add-on melatonin improves quality of life in epileptic children on valproate monotherapy: a...

Epilepsy&

Epilepsy & Behavior 5 (2004) 316–321

Behavior

www.elsevier.com/locate/yebeh

Add-on melatonin improves quality of life in epileptic childrenon valproate monotherapy: a randomized, double-blind,

placebo-controlled trial

Madhur Gupta,a Satinder Aneja,b and Kamlesh Kohlia,*

a Department of Pharmacology, Lady Hardinge Medical College and Associated Hospitals, New Delhi, Indiab Department of Pediatrics, Lady Hardinge Medical College and Associated Hospitals, New Delhi, India

Received 19 November 2003; revised 28 January 2004; accepted 29 January 2004

Available online 5 March 2004

Abstract

This randomized, double-blind, placebo-controlled study in epileptic children aged 3–12 years evaluated the effects of add-on

melatonin administration on the quality of life of these children on sodium valproate (VPA) monotherapy using a parental ques-

tionnaire. Quality of Life in Childhood Epilepsy is a questionnaire designed to assess a variety of age-relevant domains such as

physical function, emotional well-being, cognitive function, social function, behavior, and general health. Of the 31 patients, 16

randomly received add-on melatonin (MEL), whereas 15 received add-on placebo (P). The questionnaire had good internal con-

sistency reliability, because for most of the multi-item scales Cronbach�s a reliability exceeded 0.5 (range: 0.59–0.94). To our

knowledge, this is the first study assessing quality of life in epileptic children with add-on melatonin administration in the form of a

randomized, double-blind, placebo-controlled trial. The study suggests a potential use of melatonin as an adjunct to antiepileptic

therapy due to its diverse spectrum of action as an antioxidant, neuroprotector, and free radical scavenger, thus offering the ad-

vantage of reducing oxidant stress and subsequent damage. The beneficial effects of melatonin on sleep, its wide safety window, and

its ability to cross the blood–brain barrier have the potential to improve quality of life in pediatric epilepsy.

� 2004 Elsevier Inc. All rights reserved.

Keywords: Melatonin; Valproate; Sleep; Epilepsy; Children; Quality of life

1. Introduction

Epilepsy is an example of a medical diagnosis that is

retained even when signs and symptoms are well con-

trolled and all laboratory tests are normal. Jacoby de-

scribed epilepsy as ‘‘both a medical diagnosis and a

social label’’ [1]. Epilepsy still remains a stigmatizeddisease in India.

Assessing quality of life (QOL) in pediatric epilepsy is

especially important because it is during childhood when

many cognitive and social skills are being developed.

Failure to develop these skills at a developmentally ap-

propriate stage may impair QOL. Antiepileptic drugs

(AEDs) can compromise QOL through their side effects

on behavior and cognitive functioning. AEDs may cause

* Corresponding author. Fax: +91-11-23340566.

E-mail address: [email protected] (K. Kohli).

1525-5050/$ - see front matter � 2004 Elsevier Inc. All rights reserved.

doi:10.1016/j.yebeh.2004.01.012

depression, increased irritability, conduct disorders,

learning problems, anxiety, and hyperactivity [2]. Most

epilepsy research to date has considered health-related

QOL (HRQOL) in the adult population, with compa-

rably minimal research in children [3].

Valproate is one of the antiepileptic drugs widely

used as first-line treatment for epilepsy in children [4].The metabolism of valproate may trigger oxygen-de-

pendent tissue injury and elevate the levels of free rad-

icals in the body [5]. The free radicals generated cause a

cascade of neurochemical events leading to neurode-

generation and cell death [6]. Long-term use of AEDs

has been shown to increase free radical formation and

cause oxidative damage within neuronal cells [7]. Due to

the limitations posed by the conventional AEDs, theendeavor to develop AEDs with predictable efficacy,

safety, and tolerability and with neuroprotective and

antioxidant action has continued.

mail to: [email protected]

