August 2015, Vol 3, No 8 - Inside Pharmacy
Shirin Madzhidova, PharmD
Sheava K Blackman, PharmDc
Ryan D Dunn, PharmDc
Arghavan Kariman, PharmDc
Danielle Lerch, PharmDc
Joseph J Sodoro, PharmDc

According to the American Psychiatric Association, autism spectrum disorder (ASD) is classified as a persistent abnormal neurodevelopmental disorder appearing in early childhood and characterized by deficits in social, emotional, behavioral, verbal, and cognitive functioning.1

The American Psychiatric Association recently changed the definition of ASD, and the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) classifies ASD as an umbrella condition that includes 4 diagnoses nested within the disorder: autism, childhood disintegrative disorder, Asperger syndrome, and pervasive developmental disorder not otherwise specified.

The Centers for Disease Control and Prevention estimates that 1 in 68 children has ASD, and that the rate of the disease is approximately 5 times higher in boys than in girls.2 Although its exact etiology is unknown, ASD is strongly linked to a multitude of factors, including neurochemical dysfunction, genetics, familial inheritance, and perinatal development.3 The pathophysiology underlying ASD is complex and associated with oxidative stress, inflammation, immune dysregulation, excitotoxicity, mitochondrial dysfunction, and free fatty acid dysregulation.4 Because of its complex etiology, there is no cure for this condition, and treatment is multidisciplinary, ranging from behavioral modification therapy to dietary restrictions.5

In 2014, the American Academy of Child and Adolescent Psychiatry published clinical guidelines for conventional medications in ASD.3 The pharmacologic agents used to relieve the symptoms associated with the illness, risperidone and aripiprazole, are currently the only 2 US Food and Drug Administration approved medications for ASD-related irritability in children aged 5 to 16 years.6,7 Other psychotropic medications can be used to improve functioning, including hyperactivity, communication, stereotypy, speech, inattention, and social withdrawal.3 Risperidone, aripiprazole, haloperidol, olanzapine, methylphenidate, dextroamphetamine, atomoxetine, clonidine, guanfacine, fluoxetine, clomipramine, lithium, lamotrigine, and valproic acid have all been studied in children with ASD to manage these symptoms.3

Since there are no mainstream pharmacologic agents available for the treatment of ASD, a growing number of parents and caregivers are willing to explore therapies with complementary and alternative medicine (CAM).8

Data published by Hanson and colleagues suggest that parents of children with ASD were willing to try alternative treatment modalities; CAM was used in 74% of the families included in their analysis.9 The authors surveyed caregivers of children with ASD and reported that the most common reasons caregivers sought out CAM was because of the safety concerns of prescription medications and unacceptable side effects. In addition, the authors reported that the frequency of CAM use by parents tended to be higher in children with more severe diagnosis.

One popular CAM therapy consists of a gluten-free/casein-free diet in which most dairy and wheat products are excluded. It is believed that gluten and casein peptides may cross the intestinal mucosa and the blood–brain barrier intact, reaching the central nervous system and affecting brain functioning in children with ASD.10 Although the diet is widely studied, the evidence to support its implementation is limited and weak.

We performed a search on the current literature of the most commonly used CAM supplements/interventions, and found that the most popular and frequently used methods in pharmacy practice include melatonin, vitamin B6/magnesium (Mg), methylcobalamin, folic acid, N-acetylcysteine, coenzyme Q10, L-carnosine, omega-3 fatty acids, and probiotics.11 The search criteria for our analysis comprised articles published within the past 10 years including a patient population of children aged 0 to 18 years with an ASD-defining condition, and an intervention classified as CAM. Only English manuscripts and human studies were included in the analysis. The most common search terms used included “complementary and alternative medicine,” “autism spectrum disorder,” “autism,” “ASD,” “CAM,” “alternative,” and “homeopathic.”

Based on the high prevalence of CAM use in patients with ASD, and the variety of options available, it is impor­tant for pharmacists and retail clinicians to provide clinical recommendations to caregivers using available data. This review evaluates the evidence supporting CAM use in children with ASD, and provides clinical expertise and advice regarding the safety and efficacy of specific agents.

