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The World Federation of ADHD Guide 89 In children with autism spectrum and anxiety disorders, the therapeutic win- dow of stimulants tends to be narrower and shifted to left. For this reason, these children are more often sensitive to medications and require lower doses to avoid side-effects such as over-focusing, agitation, anxiety and aggression. The general advice for commencing medication in ADHD individuals with comorbidities is to “start low and go slow”. Noradrenergic receptors In the NA system, the alpha 2A receptors have a high affinity with NA and are engaged at low concentrations of synaptic NA. Selective alpha 2A agonists like clonidine and guanfacine enhance neuronal ‘signals’, and this effect also follows an inverted U shape dose-response curve, as illustrated in Figure 5.1. The optimal balance between DA and NA synaptic concentrations results in an optimal balan- ce between D1 and alpha2A activity, 11 which can improve working memory and cognitive performance. However, excessive NA concentration leads to activity in the low affinity NA receptors, such as beta and alpha1 receptors. 12 This can result in agitation, anxiety, fear, arousal, aggression and rage. From a clinical perspective understanding the neurobiology pathways provides some explanation on (1) why careful dose titration of stimulant and psychotropic medications is essential; (2) why combination of stimulants and antipsychotic can reduce emotionality, anxity, agitation and aggression – given that stimulants tar- get D1 and alpha2A receptors, while anti-psychotics target D2 receptors; (3) why guanfacine and clonidine – alpha 2A agonists – have a role in ADHD management as a monotherapy or combination therapy. The relevance of pharmacokinetics of drug preparations Having explained why it is pivotal to titrate the correct dosage of medication in relation to the inverted-U response curve, we now turn to how different prepara- tions of drugs can determine fluctuations in the blood levels and symptoms across the day. Both methylphenidate and amphetamine are available as immediate release and extended release formulations. But the patterns of availability differ widely across the world. Different extended release preparations utilise different mecha- nisms for slowing down absorption or release into the cirulation compartment. 5 For example Concerta (‘OROS MPH’) utilises an ‘osmotic pump’ mechanism – with 22% of the dosage available as immediate release from the coating of the capsule. Also as around 20% of the dose is not released by the ‘pump’ mechanism, this proportion does not add to activity. Taking this into account, and because these formulations were designed in a way that the extended release portion is adequate to continue the effects of the immediate release portion, it is suggested