M. Gupta et al. / Epilepsy & Behavior 5 (2004) 316–321 317

In the last decade, much interest has arisen in mela-tonin, which helps to regulate sleep–wake cycles through

the action on SCN in the hypothalamus. Melatonin (5-

methoxy-N -acetyltryptamine), a pineal hormone, has

been extensively tried in the treatment of sleep–wake

cycle disorders [8]. Compared with normal controls,

children with epilepsy have higher rates of sleep prob-

lems and disturbed daytime behavior [9]. Chronic sleep

disorders can affect a child�s development adversely, assleep plays a major role in the early maturational pro-

cesses in the brain [10]. Sleep deprivation leads to re-

duced attention span, low frustration threshold, mood

changes, impaired social interactions, and difficulties

with memory formation and recall [11]. Epilepsy is ex-

acerbated by sleep deprivation [12]. Sleep disorders have

also been reported to resemble seizures [13]. Some chil-

dren with incompletely controlled epilepsy may experi-ence fewer seizures following melatonin treatment once

they are no longer sleep-deprived [8].

Melatonin, a neuromodulator, has been shown to

have antiepileptic activity in animal studies using dif-

ferent seizure models [4–15] as well as in cases of

childhood epilepsy [16]. A few mechanisms for the an-

ticonvulsant activity of melatonin have been suggested.

It exerts neuroprotection due to its antioxidant, anti-excitotoxic, and free radical scavenging properties

within the central nervous system [17–19]. In addition, it

has been demonstrated to be safe in humans even at high

pharmacological doses [20]. The function of melatonin

as an oxidant and free radical scavenger is facilitated by

the ease with which it crosses morphophysiological

barriers, like the blood–brain barrier and intracellular

and subcellular barriers [21]. However, effects of mela-tonin treatment on QOL parameters have not been

studied. Therefore, a randomized, double-blind, place-

bo-controlled trial was conducted in epileptic children to

assess the effects of add-on melatonin administration on

QOL in epileptic children on valproate monotherapy.

To our knowledge, this is the first study to assess the

effect of add-on melatonin on QOL in a randomized,

placebo-controlled trial.

2. Patients and methods

The study was a randomized, double-blind, placebo-

controlled trial. Epileptic children, aged between 3 and 12

years of either sex, who presented to the seizure clinic at

the Kalawati Saran Children�s Hospital, Lady HardingeMedical College, New Delhi, India, between April 2002

and February 2003, were enrolled. All patients were as-

sessed and screened for inclusion/exclusion criteria

(n ¼ 45). The institutional scientific and ethical commit-

tee approved the study protocol, and written informed

consent was obtained from the accompanying parent/

relative. As part of the consent procedure, information

was read aloud from a consent form to ensure consis-tency, and any questions from the parents/relatives were

answered to their satisfaction. Only those patients were

included who were on valproate monotherapy, had a

confirmed diagnosis of epilepsy limited to partial or

generalized seizures as classified according to the Inter-

national Classification of Epileptic Seizures, and were

seizure-free at least for the last 6 months. All children

with a history of psychiatric or other progressive neuro-logical disorder or a chronic hematological, cardiac, he-

patic, renal, or thyroid disorder were excluded. Only

those children were included who had been taking so-

dium valproate (10mg/kg/day) for the last 6 months,

were seizure-free, and, at the time of inclusion in the

study, had serum blood levels in the range 75–125 lg/mL.

A randomization code list was prepared by a statis-

tician who was not connected to the study. The per-mutation of code numbers was computer generated for

the treatment groups. Patients were then randomly di-

vided into two groups: one group received add-on mel-

atonin (n ¼ 16), and the other received placebo (n ¼ 15),

1 hour before bedtime. Melatonin (fast-release) tablets

of 3-mg strength (Aristo Pharmaceuticals Ltd, Mumbai,

India) were used. The placebo tablets, identical in shape,

size, color, and packaging, were specially prepared forthe study by Aristo Pharmaceuticals Ltd. The placebo

tablets contained dicalcium phosphate in place of mel-

atonin along with other similar excipients. The dose of

melatonin was 6mg (2 tablets) for children younger than

9 years/weighing less than 30 kg and 9mg (3 tablets) for

children older than 9 years/weighing more than 30 kg.

