38 - Pharmacological treatment of co occurring dis

Pharmacological treatment of co-occurring disorders and problem behaviours in ASD

Prescribing in children and adolescents CHAPTER 5 Pharmacological treatment of co-­occurring disorders and problem behaviours in ASD Inattention, overactivity and impulsiveness in ASD (symptoms of ADHD) Individuals with ASD have high rates of inattention, overactivity and impulsiveness and in around a third of patients these symptoms merit the diagnosis of ADHD.1,39 The largest controlled trial to date has been with methylphenidate, conducted by the Research Units on Paediatric Psychopharmacology (RUPP) Autism Network.40,41 In a previous retrospective and prospective study of children with ASD, Santosh and colleagues42 reported positive benefits of treatment with methylphenidate. In general, methylphenidate produces highly variable responses in children with ASD and ADHD symptoms, ranging from marked improvement with few adverse effects to poor response with or without problematic adverse effects. A large double-­blind placebo-­ controlled trial of methylphenidate in children with intellectual disability and ADHD showed that optimal dosing with methylphenidate was effective in some.43 Adverse effects are more commonly reported than in children with ADHD alone.­44–­46 However, where ADHD symptoms are severe and/or disabling, it is reasonable to proceed with a treatment trial of methylphenidate. It is advisable to warn parents of the lower likelihood of response and the potential adverse effects and to proceed with low initial doses (around 0.125mg/kg three times daily, depending on the preparation) increasing by small increments. Treatment should be stopped immediately if behaviour deteriorates or there are unacceptable adverse effects. A systematic review6 confirms that, although effective, the efficacy of methylphenidate for treatment of ADHD in ASD is less than in ADHD alone and that more adverse effects (decreased appetite, sleeping difficulties, abdominal discomfort, social withdrawal, irritability and emotional outbursts) should be expected in ASD. A 2021 meta-­analysis supports the efficacy of methylphenidate and atomoxetine.47 There are no published data on the efficacy of amfetamines in children with ASD even though they have been used to treat ADHD in these patients as well as in typically developed children. Lisdexamfetamine (a pro-­drug containing d-­amfetamine bound to amino acid lysine) has been found to have efficacy and tolerability in treating ADHD in children and young people48 but with no specific data about those with ASD. Atomoxetine is a noradrenergic reuptake inhibitor licensed to treat ADHD with similar efficacy to methylphenidate.6 Preliminary evidence from small open-­label trials and a handful of randomised double-­blind trials49,50 showed that it may be useful in children with ASD, with the most common adverse effects being nausea, fatigue and sleep difficulties. These studies were followed by a larger trial that confirmed that atomoxetine (alone and combined with parent training) significantly reduced ADHD symptoms.51 In a 24-­week extension of the same study, atomoxetine combined with parent training was superior in reducing ADHD symptoms to atomoxetine alone.52 There is evidence that α2 agonists (clonidine and guanfacine) can be used as alternative treatments. A multisite RCT of extended-­release guanfacine compared with placebo in children with ASD (mean age 8.5 years) over a period of 8 weeks showed that it is safe and effective in managing hyperactivity in this group.53 No serious adverse events except for drowsiness, fatigue and decreased appetite were reported.

608 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 5 There are reports from controlled studies supporting the use of risperidone or ­aripiprazole for ADHD symptoms. However, these were not primary outcomes of the studies and therefore need further investigation. Irritability (aggression, self-­injurious behaviour, severe disruptive behaviours) Aggression towards others and self, frequently underlined by irritability, is a common problem in ASD. Although behavioural and environmental approaches should be first-­ line treatments, more severe and dangerous behaviours usually necessitate pharmacotherapy.54 The duration of recommended treatment is difficult to derive from published evidence but treatment appears to be beneficial for up to ­6–­12 months.55 Efforts to reduce and possibly discontinue such treatment at the end of this period should be strongly considered.54,55 SGAs are the first-­line pharmacological treatment for children and adolescents with ASD and associated irritability.­55–­58 Risperidone59,60 and aripiprazole61 have been reliably shown to help with irritability and associated disruptive behaviours5 in ASD and have been approved for this use by the US FDA. In a meta-­analysis of data from 46 RCTs62 comparing efficacy of risperidone, aripiprazole and other compounds with placebo, risperidone and aripiprazole were the most effective, with moderate to large effect sizes. Another meta-­ analysis of short-­term (8 weeks) aripiprazole in the treatment of irritability in ASD children aged ­6–­17 years63 found similar results when compared with placebo. The most recent Cochrane review64 concluded that aripiprazole and risperidone probably reduce both irritability and self-­injury with a large effect size. However, no effect was shown for aggression. The usual recommended dose of aripiprazole for maintenance is between 5 and 15mg daily.55 The starting dose is 2mg/day. The dosing of risperidone is rather more ­complicated –­ FDA-recommended dosages for risperidone are outlined in Box 5.2. Despite their promising efficacy, adverse effects such as weight gain and metabolic changes, increased appetite and somnolence (even with aripiprazole) can be problematic.16,­65–­68 Research is underway to determine if therapeutic drug monitoring of risperidone and aripiprazole will help in optimising treatment while minimising weight gain.69 One long-­term placebo discontinuation study found that relapse rates did not differ between those who stayed on aripiprazole versus those randomised to switch to only placebo, suggesting that re-­evaluation of aripiprazole use after a period of stabilisation in irritability symptoms is warranted.70 There is only one study that makes a direct head-­to-­head comparison71 showing similar tolerability and efficacy profiles for risperidone and aripiprazole. Risperidone usually causes hyperprolactinaemia which, although it may be asymptomatic, may have longer-term effects, therefore necessitating close monitoring. Aripiprazole has no effect on prolactin, which makes it a preferred option. Aripiprazole may on the other hand be ineffective for self-­injurious behaviours.6 Lurasidone, in fixed doses of 20 or 60mg/day, has been shown to be ineffective in a randomised double-­blind trial over 6 weeks.72 The effectiveness of other SGAs such as olanzapine,73 quetiapine, ziprasidone and clozapine has not been tested in adequately powered RCTs. While controlled studies support the use of mood stabilisers such as lithium74,75 and sodium valproate76 in the treatment of persistent aggression in children they are not as effective as SGAs for the treatment of irritability in ASD.77 Limited data support the combination of risperidone and topiramate being better than risperidone alone.78 Further RCTs are probably warranted of brain-­derived neurotrophic factor stimulators such as loxapine and amitriptyline.79

