Lithium in children of lithium-responding parents

Ps_~chiatrv Research, ElsevierlNorth-Holland

Lithium

171

4, 171-180 (1981) Biomedical Press

in Children

of Lithium-Responding

Parents

Donald H. McKnew, Leon Cytryn, Monte S. Buchsbaum, Joel Hamovit, Martine Lamour, Judith L. Rapoport, and Elliot S. Gershon Received August 12. 1980; revised manuscript received January 29, 1981; accepted February 2, 1981. Abstract. Six offspring responders, treatment crossover

of manic-depressive patients, whose parents were lithium were selected on the basis of their incapacitating psychopathology for with lithium. The children ranged in age from 6 to 12. A double-blind, design was used over 16-18 weeks. Weekly ratings were done, and

average evoked potentials (EPs) were measured at each crossover. Two children diagnosed as having a bipolar affective disorder had a clear-cut response to lithium and were strong augmenters on the EP. This, taken together with the similarity of the EP changes on lithium to those occurring in adult patients treated with lithium, supports a physiological parallel between bipolar affective illness in adults and children. Key Words. Lithium,

children,

evoked

potentials,

depression.

is growing interest in the use of lithium in child psychiatry (Frommer, 1968; Youngerman and Canino, 1968; Annell, 1969; Dyson and Barcai, 1970; Campbell et al., 1972; Rifkin et al., 1972; Greenhill et al., 1973; DeLong, 1978; Rapoport et al., 1978). A recent survey of the world literature reviewed a total of 223 cases of children and adolescents treated with lithium. Of these, 165 cases were not described in sufficient detail to allow relevant conclusions to be drawn. The remaining 58 cases were more completely reported. Even in these cases, however, not all authors recorded a complete family history, parental response to lithium, or a complete diagnostic evaluation of the subjects. Of the 58 cases, 32 were reported as having a positive family history of affective disorders and, of these, five were reported to be children of lithium-responding family members (Youngerman and Canino, 1968). The diagnostic categories of these youngsters included: manic-depressive illness, other periodic mood swings, behavior disorders, hyperkinesis, and childhood psychosis. Most reported There

Leon Cytryn, M.D., and Donald H. McKnew, Jr., M.D., are Staff Psychiatrists in the Unit on Childhood Mental Illness of the Biological Psychiatry Branch (BPB), National Institute of Mental Health (NIMH). They are also with the George Washington School of Medicine, where Dr. Cytryn is Clinical Professor and Dr. McKnew is Clinical Associate Professor, Departments of Psychiatry and Behavioral Sciences and Child Health and Development. Monte S. Buchsbaum, M.D., is Chief, Section on Clinical Psychophysiology, BPB. Martine Lamour, M.D., and Joel Hamovit, M.S.W., are also in the Unit on Childhood Mental Illness. Dr. Lamour is supported by a fellowship from the Fondation pour la Recherche Medicale Francaise. Judith L. Rapoport, M.D., is Chief, Unit on Childhood Mental Illness. Dr. Gershon is Chief, Section on Psychogenetics, BPB. (Reprint requests to Dr. McKnew, National Institute of Mental Health, Bldg. IO, Rm. 3N204, 9000 Rockville Pike, Bethesda, MD 20205.)

An earlier version of this article was presented Association. San Francisco, CA, 1980.