QOL was assessed using the Quality of Life in Child-

hood Epilepsy (QOLCE) questionnaire [3]. This paren-tal questionnaire has proven validity and reliability. For

most of the multi-item scales the internal consistency

(Cronbach�s a) reliabilities were calculated, and it was

found that the 13 multi-item scales had internal consis-

tency (Cronbach�s a) reliabilities that exceeded the gen-

erally accepted criterion of 0.50 for adequate reliability

when making group comparisons. These reliabilities

ranged from 0.59 to 0.94 in our study population. Thequestionnaire was administered before add-on melato-

nin/placebo and 4 weeks after (28–32 days). The patients

were called for regular follow-up visits at weekly inter-

vals. Clinical laboratory tests (liver function tests, he-

moglobin, etc.) were performed at baseline and at each

visit during the study period. Each patient was provided

with a diary and instructed to record any side effects or

unusual symptoms observed.

2.1. Statistical analysis

Descriptive statistics were calculated for all outcome

variables, and expressed as means� SD or medians and

ranges as appropriate. The v2 testwas used to compare the

categorical variables (e.g., sex, type of seizure, family,

318 M. Gupta et al. / Epilepsy & Behavior 5 (2004) 316–321

history of epilepsy, CT, etc.) between two differentgroups.

Scores on the different scales derived from the QOLCE

questionnaire were compared among the groups using

the Kruskal–Wallis test. The baseline scores on the

multi-item scales and the scores after treatment (add-on

melatonin/placebo) were compared using the Wilcoxon

rank-sum test.

For multi-item scales, the internal consistency(Cronbach�s a) reliabilities were calculated and reported.

All data were analyzed using STATA 7.0 (intercooled

version). Differences with a P value <0.05 were consid-

ered significant.

3. Results

Between April 2002 and February 2003, 31 patients

met the entry criteria. Sixteen patients were randomly

allocated to receive add-on melatonin and 15 to receive

placebo, 1 hour before bedtime. One patient in the pla-

cebo group was lost to follow-up, and data for this

patient could not be included in the analysis. Thus, 16

patients in the add-on melatonin group and 14 in the

add-on placebo group could be assessed. The valpro-ate +melatonin group and valproate + placebo group

did not differ significantly with respect to median age,

sex, and weight (Table 1). The groups were quite com-

parable with respect to these characteristics, and there

were no statistically significant differences. The hema-

tological and biochemical investigations (liver function

tests, hemoglobin, etc.) carried out at weekly intervals

were found to be within normal limits in all patients. Noadverse event warranting discontinuation of the therapy

was reported. The QOLCE administered to the study

groups was a 72-item instrument with 16 subscales.

These subscales measured Physical Restrictions, Energy/

Fatigue, Attention/Concentration, Language, Other

Cognitive Processes, Depression, Anxiety, Control/

Table 1

Demographic characteristics of the study groups

Study variable Valproate + placebo group

Age (years) 6.6 (3.9)a

Sex

Female 4

Male 10

Weight (kg) 18.3 (10.4)a

Age at onset of seizures (years) 5.0 (5.0–5.0)b

Type of seizure

Absence 3

Complex partial 3

Generalized tonic–clonic seizures 7

Lennox–Gastaut syndrome 1

aMean (SD).bMedian (range).�P < 0:05, significant.

Helplessness, Self-esteem, Social interactions, Socialactivities, Stigma, Behavior, General Health, and QOL.

All scores on the 16 subscales are listed in Table 2.