Melatonin

Sleep difficulty is common among children with ASD and has been reported in approximately 80% of patients.12 Melatonin is a commonly used supplement for insomnia in otherwise typically developing children, and has been evaluated in children with ASD who have sleeping difficulties.13

It is a neurohormone that is produced primarily in the pineal gland, which regulates the circadian rhythm. Several published studies have reported melatonin to be safe and effective for sleep latency in children with ASD, at dosages ranging from 2 mg to 10 mg per night for 10 days to 3 months,13 and 1 mg to 3 mg for 14 weeks.14

Notable side effects of melatonin include daytime drowsiness, headache, and dizziness. It should be used with caution in children with higher risk of seizures because it could potentially reduce the seizure threshold.15,16

Vitamin B6 and Magnesium

Vitamin B6, also known as pyridoxine, is essential for the formation of neurotransmitters such as serotonin, gamma-aminobutyric acid, dopamine, norepinephrine, and epinephrine, as well as myelin.17

Its use, in combination with magnesium, has been studied in children with ASD and associated with improvements in speech and language.13 Mg is thought to counter the side effects of high doses of vitamin B6 supplementation (eg, hyperactivity, irritability, hypersensitivity to sound, enuresis, and mineral depletion).13,18 Although several double-blind studies report a significant improvement in mental functioning, such as verbal IQ,13 a systematic Cochrane review of such studies concluded that the evidence is not substantial to convey therapeutic benefit of vitamin B6 and Mg supplementation in children with ASD.18

Most studies report minimal adverse effects and drug interactions associated with B6-Mg supplementation, even when used in combination with the most common pharmacologic agents in ASD.18 However, a potential interaction exists with the concomitant use of vitamin B6 and phenobarbital or phen­ytoin. Vitamin B6 may reduce the plasma levels of phenytoin or phenobarbital when the dose of vitamin B6 exceeds 200 mg daily.16

Methylcobalamin

Methylcobalamin (methylated vitamin B12) serves as a cofactor for the enzyme methionine synthase, which is responsible for the regeneration of methionine. Methionine is required for the production of glutathione and other antioxidant pathways, and therefore prevents cell damage from free radicals.4 In a study evaluating the effects of methylcobalamin 64.5 µg/kg subcutaneously every 3 days for 12 weeks on serum glutathione levels and behavioral improvements, investigators demonstrated an increase in serum antioxidant biomarkers; however, no statistically significant improvement in behavioral outcomes was observed.19

Methylcobalamin, administered orally in children with ASD, is generally well tolerated, with no known drug interactions with other agents frequently used in ASD.20 However, parents who choose to supplement their children with methylcobalamin should be aware that concomitant use with vitamin C supplements may decrease the blood levels of methylcobalamin, and decrease its effectiveness.20

Folic Acid

Folic acid is a form of vitamin B that can be found naturally in leafy vegetables, fruits, meats, and other foods. Folic acid is not endogenously produced, must be consumed through diet or supplementation, and is essential for the proper development of the fetal nervous system.18

Elevated urine homocysteine levels have been shown to prevail among children with ASD and are correlated with greater ASD symptoms.21 Supplementation with 400 µg of folic acid in conjunction with 200 mg of vitamin B6 and 1.2 µg of vitamin B12 has been shown to reduce the level of homocysteine in children with ASD; however, a correlation with symptom improvement was not found.21

Folic acid supplementation is an essential part of a well-balanced diet and is regarded as safe in children when administered at an appropriate dose.5

N-Acetylcysteine

N-acetylcysteine (NAC) is a derivative of the amino acid L-cysteine, and acts as a potent antioxidant by increasing the levels of glutathione in the plasma and bronchoalveolar fluid.12

One study suggests that an imbalance of the neurotransmitters—both excitatory and inhibitory—in the glutamatergic pathways of children with ASD may be linked to the behavioral complications of the disorder.22 In addition, an altered equilibrium between oxidants and antioxidants may lead to an accumulation of reactive oxygen species, which could lead to cellular dysfunction.22

A well-designed study with a small sample of children with ASD reported significant improvement in behavior (eg, irritability and aggression), with minimal side effects after supplementation with NAC.22 NAC 900 mg was administered daily for 4 weeks, then 900 mg twice a day for 4 weeks, followed by 900 mg 3 times a day for 4 weeks.22 Although the results are promising, the study is limited, and further larger studies are needed to establish efficacy. NAC is generally well tolerated, and is regarded as safe in children, although it has an unpleasant taste.16

Coenzyme Q10

Some experts have speculated that some individuals with ASD may have concomitant mitochondrial dysfunction, which can lead to oxidative stress.23 Although no reliable biomarkers exist to diagnose mitochondrial dysfunction, certain direct and indirect biomarkers, such as ubiquinone (coenzyme Q10), creatine kinase, and carnitine, may be correlated with mitochondrial dysfunction.

