Valproate in very young children: an open case series with a brief follow-up - Psychiatricanswers

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Valproate in very young children: an open case series with a brief follow-up

Manuel Mota-Castillo*, Alicia Torruella, Bonnie Engels, Javier Perez, Carole Dedrick, Mark Gluckman
Youth Developmental Institute, 5050 North 8th Place, #8, Phoenix, AZ 85014, USA
The Journal Of Affective Disorders
Received 6 February 1999; accepted 17 December 1999

We report nine cases of juvenile mania, of which six began in the preschool years. We provide validation by clinical description, family history of bipolar disorder, worsening on stimulants, and considerable mood stabilization with divalproex.

This is a relatively new area of clinical observation, and systematic studies are needed to firmly establish this diagnostic category in very young children. Our case series enriches the existing scant literature and provide the rationale for the use of mood stabilizers rather than stimulants in this juvenile population. However, no controlled studies exist on the efficacy and safety of valproate in this age group; lithium that has received greater clinical attention, has not been subjected to controlled studies either. Our clinical observations with divalproex are preliminary but encouraging.

1. Introduction
Although much skepticism surrounds childhood bipolar disorders, clinical research during the past decade has established their existence (Akiskal et al.,1985; Weller et al., 1986, 1995; Geller and Luby, 1997). The major controversy today is not the existence of this disorder in this age group, but how to distinguish it from ADHD or attention deficit hyperactivity disorder (Geller et al., 1998b). The November 1998 issue of this journal (Carlson et al., 1998) was devoted to the Proceedings of the National Institute of Mental Health Conference examining this and related questions in great depth. While many questions remain unanswered, it is quite clear that the two disorders can exist separately, but not uncommonly together. The form of bipolar disorder in children more often than not is complex, involving rapid cycling, as well as mixed states (Geller et al.,1998a); euphoric mania is rare, and hostile-aggressive behavior is prevalent, as is conduct disturbance.

On the other hand, many classical features of mania can be seen in these children, such as increased confidence, psychomotor acceleration, push of speech, grandiosity, and hypersexuality.

There is virtually no research experience in the treatment approach to these patients, but clinicians are expected to manage the extreme behavior of these children. This paper reports our clinical experience in young and very young children who exhibit clear-cut manic behavior, often associated with restless hyperactive behavior that may or may not meet the full criteria for attention deficit hyperactivity disorder.

2. Methods
This collection of cases comes from two outpatient clinics that provide psychiatric services for low income people in Maricopa County, and from a private group practice. We have evaluated many children who met the DSM-IV criteria for mania, both with and without ADHD. The case series reported here represent those that remained under our care for a sufficient length of time for us to be reasonably confident in our diagnosis of mania. All but one were successfully treated with the same type of medications used for adults with that diagnosis. The exception pertains to patient 2, whose mother objected to the bipolar diagnosis, and preferred the teacher's diagnosis of ADHD, which she felt offered 'better hope'. We regret that we did not have the chance to provide more specific treatment to this very young child with very disruptive behavior with strong manic coloring.

One of our motivations in writing this paper is to record the difference that a specific affective diagnosis can make in the treatment of these young children, how their and their family's quality of life improves .

3. Results
3.1. Case 1
This is a 25-month-old boy who was referred because of aggressive and disruptive behavior in his home and daycare. Besides head banging, he bit, kicked and hit children and adults alike. He could not play in a group. He was defiant of authority and failed to (or could not) listen or follow instructions. He had episodes of 'disinhibition' (e.g., taking his clothes off and exposing his genitals to his peers). Once he followed a girl his age to the bathroom, grasped her crotch and laughed about it. He had been expelled from two daycare centers and several babysitters refused to continue to care for him.

In the diagnostic evaluation, he presented as a friendly Caucasian 2 year old. He did not fidget, run about excessively or appear restless. He showed age appropriate ability to concentrate and complete tasks. His affect was labile, abruptly shifting back and forth  from happy or content to angry. Family history was significant. The father and grandfather have confirmed bipolar disorder, the maternal grandmother is alcoholic and the mother's side was notable for several members with depression. There was no family history of attention problems with or without hyperactivity. Patient had never been exposed to pornographic movies, and had not been subjected to sexual abuse; nor was he ever witness to sexual activity between parents .