0165

1781 kl 0000 ~0000:$02.50

at the Annual

0 Elseviers North-Holland

Meeting

Biomedical

of the American

Press

Psychiatric

172 cases did not include controls, systematic behavioral observations, or double-blind methodology. In the better documented studies, most of the children who responded to lithium had symptoms of a manic-depressive illness, a positive family history for affective disorders, and at least one lithium-responding parent (Youngerman and Canino, 1968; DeLong, 1978). The dosage used in these studies ranged widely from 50 mg to 2,400 mg per day. Most investigators strived for a blood level of 0.5-1.5 mEq/liter. Some authors (Dostal and Zvolsky, 1970; Campbell et al., 1972) reported side effects which seem identical to side effects in adults: polydipsia, polyuria, hand tremor, gastrointestinal complaints, and other less defined symptoms. It is of interest, however, that in all 223 reported cases, relatively few side effects were reported. In fact, some of the above investigators gave lithium to brain-damaged children, with a deviant EEG and even epilepsy, without any ill effects. A recent position paper (Campbell et al., 1978) of the Committee on Biological Psychiatry of the American Academy of Child Psychiatry also deplores the fact that most reports on lithium therapy of children and adolescents are based on uncontrolled studies of patient samples that are not well-defined either diagnostically or behaviorally. In view of the unsatisfactory state of treatment of certain moderate to severe child disorders and their poor outcome (Robins, 1966), lithium should be explored and its effects critically assessed under controlled conditions. The Committee anticipates greater use of lithium with pediatric patients in the future, and identifies children with behavioral symptoms whose parents are lithium responders as the group most likely to respond to lithium. There is reason to believe that drug response is influenced by genetic factors (Dyson and Barcai, 1970; Ayd, 1975; Liebowitz et al., 1976). To date, despite many extensive studies of the heredity of affective disorders, no consistent genetic markers have been found (Gershon, 1978). Yet, family histories and the pharmacological and biochemically distinctive characteristics found in affective disorders indicate hereditary factors (Cytryn and McKnew, 1980). There are several strategies that could identify children at genetic risk: (1) to find a clinically homogeneous subgroup, (2) to find a subgroup responsive to a drug regardless of the kind of psychopathology, and (3) to find a subgroup with a distinctive physiological characteristic such as the average evoked potential measure of augmenting/reducing which has been shown to be predictive of clinical lithium response in adults (Buchsbaum et al., 1971; Baron et al., 1975; Nurnberger et al., 1979). Our previous study (McKnew and Cytryn, 1979) indicates that children of manicdepressive patients are themselves at risk for depression. Many of our patients have a parent with affective disorder who has responded to lithium. It would seem warranted to treat the psychiatrically disturbed offspring of such parents with lithium, provided that there is careful and frequent monitoring of the doses of lithium, blood levels, and side effects.

Hazards Before we began our study, we carefully reviewed the recent literature on the hazards of lithium because of its infrequent use in children. Bakker (1977), in an extensive study of lithium carbonate, found the following: Lithium carbonate at serum levels from 0.4 to 1.2 has a rapid effect on thyroid

173 hormone release. This leads to an initial decrease of free thyroxine (TJ and triiodothyronine (TJ during the first 4 months. In euthyroid patients, a compensatory rise of levels of thyroid-stimulating hormone (TSH) in response to thyrotropin releasing hormone (TRH) results in normalizing thyroid hormone levels. Patients on long-term lithium therapy with low thyroid reserve based on present thyroid antibodies, a known history of thyroiditis, and a positive family history of thyroid disease are often predestined to develop transient or, in some cases, permanent hypothyroidism. This does not occur in short-term treatment. Shopsin and Gershon (1973) also state that lithium-related thyroid dysfunction occurs only in patients with previous clinical or subclinical thyroid disorders. They stressed that lithium-induced goiter was only reported after prolonged lithium treatment and, as noted, in patients with previously marginal thyroid function. There have also been rare cases of thyrotoxicosis reported which also occurred only after years of lithium therapy (Rosser, 1976). The renal side effects may include sodium diuresis, polyuria, and polydipsia which are usually reversible after discontinuation of treatment or reducing the lithium doses (Baldessarini, 1976). Diabetes insipidus has been rarely reported, only after prolonged lithium treatment of many months or years. Usually, this too is reversible when lithium treatment is stopped. However, there have been some recent reports (Chapman and Lewis, 1972; Lindop and Padfield, 1975; Hestbech et al., 1977) of irreversible decreased renal function and diabetes insipidus only after a prolonged maintenance treatment with lithium over a period of many months or years. Biopsy or necropsy material in these patients indicated chronic tubular necrosis, fibrosis, and nephron atrophy. The only case of EEG abnormality in a child on lithium (without clinical symptoms) was reported in a patient with a previous history of encephalitis. The EEG returned to normal when lithium therapy was stopped (Brumback et al., 1975). The available literature on lithium administration in children indicates that due to superior renal clearance, children tolerate lithium as well or better than adults (Schou, 1972).

Methods As part of an ongoing investigation, six patients (four boys and two girls) who range in age from 6 to 12 have been studied (Table 1). Each patient was selected on the basis of psychopathology of sufficient severity to be incapacitating and of concern to parents, school authorities, or both. Any children with significant brain damage or an IQ below 80 were excluded from the study. Five of the children had a lithium-responding parent with primary affective illness, and one child had an affectively ill lithium-responding grandmother. The parental illness was verified by the Schedule of Affective Disorders and Schizophrenia (SADS) and diagnosed by the Research Diagnostic Criteria (RDC) as modified by Gershon (Leckman et al., 1977; Spitzer et al., 1977; Mazure and Gershon, 1979). Admission Workup. A psychosocial history of the child and his family was obtained. In addition, the parents were requested to do a Q-sort of target symptoms from the Deviant Behavior Inventory (DBI; Novick et al., 1966). A diagnostic evaluation of the child was obtained including a structured interview and a routine physical examination. The Children’s Psychiatric Rating Scale (CPRS) of the ECDEU and the Children’s Affective Rating Scale (CARS) were filled out, and a list of target symptoms was formulated by the child interviewer. On the basis of all available information, each child received one or more clinical diagnoses based on DSM-III.