Coenzyme Q10 is a significant component of the electron transport chain in aerobic respiration, and it functions as an antioxidant for patients with coenzyme Q10 deficiency.23 A recently published case series report examining the use of coenzyme Q10 30 mg divided twice daily in combination with other supplements in 3 ASD patients showed a variable clinical response of central nervous system manifestations.24 Although coenzyme Q10 is generally well tolerated in children and has limited adverse effects, the evidence for its use is limited and insufficient.25

L-Carnosine

L-carnosine is an endogenous dipeptide consisting of the 2 amino acids beta-alanine and histidine, that is highly concentrated in muscle, heart, and brain tissues.26 Although the exact mechanism of action of L-carnosine on neuronal function is not well understood, it is believed to help those children with ASD that have cortical underactivity, which may lead to social, behavioral, and communication challenges in these patients.27 In an 8-week open trial of oral supplementation with 800 mg of L-carnosine in 31 children, significant improvement in behavior and social interaction was shown.26 However, a systematic review of studies on L-carnosine showed an overall low level of evidence supporting use.26,28 Although there is insufficient data available regarding the safety of L-carnosine, parents of children using the supplement should be advised of possible worsening in irritability, hyperactivity, excitability, and insomnia associated with higher doses of the supplement.26

Omega-3 Fatty Acids

Omega-3 fatty acids are a class of long-chain polyunsaturated fatty acids, such as docosahexaenoic acid and eicosapentaenoic acid, and are essential for brain structure and function. Although the exact mechanism of action of omega-3 fatty acids in patients with ASD is unknown, some studies suggest that there is an imbalance of the omega-3 to omega-6 fatty acid ratio, contributing to abnormal brain functioning and other neurodevelopmental disruptions.29 A systematic review examining the impact of omega-3 fatty acid supplementation on social interaction, communication, stereotypy, aggression, hyperactivity, insomnia, self-injury, and quality of life in children with ASD showed no significant impact of supplementation in any of the outcomes evaluated.15 However, some studies suggest that 1 g to 3 g of omega-3 fatty acid supplementation daily may be effective in controlling hyperactivity in some children with ASD.30,31

Although the majority of studies have failed to show a significant clinical benefit, experts support their use as safe and sensible in light of the known nutritional need for omega-3 fatty acids, and their benefit for cardiovascular health, attention-deficit/hyperactivity disorder, and mood disorders.11 Potential side effects of omega-3 fatty acid supplementation include gastrointestinal (GI) disturbances (eg, nausea and diarrhea), which may be alleviated by taking the supplement with food, or dividing the dose using a twice-daily to 3-times-daily regimen.30

A dose-dependent, increased risk for bleeding exists with concomitant use of omega-3 fatty acid supplements and nonsteroidal anti-inflammatory drugs and anticoagulants, and is more common in doses higher than the recommended daily dose of 1 g to 1.5 g.16

Probiotics

Probiotics are living, nonpathogenic microorganisms that are typically used to treat and prevent diarrhea, digestion problems, and irritable bowel syndrome.12 Although the mechanism of action of probiotics is not well defined, they impact the patient’s immune system and possess direct positive effects on the GI system.12

Research shows that many children with ASD have GI symptoms, including irregular bowel movements, constipation, diarrhea, abdominal pain, vomiting/reflux, and potential microbiota abnormalities.32 Children with ASD who have GI symptoms often display more symptoms of irritability, social withdrawal, and anxiety, compared with those without GI symptoms and may potentially benefit from probiotic supplementation.32

Although there is no significant amount of evidence-based research on the use of probiotics in children with ASD, multiple, well-documented surveys and literature reviews indicate that most physicians do recommend adjunctive therapy with probiotics. Several studies showed reduction in GI symptoms and improvements in communication and behavior with the use of probiotics; however, those studies lacked quality methodology to provide conclusive results.33

Although probiotics as a class are generally well tolerated with minimal side effects, patients who are immunocompromised or on an antibiotic regimen should use caution when starting probiotics.

Conclusion

As increasingly more children are being diagnosed with ASD, the use of CAMs in addition to prescription medication is on the rise; therefore, the need for more clinical trials and research on these topics is imperative. Unfortunately, for the majority of CAMs included in this brief review, there is still an insufficient amount of evidence to make well-established, routine recommendations. Many parents of children with ASD do research on their own, and take CAMs into their own hands. Several literature reviews indicate that parents of these children did not inform their physician of their CAM use, nor did they feel as though their child’s physician was knowledgeable enough to assist in determining the best CAM treatment.

The majority of supplements mentioned, with the exception of methylcobalamin injection, are available over the counter, and, therefore, are easily accessible to the public without much availability for proper education. It is imperative for pharmacists and other community clinicians who are knowledgeable in evidence-based CAM to advise parents to optimize the safety, efficacy, and compliance of all therapeutic regimens.




References

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