The referral was made for a psychiatric and medication evaluation to rule out bipolar disorder, as the symptomatology appeared to differ sufficiently from ADHD. In addition, no improvements had occurred in his behavior in response to improved parenting skills; his parents had been taught cognitive behavior parenting techniques. When the psychiatric evaluation was completed, the diagnosis of cyclothymic disorder was made. The patient never met the criteria for full-blown mania. Clinically his problem was in the realm of the mood disorders, not simply a problem with hyperactivity and impaired attention.

The parents agreed to start a trial with a mood stabilizer. Valproic Acid was chosen because it comes in liquid form and has an acceptable safety profile when given to infants with seizures. Dose was calculated at 20 mg / kg but initiated at only 125 mg at HS to minimize the possibility of side effects.

After 1 week we went to 250 mg / day: we observed a significant decrease in his aggressive behavior. The daycare refused to take him back despite such improvement, as a result of which he was entrusted to the care of a new babysitter. This babysitter tried to convince the parents to stop the medication; she even asked them, "if she could speak to the psychiatrist to explain to him why this boy can be managed without drugs".  Fortunately the parents decided to follow the doctor's advice and increased the dose of valproic acid to 375 mg/ day. Patient was much calmer and appropriate when he came for a follow-up visit 3 weeks later. His mother said he still bit occasionally, but was less aggressive with his peers. There were no further undressing or genital exposing episodes. His sleep was longer and uninterrupted. Father said, "not perfect, but better: we can negotiate with him, and he is not taking his clothes off". Mother reported that the week before he hit her and threw a glass at her face. In the office, he was overactive and biting everything, even his shoes.

Valproic acid level was 80. Liver, kidney, and thyroid function were within normal limits, WBC was also normal. We increased the valproate to 500 mg/day. In 2 weeks the family returned with a smiling father. "He is not hitting at home or at the daycare and biting has decreased . . . he says 'thank you' and is more cooperative." Patient was noticed . to be less talkative and more appropriate. Blood work was done but this time the valproate level was even lower, 72. That could be explained in part as the medication being missed in the process of mixing it with juice or apple sauce, or his not drinking all of it. Nevertheless, the new daycare has not complained to parents about his behavior over a period of 6 months.

3.2. Case 2
This 4-year-old boy was referred to us because of restlessness at school and at home. We suspected a mood disorder, not only because of his poor response to prior stimulant treatment for ADHD, but also because of his extroverted demeanor. One day he walked up to the receptionist (a 6-foot grandmother) and talked to her like a grown man, asking her for a date! Patient's mother was a social worker and was perturbed by the prospect of her son being treated for bipolar disorder. She said all the literature on this topic by child pediatric experts was 'bunk'. Patient was evaluated by another psychiatrist who concurred with our clinical impression and recommendation. His mother refused to accept this second opinion and took her son to yet another provider. We lost contact with this patient.

3.3. Case 3
The mother of this charming 5-year-old girl requested help because, "I began to see myself in her behavior and people were telling me that she had ADHD". Symptoms had started at 2 years of age, but the evaluating psychiatrist had advised counseling for the mother. Although the mother took medication for bipolar disorder, she initially denied a family history because - she explained - she wanted an unbiased opinion.

The patient had a history of being "hyper, mouthy, talkative, and when watching cartoons she can't keep her attention". She responded to valproate at a blood level of 86. Despite her bronchial asthma, which requires bronchodilators, she has been doing very well during 6 months of follow-up. At last follow-up, the mother stated that patient's behavior was "excellent ... she sleeps all night without arguing ... she has slowed down". She is attending kindergarten and behaving well.

3.4. Case 4
Patient was previously treated for ADHD at a pediatric hospital. The boy, a 40-lb, 4 year old, was rece1vmg clonidine 0.8 mg/day along with methylphenidate ( 10 mg I day). Despite this regimen, patient's father said it is as though his son was on 'speed'.
When first seen by us, he was tachycardic (184/min, double-checked 10 min apart). Presenting complains were: mood swings, aggressive behavior and impulsivity. Parents reported that when he was 1 year old he would not follow directions, had poor sleep patterns and was bossy with his older siblings.
Family revealed that the mother had OCD and the father had severe 'mood swings'; a 14-year-old brother had been diagnosed ADHD and parents recently requested that our clinic evaluate him, because "he had not done well on many different medications". On initial interview, patient was restless, intrusive, very happy and friendly. This is in contrast to his past behavior when he was diagnosed as 'autistic' at 2 years. He had a peculiar gait. We advised the parents to start a gradual tapering off on the clonidine and start him on valproic acid. His medical management was very complicated and required frequent follow-up visits for 3 months. He now takes valproate (250 mg / day) and clonidine (0.1 mg bid). At 6 months follow-up he is stable.