174

Table

1. DemoaraDhic

data on the children

and their families

Diagnosis of lithium-responding relatives’

Diagnosis of other relatives’

Patient

Aae

Sex

A

9

F

Mother: Bipolar II with major depression Drug abuse

Father:

B

12

F

Paternal grandmother: Unipolar

Mother: Hyperthymic personality Father: Hyperthymic personality Paternal uncle: Unknown psychiatric disorder which required hospitalization

C

11

M

Mother: Bipolar depression Alcoholism Drug abuse

II with major

Father: No information available

D

11

M

Mother:

Bipolar

I

Father: Alcoholism, Minor depression Brother: Bipolar I

E

12

M

Mother:

Unipolar

F

10

M

Father:

Bipolar

Father: I

Mother:

Phobic

disorder

Minor depression Minor depression

1. RDC as modified by Gershon

Blood was drawn for creatinine, BUN, Tj, T,, and TSH to rule out renal or thyroid pathology. These tests were also repeated at the end of the study. The average evoked potential (EP) measure of augmenting/ reducing was recorded using four intensities of light stimulation as described previously (Buchsbaum, 1979). Details of stimulus presentation, computation, and method reliability are reported elsewhere (Buchsbaum et al., 1977; Buchsbaum, 1978, 1979). The teacher was asked to fill out the abbreviated Conner’s Teacher Rating Scale (TRS; Conners, 1969). Weekly Procedures. A double-blind, crossover design was used over 16-18 weeks and included two alternating lithium and two placebo periods. Patients were randomly assigned to lithium or placebo first. No patient had been on any psychoactive medication for 1 year. The adequacy of lithium administration was assessed by weekly blood levels and was adjusted until a blood level between 0.8 and 1.2 mEq/l was obtained. The case coordinator (J.R.), who was not involved in any assessment, adjusted the number of tablets for a placebo period to parallel the adjustment of the active drug. Side effects were monitored. The second period of lithium administration was begun with the previously determined child’s effective dose. The parent and child were seen on a weekly basis for evaluation by three of us (D.M., L.C., J.H.) who were all unaware of medication type. A brief structured interview of 15-30 minutes with a special focus on the target symptoms was done. The interview was rated on the target items of the CPRS and the CARS. The parents rated their target symptoms (derived from the DBI) and were interviewed about the week’s events. Global rating of the child’s status was done independently by the child’s interviewer and the parent’s interviewer for each diagnosis separately.

175

The teacher filled out a Conners’ TRS weekly. EPs were recorded during a baseline session before the drug trial began and once during each crossover. Statistics. The statistical analysis used for rating scales was an unpaired two-tailed t test of the global ratings for lithium versus placebo periods in each subject. Following the procedure of Bartlett (I 9354, the degrees of freedom were reduced by 0.66 because of the correlated measures. Spearman rank order correlation was used to compare the EP and the ratings. For the EP data, a two-way analysis of variance was used, with lithium/ placebo as a repeated measures dimension and the amplitude of the EP at the four intensities as a repeated measure with linear trend analysis. Conservative degrees of freedom were used.

