM (1978), Age at onset of bipolar affective illness. Arch Gen Psychiatry 35:1345-1348 MaggiA, EnnaSJ (1980), Regionalalterations in rat brain neurotransmitter systems following chronic lithium treatment. J Neurochem 34:888-892 Manji HK, Hsiao JK, Risby ED, Oliver J, Rudorfer MV, Potter WZ (1991), The mechanisms of action of lithium I: effects on serotoninergic and noradrenergic systems in normal subjects. Arch Gen Psychiatry 48:505-512 Mattes JA (1986), Psychopharmacology of temper outbursts: a review. J Nero Ment Dis 174:464-479 Mattson A, Seltzer RL (1981), MAOI-induced rapid cycling bipolar affective disorder in an adolescent. Am J Psychiatry 138:677-679 McKnew DH, Cytryn L, Buchsbaum MS et al. (1981), Lithium in children of lithium responding parents. Psychiatry Res 4:171-180 Miller F, Menninger J (1987), Correlation of neuroleptic dose and neurotoxicity in patients given lithium and a neuroleptic. Hosp Community Psychiatry 38:1219-1221 MorkA, GeislerA (1987), Mode of action of lithium on the catalyticunit of adenylate cyclase from rat brain. Pharmacol Toxicol 60:241-248 Mork A, Geisler A (1989a), Effects of GTP on hormone-stimulated adenylate cyclase activity in cerebral cortex, striatum, and hippocampus from rats treated chronically with lithium. Biol Psychiatry 26:279-288 Mork A, Geisler A (1989b), The effects of lithium in vitro and ex vivo on adenylate cyclase in brain are exerted by distinct mechanisms. Neuropharmacology 28:307-311 Naylor GJ, Donald JM, Le Poidevin D, Reid AH (1974), A doubleblind trial of long-term lithium therapy in mental defectives. Br J Psychiatry 124:52-57 Neil JF, Himmelhoch JM, Licata SM (1976), Emergence of myasthenia gravis during treatment with lithium carbonate. Arch Gen Psychiatry 33:1090-1092 Newman ME, Belmaker RH (1987), Effects of lithium in vitro and ex vivo on components of the adenylate cyclase system in membranes from the cerebral cortex of the rat. Neuropharmacology 26:211-217 Nielsen-Kudsk F, Amdisen A (1979), Analysis of pharmacokinetics of lithium in man. Eur J Clin PharmacolI6:271-277 Odagaki Y, Koyama R, Matsubara S, Matsubara R, Yamashita I (1990), Effects of chronic lithium treatment on serotonin binding sites in rat brain. J Psychiatry Res 24:271-277 Ogura C, Okuma T, Nakazawz K, Kishimoto A (1976), Treatment of periodic somnolence with lithium carbonate (letter). Arch Neural 33:143 Parmelee DX, O'Shanick GJ (1988), Carbarnazepine-lithium toxicity in brain-damaged adolescents. Brain Inj 2:305-308 Peatfield RC, Rose FC (1981), Exacerbation of migraine by treatment with lithium. Headache 21:140-142 Perry R, Campbell M, Grega DM, Anderson L (1984), Saliva lithium levels in children: their use in monitoring serum lithium levels and lithium side effects. J Clin PsychopharmacoI4:199-202 Picker W, Solomon G, Gertner J (1990), Lithium side effect. JAm Acad Child Adolesc Psychiatry 29:489 Platt JE, Camobell M, Green WH, Perry R, Cohen IL (1981), Effects of lithium carbonate and haloperidol on cognition in aggressive hospitalized school-age children. J Clin Psychopharmacoll:8-13

J.

