nei THIS MONTH IN
PSYCHOPHARMACOLOGY
Autism Awareness: Review of Pharmacotherapy for Emotional/Behavioral Symptoms and Potential Future Targets
March 20, 2018   

Autism spectrum disorder (ASD) is a neurodevelopmental disorder typically diagnosed in childhood and characterized by persistent deficits in social communication and interaction and restricted, repetitive patterns of behavior, interests, and activities. There are no pharmacological agents approved for the treatment of the core symptoms of ASD; however, medication is frequently used to treat the associated emotional and behavioral disturbances (irritability, anxiety, mood lability, inattention, hyperactivity, sleep impairment). In fact, as much as one-third of commercially-insured children receive two or more psychotropic medications, while 15% receive three or more. To date, there is very limited evidence for the pharmacological treatment of the emotional and behavioral symptoms of ASD; what evidence does exist is briefly summarized below.

Irritability

The atypical antipsychotics risperidone and aripiprazole have the most evidence for the treatment of irritability associated with ASD and are approved by the Food and Drug Administration (FDA) for this use (Table). Small trials suggest possible efficacy of paliperidone, olanzapine and ziprasidone, but the data are currently too limited to establish safety and efficacy. Efficacy was not demonstrated in a 6-week study evaluating lurasidone for the treatment of irritability in autism in children ages 6–17, and study of quetiapine has yielded mixed results. Other pharmacological agents that have been investigated as monotherapies for the treatment of irritability in autism include divalproex (mixed results) and lamotrigine (negative results).

Medication Approved ages Usual dose Titration
aripiprazole 6–17 5–15 mg/day Initial dose 2 mg/day; can increase by 5 mg/day at intervals of no less than 1 week; maximum dose 15 mg/day
risperidone 5–16 0.5–3 mg/day Patients weighing less than 20 kg: initial dose 0.25 mg/day; after at least 4 days can increase to target dose of 0.5 mg/day; this dose should be maintained for at least 14 days, after which, depending on response, dose can be increased at intervals of no less than 2 weeks in increments of 0.25 mg/day

Patients weighing at least 20 kg: initial dose 0.5 mg/day; after at least 4 days can increase to target dose of 1 mg/day; this dose should be maintained for at least 14 days, after which, depending on response, dose can be increased at intervals of no less than 2 weeks in increments of 0.5 mg/day
Table. FDA-approved medications for the treatment of irritability associated with autism.

Repetitive behaviors, anxiety

Fluoxetine, fluvoxamine, sertraline, paroxetine, and escitalopram have shown some potential benefit for repetitive behaviors and anxiety; however, these agents were also associated with activating side effects, and as a result are not currently recommended. A single trial of citalopram yielded negative results, and data are limited and mixed for the use of imipramine, nortriptyline, and clomipramine.

Hyperactivity, inattention

Methylphenidate has demonstrated efficacy in treating attention deficit hyperactivity disorder (ADHD) in children with autism, although improvement is less than that seen in patients with only ADHD; patients with autism may also be more sensitive to stimulant side effects. Guanfacine, clonidine, and atomoxetine have some data demonstrating potential efficacy for hyperactivity in children with ASD.

Future Targets

Autism spectrums disorders are heterogeneous both in phenotype and in the underlying etiopathogenesis, which appears to involve numerous potential risk genes as well as possible prenatal insults. Avenues of investigation into potential future targets for treatment are currently centered around synaptic dysfunction, and specifically addressing excitatory (glutamate)/inhibitory (GABA) imbalance. Specific pharmacological targets under investigation in preclinical trials include metabotropic glutamate (mGlu) 5 receptors, mGlu 2 and 3 receptors, and NMDA receptors antagonists (e.g., memantine). Modulation of GABA is also a potential strategy, although clinical trials of various GABA-ergic agents have had mixed results. Other potential targets to address synaptic dysfunction include glycogen synthase kinase 3 (GSK-3), which is inhibited by lithium; the P13K/mTOR pathway, which regulates protein translation in dendrites near excitatory synapses; and insulin-like growth factor (IGF-1), which is involved in development and maturation of neurons and glial cells.

The other two major areas of investigation for the pharmacological treatment of ASD include targeting central neurotransmission (specifically, serotonin, acetylcholine, and oxytocin), and targeting neuroinflammation. Prenatal inflammation has recently been linked to multiple neurodevelopmental disorders, including ASD as well as schizophrenia and others.

Conclusion

Unfortunately, evidence for the use of pharmacological agents to manage the emotional and behavioral symptoms of autism spectrum disorders remains limited. Two agents—risperidone and aripiprazole—are approved for the treatment of irritability; no other approvals exist for any core or associated symptoms. Children or adolescents with autism spectrum disorders may be particularly sensitive to side effects, so if psychotropic treatment is warranted it is necessary to start with low doses and titrate slowly.

References

Jobski K et al. Use of psychotropic drugs in patients with autism spectrum disorders: a systematic review. Acta Psychiatr Scand 2017;135:8-28.

Lacivita E et al. Targets for drug therapy for autism spectrum disorder: challenges and future directions. J Med Chem 2017;60:9114-9141.

NEI Prescribe.

Stepanova E et al. Pharmacotherapy of emotional and behavioral symptoms associated with autism spectrum disorder in children and adolescents. Dialogues Clin Neurosci 2017;19:395-402.



For more on autism spectrum disorders:

Pre-Conference Academy: Child and Adolescent Psychiatry, November 7, 2018
Agenda and registration information
28-Year-Old Woman With Autism Needs Reassessment of Her Medications. (Members only)
Association Between Maternal Folic Acid Use and Risk of Autism Spectrum Disorder in Offspring. (Members only)
Antipsychotic Use in Intellectually Disabled Adults.
Antidepressants and Risk for Autism, ADHD. (Members only)