Results A total of six patients were screened, of whom five completed all phases of the study. Four of the subjects had more than one diagnosis. On the basis of our information, it was impossible to ascertain which disorder was primary. There was no discernible pattern for clustering of specific diagnoses. Table 2 gives the children’s diagnoses and the children’s response to lithium, as rated independently by the child’s interviewer, the parent’s interviewer, and the teacher. Two girls (A and B), ages 8 and 12, diagnosed as having a bipolar affective disorder, mixed, responded to lithium on both the child’s and parent’s ratings. B had a dramatic response to lithium in both manic and depressive symptoms, but the mother kept occasionally giving lithium (from grandmother’s prescription) during placebo periods, verified by positive lithium blood levels, making statistical evaluation impossible. A boy (C), age 11, diagnosed as having an attention deficit disorder with hyperactivity and overanxious disorder, was rated as lithium responsive on the basis of the parents’ reports, but not on the reports of the child’s interviewer. The teacher’s rating closely approached significance. An 1 l-year-old boy (D) with three diagnoses-major depressive disorder, recurrent, attention deficit disorder with hyperactivity, and overanxious disorder-was rated as lithium responsive by the child’s rater only on overanxious disorder, but not on the other diagnoses. The parent’s and teacher’s ratings were negative for all diagnoses. The two remaining children showed no response to lithium on any rating: a boy (E), age 12, with an attention deficit disorder with hyperactivity and cyclothymic disorder, and a boy (F), age 10, with encopresis and major depressive disorder, recurrent. EP Findings. The full set of visual EPs was obtained for five children; one child (B) received only the baseline and two lithium sessions. To predict lithium response, we used the average of the P 100 amplitude/ intensity slope for the two placebo sessions in five children and the baseline in the sixth (B). The evaluation of the efficacy of the EP augmenting/ reducing measure in predicting lithium response cannot be statistically confirmed in this small sample. Global child rating correlated with EP amplitude/intensity slope, TS = 0.66 (n = 6, p < 0.20). However, it is of interest that the strongest augmenter, patient A, was the only child to show both significant global child and global parent rating improvement. The two patients with significant global parent rating improvement also had higher amplitude/intensity slopes than the three with nonsignificant rating change (Table 2). Patient B, who clinically appeared to respond dramatically, was the second highest augmenter.

mixed

Bipolar,

Overanxious disorder Attention deficit disorder

Major depressive disorder, recurrent Attention deficit disorder with hyperactivity Overanxious disorder

Attention deficit disorder with hyperactivity Cyciothymic disorder

Encopresis Major depressive disorder, recurrent

B

C

D

E

F

0.93

4.00

4. 5. 6. 7.

Not significant. p < 0.001, t test. p = 0.06, t test. Child denied symptom.

response

3.634

1.07

2.334

2.254

2.751

3.004

2.114

2.894

2.504

responsive3

2.111

Mean

SD

1.60

0.00

1.00

1.04

1.39

1.07

1.05

0.09

1.77

0.60

Lithium

child rating

placebo

0.00

1.0

0.90

2.14

1.21

4.33

0.74

1.54

3.11

1.38

1.81

0.71

3.25

3.13

1.12

Lithium

1.13

SD

2.00

3.13

Mean

3. Lack of parental cooperation/invalidated

1. p < 0.05,

t test. 2. p c 0.01, f test.

mixed

Bipolar,

Diagnosis (DSM-iii)

A

Patient

Placebo

Global

3.71

3.86

2.00

2.57

3.67

3.22

2.44

5.88

4.13

3.50

0.76

SD

rating

2.332

0.95

2.27

1.83

1.72

1.97

1.30

1.33

0.99

0.83

2.674

2.334

4.444

4.334

4.254

2.634

2.384

3.785

2.335

1.22

1.66

1.74

1.50

0.71

1.06

1.41

0.97

0.87

0.71

SD

Lithium Mean

parent

Lithium responsive3

Mean

Placebo

Global

Table 2. Children’s diagnoses and their response to lithium

0.0

13.75

19.88

Mean

Mean

0.04

11.254

14.29s

Not available

Not available

11.88

5.91

Not available

Not available

SD

6.41

3.77

SD

Lithium

Teacher rating Placebo

0.27

0.27

0.43

0.08

0.49

0.54

0.69

Placebo

Evoked potential augmenting/ reducing (pV/iog FLiamberts)

=!

v.