The Attention (P ¼ 0:001), memory (P ¼ 0:05), and

language (P ¼ 0:004) subscales showed significant in-

tragroup improvement in the VPA+MEL group after

addition of melatonin. The median score on the Other

Cognitive Processes subscale for the VPA+MEL group

was 4.0 (range: 1.0–5.0) pretreatment, as compared with4.7 (range: 2.5–5.0) posttreatment, the difference being

statistically significant (P ¼ 0:05) within the group. On

the Anxiety subscale, the difference between the pre-

treatment and posttreatment scores within the VPA+

MEL group was significant (P ¼ 0:02).Within the VPA+MEL group, the pretreatment Be-

havior subscale median score was 3.2 (range: 2.65–3.5),

as compared with 3.3 posttreatment (range: 2.6–3.5), thedifference being statistically significant (P ¼ 0:004). Inthe same group, the difference on the General Health

score before and after addition of melatonin was mar-

ginally significant (P ¼ 0:08). The difference between

pre- and posttreatment QOL scores was also marginally

significant (P ¼ 0:08).The median total QOL score was 3.7 (range: 2.6–4.0).

The median QOL score posttreatment in the VPA+MEL group was 4.0 (range: 3.0–4.0), as compared with

3.0 (range: 2.0–4.0) in the VPA+P group, the difference

being marginally significant (P ¼ 0:08) in the

VPA+MEL group Table 3.

Although the effect on appetite was not objectively

assessed in the study, parents of 13 of 16 children in the

melatonin group reported a perceptible increase in ap-

petite as compared with 4 of 15 in the placebo group.

4. Discussion

To our knowledge, this is the first study assessing

QOL in epileptic children with add-on melatonin

(n ¼ 14) Valproate+melatonin group (n ¼ 16) P value

7.4 (3.2)a 0.56

8 0.4

8

19.5 (6.8)a 0.72

2.0 (0.6–11.0)b 0.5

5

2 0.3

7

2

Table 2

QOLCE subscales: VPA+MEL group versus VPA+P group

Scale Study variable VPA+MEL VPA+P

1. Physical restrictions Premelatonin/placebo 2.67 (2–4) 2.67 (2.4–3.3)

Postmelatonin/placebo 2.7 (2.1–4) 2.67 (2.2–3.3)

Intragroup P value 0.38 0.16

2. Energy/fatigue Premelatonin/placebo 3 (2.5–3) 3.5 (3–3.5)

Postmelatonin/placebo 3.0 (2.5–3.0) 3.0 (2.5–3.5)


3. Attention/concentration Premelatonin/ placebo 3.2 (1.4–4.8) 3.8 (2.0–4.6)


Intragroup P value 0.001� 0.09

4. Memory Premelatonin/placebo 5.0 (1.0–5.0) 4.7 (1.0–5.0)



5. Language Premelatonin/placebo 3.9(1.0–5.0) 4.5 (2.3–4.9)



6. Other cognitive processes Premelatonin/placebo 4.0 (1.0–5.0) 3.3 (2.0–5.0)



7. Depression Premelatonin/placebo 3.0 (1.5–3.3) 3.7 (2.3–5.0)



8. Anxiety Premelatonin/placebo 4.2 (2.0–5.0) 5.0 (4.0–5.0)



9. Control/helplessness Premelatonin/placebo 5.0 (1.0–5.0) 4.5 (3.7–5.0)



10. Self-esteem Premelatonin/placebo 2.6 (1.5–4.0) 3.2 (3.0 – 4.0)


Intragroup P value 0.5 0.08�

11. Social interactions Premelatonin/placebo 5.0 (2.0–5.0) 5.0 (4.0–5.0)



12. Social activities Premelatonin/placebo 2.6 (2.0–3.3) 2.0 (2.0–2.7)


Intragroup P value — —

13. Stigma Premelatonin/placebo 5.0 (5.0–5.0) 5.0 (5.0–5.0)


Intragroup P value — —

14. Behavior Premelatonin/placebo 3.2 (2.65– 3.5) 3.5 (3.2–3.54)



15. General health Premelatonin/placebo 4.0 (3.0–5.0) 4.6 (3.0–4.0)



16. QOL Premelatonin/placebo 4.0 (3.0–5.0) 3.0 (3.0–4.0)



* P < 0:05, significant.