Prescribing in children and adolescents CHAPTER 5 Use of risperidone in children and adolescents Box 5.2  US Food and Drug Administration guidance for risperidone dosing in children and adolescents80 ■ ■Risperidone is indicated for the treatment of irritability associated with autistic spectrum disorder (ASD) in children (aged 5 years and over) and adolescents in the UK/EU and USA ■ ■The dosage of risperidone should be individualised according to the response of the patient Doses of risperidone in paediatric patients with autism spectrum disorders (by total mg/day) Weight categories Days ­1–­3 Days ­4–­18 Increments if dose increases are needed Dose range <20kg* 0.25mg 0.5mg +0.25mg at ≥2-­week intervals 0.­5–­3mg† ≥20kg 0.5mg 1.0mg +0.5mg at ≥2-­week intervals 1.­0–­3mg‡ *Caution should be exercised for children <­15kg –­ no dosing data available †Therapeutic effect plateaus at 1mg/day ‡Those weighing >45kg may require higher ­doses –­ therapeutic effect plateaus at 3mg General considerations ■ ■Risperidone can be administered once daily or twice daily ■ ■Patients experiencing somnolence may benefit from taking the whole daily dose at bedtime ■ ■Once sufficient clinical response has been achieved and maintained, consideration may be given to gradually lowering the dose to achieve the optimal balance of efficacy and safety ■ ■There is insufficient evidence from controlled trials to indicate how long treatment should continue Adverse effects ■ ■Weight gain, somnolence and hyperglycaemia require monitoring ■ ■Long-­term safety of risperidone in children and adolescents with ASD remains to be fully determined Using benzodiazepines to manage irritability and aggression in ASD is not recommended. However, it may be necessary to manage acute aggression with a benzodiazepine. The possibility of behavioural disinhibition that may worsen aggression must be borne in mind. The use of minocycline, arbaclofen or amantadine for irritability is not recommended unless better evidence from double-­blind RCTs is available.6 Sleep disturbance Children with ASD have significant sleep problems,81 with sleep-­onset insomnia, ­sleep-­maintenance insomnia and irregularities of the ­sleep–­wake cycle being the typical problems encountered. It is essential to understand the aetiology of the sleep problem before embarking on a course of treatment. Abnormalities in the melatonin system have received some attention.82

610 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 5 Melatonin has been shown in 17 studies to be beneficial in children with ASD.83 A meta-­analysis of five studies showed good efficacy with doses ranging from 1mg to 10mg and treatment lasting from 14 days to over 4 years.84 Melatonin is usually very well tolerated.84,85 One RCT showed that, while melatonin improved sleep onset, the child’s behaviour during the day did not improve.86 There is also evidence that melatonin combined with CBT is superior to melatonin only, CBT only and placebo in reducing symptoms of insomnia.87 Risperidone may benefit sleep difficulties in those with extreme irritability. In the anxious or depressed child, antidepressants may be beneficial. Insomnia due to hyper­ arousal may benefit from clonidine or clonazepam.88 Anxiety, OCD and depression SSRIs have yet to show specific efficacy in ASD. Preliminary data from a ­randomised placebo-­blind clinical trial showed beneficial effects of fluoxetine in reducing OCD symptoms in children with ASD, although confounding factors precluded firm conclusions.89 In a systematic review,6 although risperidone was reported by ­several studies to reduce OCD and anxiety symptoms in young people with ASD, the selection of participants with high levels of irritability did not allow firm conclusions to be drawn about specific effects of risperidone on OCD and anxiety. There is little or no evidence for treating anxiety or OCD symptoms with risperidone, clomipramine or an SSRI. There are some data on buspirone effectively targeting anxiety in ASD90 and propranolol showing positive cognitive effects in ASD.91 However, further evaluation is needed. Guidance on doses of fluoxetine can be found in Box 5.3. Use of fluoxetine in children and adolescents When using fluoxetine to treat repetitive behaviours in ASD patients, doses much lower than those used to treat depression are normally required. It is advisable to use a liquid preparation and begin at the lowest possible dose, monitoring for adverse effects. A suitable regimen is outlined in Box 5.3. Box 5.3  Use of fluoxetine in children and adolescents ■ ■Liquid fluoxetine (as hydrochloride): 20mg/5mL ■ ■2.5mg/day a day for 1 week; note that 2.5mg = 0.625mL, which is difficult to measure accurately ■ ■Follow with a flexible titration schedule based on weight, tolerability and adverse effects up to a maximum dose of 0.8mg/kg/day (0.3mg/kg/day for week 2, 0.5mg/kg/day for week 3 and 0.8mg/kg/day subsequently) ■ ■Reduction may be indicated if adverse effects are problematic Adverse effects ■ ■Monitor for treatment-­emergent suicidal behaviour, self-­harm and hostility, particularly at the beginning of treatment ■ ■Hyponatraemia is also ­possible –­ see Chapter 3