Potter RL (1983), Manic-depressive variant syndrome of childhood: diagnostic and therapeutic considerations. Clin Pediatr (Phila) 22:495-499 Risby ED, Hsiao JK, Manji HK et al. (1991), The mechanisms of action of lithium. II. Effects on adenylate cyclase activity and betaadrenergic receptor binding in normal subjects. Arch Gen Psychiatry 48:513-524 Rogeness GA, Reister AE, Wicoff JS (1982), Unusual presentation of manic-depressive disorder in adolescence. J Clin Psychiatry 43:37-39 Rosenblatt JE, Pert CB, Tallman JF, Pert A, Bunney WE (1979), The effect of imipramine and lithium on alpha- and beta-receptor binding in rat brain. Brain Res 160:186-191 Ryan N, Meyer V, Dachville S, Mazzie D, Puig-Andrich J (1988), Lithium antidepressant augmentation in TCA-refractory depression in adolescents. JAm Acad Child Adolesc Psychiatry 27:371-376 Shafey H (1986), Use of lithium and flupenthixol in a patient with pervasive developmental disorder. Am J Psychiatry 143:681 Sheard MH (1975), Lithium in the treatment of aggression. J Nero Ment Dis 169:108-118 Siassi 1 (1982), Lithium treatment of impulsive behavior in children. J Clin Psychiatry 43:482-484 Somogyi I, Vetro A, Szentisvanyi I, Szekeley J, Sziland J (1988), Lithium treatment of aggressive children and the EEG. Acta Paediatr Hung 29:365-372 Spengler RN, Hollinsworth PJ, Smith CB (1986), Effects of long-term lithium and desipramine treatment upon clonidine-induced inhibition of 3H-norepinephrine release from rat hippocampal slices. Fed Proc 45:681 Stein GS, Hartshorn S, Jones J, Steinberg D (1982), Lithium in a case of severe anorexia nervosa. Br J Psychiatry 140:526-528 Steingard R, Biederman J (1987), Lithium responsive manic-like symptoms in two individuals with autism and mental retardation. JAm Acad Child Adolesc Psychiatry 26:932-935 Strayhorn JM, Nash JL (1977), Severe neurotoxiciry despite "therapeutic" serum lithium levels. Dis Nero Syst32:107-111 Strober M, Freeman R, Rigali J, Schmidt S, Diamond R (1992), The pharmacotherapy of depressive illness in adolescence, II: effects of lithium augmentation in nonresponders to imipramine. JAm Acad Child Adolesc Psychiatry 31:16-20 Strober M, Morrell W, Burroughs J, Lampert C, Danforth H, Freenan R (1988), Family study of bipolar 1 disorder in adolescence. J Affect Disord 15:255-268 Strober M, Morrell W, Lampert C, Burroughs J (1990), Relapse following discontinuation of lithium maintenance therapy in adolescents with bipolar illness: a naturalistic study. Am J Psychiatry 147:457-461 Sylvester CE, Burke PM, McCauley EA, Christopher J (1984), Manic psychosisin childhood: report of two cases. J NeroMent Dis 172:12-15 Treiser S, Kellar KJ (1979), Lithium effects on adrenergic receptor supersensitivity in rat brain. Eur J Pharmacol 58:85-86 Treiser SL, Cascio CS, O'Donohue TL, Thoa NB, Jacobowitz DM, Kellar KJ (1981), Lithium increases serotonin release and decreases serotonin receptors in the hippocampus. Science 213: 1529-1531 Tyrer SP, Walsh A, Edwards DE, Berney TP, Stephens DA (1984), Factors associated with a good response to lithium in aggressive mentally handicapped subjects. ProgNeuropsychopharmacol BioiPsychiatry 8:751-755 Varanka TM, Weller RA, Weller EB, Fristad M (1988), Lithium treatment of manic episodes with psychotic prepubertal children. Am J Psychiatry 145:1557-1559 Vetro A, Pallag P, Szentisrvanyi LI, Vargha M, Szilard J (1981), Treatment of childhood aggressivity with lithium. Agressologie 22:27-30 Vetro A, Szentistivanyi LI, Pallag P, Vargha M, Szilard J (1985), Therapeutic experience with lithium in childhood aggressivity. Neuropsychobiology 14:121-127 Vitiello B, Behar D, Malone R, Delaney MA, Ryan PJ, Simpson EM (1988), Pharmacokinetics of lithium carbonate in children. J Clin PsychopharmacoI8:355-359

AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 33:3, MARCH/APRIL 1994

303

ALESSI ET AL. Whirworth P, Kendall DA (1989), Effects on lithium on inositol phospholipid hydrolysis and inhibition of dopamine Dl receptormediated cyclic AMP formation by carbacol in rat brain slices. ]

Warneke LA (1975), Case of manic-depressive illness in childhood.

Can Psychiatr Assoc ] 20:195-200 Weinberg WA, Brumback RA (1976), Mania in childhood: case studies and literature review. Am] Dis Child 130:380-385 Weiner IB, del Gaudio AC (1976), Psychopathology in adolescence.

Neurochem 53:536-541 Will RG, Young ]PR, Thomas D] (1988), Kleine-Levin syndrome: report of rwo cases with onset of symptoms precipitated by head trauma. Br] Psychiatry 152:410-412 Winchel RM, Stanley M (1991), Self-injurious behavior: a review of the behavior and biology of self-mutilation. Am] Psychiatry 148:306-317 Wood IK, Parmelee DX, Foreman ]W (1989), Lithium-induced nephrotic syndrome. Am] Psychiatry 146:84-87 Youngerman ], Canino IA (1978), Lithium carbonate use in children and adolescents. Arch Gen Psychiatry 35:216-224 Youngerman], Canino IA (1983), Violent kids, violent parents: family pharmacotherapy. Am] Orthopsychiatry 53:152-156

Arch Gen Psychiatry 33:187-193 Weller EB, Weller RA, Fristad MA (1986), Lithium dosage guide for prepubertal children: a preliminary report. ] Am Acad Child Ado/esc

Psychiatry 25:92-95 Weller EB, Weller RA, Fristad MA, Carrwell M, Tucker S (1987), Saliva lithium monitoring in prepubertal children. ] Am Acad Child Adolesc Psychiatry 26: 173-175 Whitehead PL, Clark LD (1970), Effect of lithium carbonate, placebo, and thioridazine of hyperactive children. Am]Psychiatry 127:824-825

Coming in May: Interviewing Children about Suicidal States Leslie K Jacobsen et al.

•

Bipolar Disorder and Schizophrenia Gabrielle A. Carlson et al.

•

Rate and Predictors of Prepubertal Bipolarity Barbara Geller et al.

•

Follow-up of Delinquent Males Dorothy Otnow Lewis et al.

•

Family Structure and Aggressive Behavior Jane L. Pearson et al.

304

j. AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 33:3, MARCH/APRIL 1994