administration. This randomized, double-blind, place-

bo-controlled trial has shown the benefit of add-on

melatonin administration on QOL in epileptic children

on valproate monotherapy. No side effects warranting

discontinuation of therapy were observed. The doses of

melatonin administered were based on the favorable

results of Jan and Donnell, who successfully treated

more than 100 mentally handicapped children with 2.5–10 kg melatonin [8]. The questionnaire was designed to

assess a variety of age-relevant domains, such as physi-

cal function, emotional well-being, cognitive function,

social function, behavior, and general health. The

questionnaire, which was translated as well as validated

in Hindi (national language), had good internal consis-

tency reliability, as most of the multi-item scales had a

Cronbach a reliability exceeding 0.5 (range: 0.59–0.94).

This shows that the questionnaire was reliable in the

patients in our study.

A perceptible increase in appetite as well as improve-ment in sleep was reported by most of the patients in the

VPA+MEL group, although these factors were not

objectively assessed. The VPA+MEL group exhibited

Table 3

QOLCE: descriptive statistics and reliabilities

Scale Number of items Median Range Cronbach�s a

1. Physical Restrictions 6 2.7 1.3–4.0 0.69

2. Energy/Fatigue 2 3.0 2.0–3.5 0.88

3. Attention/Concentration 5 4.0 1.4–5.0 0.77

4. Memory 6 5.0 1.0–5.0 0.90

5. Language 8 4.5 1.0–5.0 0.83

6. Other Cognitive Processes 3 5.0 1.0–5.0 0.59

7. Depression 4 3.0 1.5–5.0 0.72

8. Anxiety 6 4.8 1.3–5.0 0.94

9. Control/Helplessness 4 4.7 1.0–5.0 0.85

10. Self-esteem 5 3.5 1.5–5.0 0.46�

11. Social Interactions 3 5.0 2.0–5.0 0.74

12. Social Activities 3 2.3 2.0–3.3 0.30�

13. Stigma 1 5.0 1.0–5.0 a

14. Behavior 14 3.3 2.6–3.5 0.49�

15. General Health 1 4.0 3.0–5.0 a

16. QOL 1 4.0 3.0–5.0 a

17. Total QOL 72 3.7 2.6–4.0

a Single-item scales, unable to calculate Cronbach�s a.*Not significant, all others significant.

320 M. Gupta et al. / Epilepsy & Behavior 5 (2004) 316–321

significant intragroup improvement on the Attention,

Memory, Language, Other Cognitive Processes, Anxiety,

and Behavior multi-item subscales posttreatment.

To our knowledge, this is the first study assessing

QOL in epileptic children with add-on melatonin ad-

ministration. On the basis of our results, it may be

postulated that the improved QOL in the add-on mel-

atonin group, as compared with the placebo group, canbe attributed to the diverse properties of melatonin, such

as its anticonvulsant, antioxidant, and free radical

scavenging properties and its favorable effects on sleep.

Moreover, melatonin at doses of 1–300mg in human

studies has been shown to be safe, with no adverse ef-

fects observed [22]. Recently, in a double-blind, placebo-

controlled clinical trial, no toxicological effects of mel-

atonin (10mg) were observed [23]. Further studies thatemploy both epilepsy-specific and generic measures of

HRQOL and larger sample sizes are needed to provide a

more comprehensive picture of the QOL of children

with epilepsy.

Acknowledgments

The authors acknowledge Dr. R.M. Pandey, De-

partment of Biostatistics, All India Institute of Medical

Sciences, New Delhi, India, for his kind help in statis-

tical analysis.

References

[1] Jacoby A. Epilepsy and quality of everyday life, findings from a

study of people with well controlled epilepsy. Soc Sci Med

1992;34:657–66.

[2] Cortesi F, Gianotti F, Ottaviano S. Sleep problems and daytime

behavior in childhood idiopathic epilepsy. Epilepsia 1999;40:

1557–65.

[3] Sabaz M, Cairns D, Lawson J, Nheu N, Bleasel A, Bye A.

Validation of a new quality of life measure for children with

epilepsy. Epilepsia 2000;41:765–74.