177

EP changes with lithium were similar to those observed with lithium in adults-a significant increase in amplitude for the N120 component, from placebo to lithium, occipital lead (Oz) for all five children. The average amplitude (across all intensities) went from 9.09 PV to 13.83 PV (F= 18.08, df= 1,4,p< 0.01). The PlOO component at Oz also showed a significant enhancement (F = 10.20, p < 0.05).This pattern was maintained in patient B, 12.91 PV baseline, 13.69 /_LVon lithium. Case Reports. Purient A comes from a stable home environment, except for the periods of mother’s bipolar affective disorder, mixed, which was most severe when the child was 5 years old. Since then, the mother has been successfully treated with lithium. The child’s history was essentially normal until age 5, when she developed frequent mood swings culminating in a suicidal episode at age 8, at which time, after leaving a will on her desk, she asked her father to crush her head with a stone. Her hypomanic periods were characterized by anger, agitation, lack of cooperation, and some grandiosity. Patient B comes from a very stable background. Her parents were free of major mental illness. However, the paternal grandmother and a paternal uncle had an episodic affective disorder. The major depressive disorder, recurrent, of the paternal grandmother was successfully treated with lithium. B’s growth and development was normal until age 12, when she developed a hypomanic episode consisting of bragging about her sexual exploits and being overtalkative, restless, and aggressive; this episode was in great contrast to her usual behavior. Shortly thereafter, she developed a severe depression with suicidal ideation and self-depreciation. The above contrasting behaviors began to alternate in an irregular fashion, culminating in a suicidal attempt by drowning. Patient C comes from a very disturbed family background, although his early development appears relatively normal. The father deserted his family when the patient was 2 years old. His mother has a history of bipolar affective disorder, mixed, associated with drug abuse and alcoholism. The mother’s illness has been relieved by lithium, and she has been functioning well for the past 3 years. Her relationship with the child was positive except for her overprotectiveness. Mother reported that the boy was always hyperactive and very anxious. This was confirmed by teacher’s reports of his short attention span, distractibility, and irritability, Despite an above normal intelligence, he has functioned consistently below his capacity in school. Patient D’s background was also very troubled. His mother and his older brother both have bipolar affective disorder, mixed, and his father has a minor depressive disorder and alcoholism. His parents were divorced when the patient was 3 years old, and since that time he has lived with his mother and her two subsequent husbands. Despite superior intelligence he was failing in school because of his impulsive behavior, short attention span, hostility, and suspiciousness. During the year before our study, D lived with his maternal grandmother, who is a mature and loving woman, although somewhat anxious. She assumed custody of the boy during one of his mother’s hospitalizations. D was in psychotherapy during the year before his entrance into our study. Patient E, age 12, had a normal and stable development until age 1% when his mother was hospitalized with a major depressive disorder which responded to lithium.

178 While she was in the hospital and for a month afterwards, the child remained very anxious, with crying spells and crib rocking. His disturbance continued to manifest itself in speech problems which remained until age 4. At age 10, he began to be hostile to his parents and developed reading problems at school. A psychiatric consultant felt he was very disturbed and not responding to psychotherapy. Patient F, age 10, had a normal development except for failure of bowel and bladder training-difficulties which have continued. His father has a bipolar affective disorder, mixed, which is well controlled by lithium. The family situation is characterized by friction because of the father’s illness and the mother’s depressive disorder. The patient was referred to the study by the father because of the encopresis, but our evaluation revealed a very depressed young boy with sleeplessness and somatic complaints. He had low self-esteem and saw himself as a scapegoat at home and with friends. Despite superior intelligence, he was doing poorly in school.

Discussion The hypothesis of an inherited response to lithium regardless of the psychopathology of the offspring is partially supported by this preliminary data and may apply to children with a clear-cut bipolar illness. Both patients with a major depressive disorder failed to respond, as did one with a cyclothymic disorder. Of the three instances of attention deficit disorder with hyperactivity, one responded and two did not. This finding therefore does not support the report of Dyson and Barcai (1970) despite the fact that both failures also had an affective illness (see Table 2). The lack of lithium response in hyperactive children reported by Greenhill et al. (1973) is more in accord with our data. Many studies, especially from Europe (Rapoport et al., 1978), report doses of 900-l ,500 mg of lithium/ day as needed to achieve a therapeutic level: OS- 1.5 mEq/ 1. In contrast, in this study 900 mg was always sufficient to achieve such a level, and one patient, a 9-year-old girl, required only 600 mg/day. In accord with the reports of other investigators, there was a remarkable lack of side effects. There was only one case of hand tremor which occurred in the aforementioned girl, and promptly subsided when her dose was reduced. There was often a disparity between the parents’, teachers’, and child interviewer’s weekly ratings of the patients. Such disagreements between home, school, and clinic ratings of child behavior have been reported by many researchers studying prepubertal psychopathology (Rutter et al., 1970; Shaffer and Greenhill, 1979). In conclusion, pharmacogenetic considerations aside, even our small sample gives further credence to the efficacy of lithium in certain childhood disorders. Our best two responders not only had a bipolar diagnosis but an electrophysiological pattern, augmenting, which has previously been associated with lithium response. This, taken together with the similarity of the EP changes on lithium to those occurring in adult patients treated with lithium, supports a physiological parallel between bipolar affective illness in adults and children. Acknowledgment. John Bartko, Ph.D., Mathematical Statistician, Division of Biometry and Epidemiology, NIMH, and Marcia Minichiello and Cathy King, Research Assistants, Biological Psychiatry Branch, NIMH, assisted in analysis of the data.

179

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