Stimulants and growth in children with attention-deficit/hyperactivity disorder

Abstract

Initial suggestions that suppression of growth may be an intrinsic characteristic of attention-deficit/hyperactivity disorder (ADHD) have now largely been disproven. Although controversy persists regarding the possible negative effect of adrenergic stimulants on growth in children with ADHD, the consensus that appears to be reached in the scientific literature is that stimulant usage may cause a manageable attenuation of growth in these children. Since it is known that stimulants increase the amount of dopamine and noradrenaline in the synapse, this writing suggests that these increases in dopamine and noradrenaline are responsible for the growth attenuation in these children. It appears that increased amounts of dopamine and noradrenaline have the ability to inhibit the secretion of growth hormone and growth-related hormones such as prolactin, thyroid hormones, sex hormones and insulin. Therefore, it would be reasonable to suggest that the increases in dopamine and noradrenaline caused by stimulant usage can disrupt the homeostasis of both growth hormone and growth-related hormones, generating the potential for the suppression of growth.

Introduction

There is, as yet, no consensus on whether children with attention-deficit/hyperactivity disorder (ADHD), who are treated with adrenergic stimulants, experience growth inhibition, or not. In order to determine whether a relationship exists between stimulant intake and growth in children with ADHD, the first question to be asked is how un-medicated children with ADHD compare in size to control subjects. Although some studies found un-medicated children with ADHD to be of normal height [1], [2], [3], weight [1], [2] and body mass index (BMI) [2], [4]; several, in fact the majority, of studies indicated that un-medicated children with ADHD are actually taller [5], [6], [7], [8], [9] and heavier than normal [3], [5], [6], [7], [8], [10]. These findings, therefore, contradict the initial suggestion [11] that height deficits in ADHD may be mediated by the disease itself.

Since the above-mentioned findings indicate that children with ADHD are generally average to above-average in height, weight and BMI, this suggests that growth retardation is not an intrinsic characteristic of ADHD. It, therefore, led to the next question, i.e. can the use of stimulant medication be associated with growth inhibition in children with ADHD? Although this topic is highly controversial, with some studies indicating that stimulant treatment has no effect on the growth of children with ADHD [2], [3], [12], [13]; the overriding evidence in the scientific literature is that stimulant treatment can indeed cause an attenuation of growth. However, this problem seems to be manageable [5]. Most studies agree that stimulant medication causes an attenuation of height velocity, specifically during the first few years of treatment [1], [6], [7], [8], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], with an estimated height deficit of about 1 cm/year for the first 3 years [8]. Although some studies suggest that, in most cases, this stunting of linear growth normalises after approximately 3 years of treatment and that adults with ADHD do not differ significantly in height from control subjects [1], [4], [8], [12], [22], others are of the opinion that no tolerance to the height suppressant effects of stimulants develops [19] and no evidence of growth rebound exists in these subjects [6].

Regarding the effect of stimulant medication on weight, the consensus appears to be that adrenergic stimulants can cause a significant decrease in weight, specifically during the first few months of treatment [3], [4], [5], [6], [7], [8], [10], [14], [15], [19], [21], [22], [24]. However, this effect appears to be more pronounced in children that are over-weight to begin with [10], [12]. Moreover, it is believed that the weight suppressant effects of stimulants decrease over time and that these children re-gain the weight loss in later years [5], [10], [12], [19], [22].

Further indications regarding the relationship between stimulant usage and growth are that the effects of stimulant medication on growth are dosage dependent, with higher doses of stimulant medication causing greater growth deficits [5], [19], [21], and that amphetamines cause more growth suppression than methylphenidate [19], [22]. However, it should be mentioned that the dosage dependent effects of stimulants on growth are not supported by all studies [10], [20]. The effect of drug holidays on growth also remains controversial. Although there are some indications that drug holidays may reduce the potential growth-inhibitory effects of stimulants [19], scepticism regarding the effect of drug holidays still exists [3], [14], [25]. Pliszka et al. [25] specifically, found that drug holidays had no effect on change in height z scores in children with ADHD.

Since the overriding evidence is that stimulant medication has the potential to cause growth attenuation in children with ADHD, the question remains as to the possible mechanism/s by which stimulants may affect growth. Although the mechanism of action of the stimulants commonly used to treat ADHD, such as amphetamines and methylphenidate, is not completely understood, it is generally accepted that they function by increasing the amount of extracellular dopamine and noradrenaline in the synapse [26], [27], [28], [29]. They accomplish this by increasing the efflux of dopamine into the synapse, with methylphenidate specifically shown to cause an increased transport of dopamine into vesicles [30] and, moreover, an increase in the release of dopamine from these vesicular stores [30], [31].

Furthermore, stimulants also decrease the re-uptake of dopamine and noradrenaline [28], [29] by inhibiting dopamine and noradrenaline transporters [31], [32], [33], with high affinity [34]. Indeed, it has been shown in mice that enhanced dopaminergic neurotransmission is necessary for methylphenidate to exert its stimulating and rewarding effects, while enhanced noradrenergic neurotransmission is required to inhibit locomotor activity [34]. Areas in which methylphenidate-induced increases in dopamine have been shown to occur include the dorsal striatum [33], prefrontal cortex, nucleus accumbens and caudate-putamen [31]. Important receptors which appear to be involved in the therapeutic effects of methylphenidate in the prefrontal cortex include the noradrenergic α-2 adrenoreceptors and dopamine D1 receptors [27]. Although it is believed that amphetamines function by increasing the extracellular concentration of noradrenaline, dopamine and serotonin, indications are that methylphenidate has no effect on extracellular serotonin [35]. Therefore, the focus in this writing will be on the effects of dopamine and noradrenaline on growth. The question then is what impact do increases in dopamine and noradrenaline have on the growth axis?