[4] Kurekci AE, Alpay F, Tanindi S, et al. Plasma trace element,

plasma glutathione peroxidase, and superoxide dismutase levels in

epileptic children receiving antiepileptic drug therapy. Epilepsia

1995;36:600–4.

[5] Cengiz M, Yukcel A, Seven M. The effects of carbamazepine and

valproic acid on the erythrocyte glutathione, glutathione perox-

idase, superoxide dismutase and serum lipid peroxidation in

epileptic children. Pharmacol Res 2000;41:423–5.

[6] Gilgun-Sherki Y, Rosenbaum Z, Melamed E, Offen D. Antiox-

idant therapy in acute central nervous system injury: current state.

Pharmacol Rev 2002;54:271–84.

[7] Maertens P, Dyken P, Graf W, et al. Free radicals, anticonvul-

sants, and the neuronal ceroid lipofuscinoses. Am J Med Genet

1995;57:225–8.

[8] Jan JE, O�Donnell ME. Use of melatonin in the treatment of

paediatric sleep disorders. J Pineal Res 1996;21:193–9.

[9] Zaiwalla Z, Stores G. Sleep and arousal disorders in childhood

epilepsy. Electroencephoger Clin Neurophysiol 1989;72:107.

[10] Dahl RE. The regulation of sleep and arousal. Dev Psychobiol

1996;8:3–27.

[11] Jan JE, Freeman RD, Fast DK. Melatonin treatment of sleep

wake cycle disorders in children and adolescents. Dev Med Child

Neurol 1999;41:491–500.

[12] Rajna P, Veres J. Correlation between night sleep deprivation and

seizure frequency in temporal lobe epilepsy. Epilepsia

1993;34:574–9.

[13] Morrell MJ. Differential diagnosis of seizures. Neurol Clin

1993;11:737–54.

[14] Mevissen M, Ebert U. Anticonvulsant effects of melatonin in

amygdala kindled rats. Neurosci Lett 1998;257:6–13.

[15] Srivastava AK, Gupta SK, Jain S, Gupta YK. Effect of melatonin

and phenytoin on an intracortical ferric chloride model of post-

traumatic seizures in rats. Methods Find Exp Clin Pharmacol

2002;24:145–9.

[16] Molina-Carballo A, Munoz-Hoyos R, Reiter RJ, et al. Utility of

high dose of melatonin as adjunctive anticonvulsant therapy in a


child with severe myoclonic epilepsy: two years experience. J

Pineal Res 1997;23:97–105.

[17] Espinar A, Garcia-Olivia A, Isorna EM, Quesada A, Prada FA,

Guerrero JM. Neuroprotection form glutamate induced excito-

toxicity during development of cerebellum in chick embryo. J

Pineal Res 2000;28:81–8.

[18] Reiter RJ, Tan DX, Cabrera J, Darpa D. Melatonin and

tryptophan derivatives as free radical scavengers and antioxidants.

Adv Exp Med Biol 1999;467:379–87.

[19] Allegra M, Reiter RJ, Tan DX, Gentile C, Tesoriere L, Livrea

MA. The chemistry of melatonin�s interaction with reactive

species. J Pineal Res 2003;34:1–10.

[20] Reiter RJ, Tan DX, Poeggler B, Menedez-Palaez A, Chen LD,

Saarela S. Melatonin as a free radical scavenger: implications for

ageing and age related diseases. Ann NY Acad Sci 1994;719:1–19.

[21] Reiter RJ, Tan DX, Cabrera J, Arpa D. Melatonin and

tryptophan derivatives as free radical scavangers and antioxi-

dants. Adv Exp Med Biol 1999;58:321–34.

[22] James SP, Sack DA, Rosenthal NE, Mendelson WB. Melatonin

administration in insomnia. Neuropsychopharmacology 1990;3:

19–23.

[23] De Lourdes V, Seabra M, Bignotto M, et al. Randomized, double

blind clinical trial, controlled with placebo, of the toxicology of

chronic melatonin treatment. J Pineal Res 2000;29:193–200.

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