3 .5. Case 5
This patient began to have a difficult temper when he was 18 months old. He was expelled from preschool for biting and hitting. He was described as talkative and noisy but "trying to be good, but just can't" . His father attends AA, has mood swings and is described as 'very aggressive'; maternal aunt is reportedly 'manic depressive' and mother is taking anti-depressants . We saw patient at his fourth birthday.
After a trial with valproate (125 mg / bid) he has calmed down over a period of 4 months. His sleep, that used to be less than 6 h, is now 10 h. Aggression at school has completely ceased.

3.6. Case 6
This 5-year-old girls' problems started a year earlier but now "are getting out of hand". Her behavior in school is so difficult that her teacher recently had a crying episode. Patient keeps an adultlike attitude and bosses around her peers and relatives.
Her need for sleep was decreased to 5 h. There is no family history of mood disorders, but a maternal cousin has been diagnosed ADHD. Mother works as a receptionist in a psychiatric hospital, and she saw "similar behavior in adult girls diagnosed as bipolars". She therefore consented that we treat her daughter with valproic acid 125 mg bid. After 2 weeks she reported that her daughter was less aggressive, and she is not bossing or defying adults . Sleep has also improved. Improvement has been maintained at 6-month follow-up.

3. 7. Cases 7 and 8
These 5-year-old and 21-month-old girls come from a family of established bipolars traced back to their great-grandfather. Their mother is under treatment for bipolar disorder, while the father is "aggressive and a drug abuser" . Both girls exhibited extreme restlessness and management problems at home. Follow-up is insufficient to conclude that they have responded to valproate.

3.8. Case 9
This 7-year-old boy started having problems at the age of 7 months when he started banging his head and biting his arms . According to the mother he "went more crazy on Adderal 20 mg/ day". On mental status examination he was actively hallucinating.
We discontinued the Adderal , and a week later started him on valproate 125 mg/bid. He is now free of psychosis, and has calmed down considerably.

We are aware that some of our colleagues in child psychiatry and psychology are skeptical of childhood bipolarity in the preschool age. We are not the first to report this (LaGrone, 1981; Weller et al., 1986), but ours may even be the largest case series: six of nine patients belong to this age group. We submit that family history for bipolar disorder and worsening on stimulants provide external validation that increased confidence, grandiosity, hypersexuality , and restless or stormy behavior in these very young children represent genuine bipolar disorder, not just variants (Davis, 1979) of bipolar disorder. Our case series represents an attempt to enrich the descriptive aspects of bipolarity in very young children that hitherto has remained largely at the level of single case reports. We also provide very preliminary clinical evidence on the potential utility of valproate in this population. It is imperative to diagnose bipolar disorder as soon as it manifests, before it becomes more virulent over time and self-esteem and school performance can be tarnished forever. More scholarly reviews on the clinical picture and validation of juvenile bipolarity have appeared elsewhere (Weller et al., 1995; Akiskal, 1995).

Since many of the cases we reported are in the preschool age, we wish to caution readers that the use of valproate in this - and older child - populations is not established with proper controlled investigation (AACAP, 1997; Kowatch and Bucci, 1998; Ryan et al., 1999). However, valproate has been used effectively to treat seizure disorders in preschoolers . There have been anecdotal reports of death in very young children below the age of 2 on valproate; this is usually valproate combined with other medications . To date there are no studies available looking at safety and efficacy of valproate in preschoolers. There is more known about lithium - albeit non-blind uncontrolled data - and many consider lithium first mood stabilizer of choice (Annell, 1969; Hagino et al., 1998), pending studies done on manic children treated with valproate. In those where lithium is not tolerated or proves ineffective, valproate can be given after liver function tests and complete blood count with differential, as well as thyroid stimulating hormone and T4 , are done . Finally, one should weigh the risk-benefit ratio in female children on valproate - pending more definitive data on polycystic ovary syndrome as a potential rare complication.

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