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Theoharis C. Theoharides, BA, MS, MD, PhD*Þþ§ Autism spectrum disorders (ASD) are pervasive neurodevelopmental disorders affecting approx- imately 1% of children and characterized by varying degrees of deficiencies in social interac- tions, concentration, language, learning, and as stereotypic behaviors.1Y3 Many children develop ASDby regression at approximately age 3 years, often after a specific event such as vaccination or infec-tion, although they were developing normally.4,5 Some gene variants in ASD confer altered vulnera-bility to environmental stressors and exposures.6 Behavioral interventions alone are not sufficient to adequately address the disruptive nature of ASD symptoms and their persistence throughout life.7,8 Instead, psychotropic drug therapy is typicallyused to treat irritability, hyperactivity, inattention, obsessive-compulsive symptoms, aggression, andself-injury.9Y11 Many children with ASD also develop seizures with no apparent underlying patholog-ical cause,12Y14 but traditional antiseizure medications seem to worsen ASD symptoms.15 Overall, 70% of children with ASD take at least 10 different drugs, dietary supplements, vitamins, or other treatments10,16Y18 including intravenous immunoglobulin.19 Secretin is also commonly usedalthough it has no effect20 and could lead to the risk of possible inflammatory complications.21 Thereis little attention to unwanted drug-drug or drug-supplement interactions.
A cross-sectional study of a child and adolescent psychiatric sample nationwide in Denmark found that the prevalence of treatment with antipsychotic medications was 6.4%.22 Some pediatricpatients were prescribed additional medications, with 24% receiving antidepressants, 8% receivingsedative medications, and 4% receiving psychostimulants.22 Many children with ASD also take anti-psychotic medications.23 In a national sample of children and adolescents with ASD, the percentageof outpatients being treated with antipsychotic medications was almost 30%.24 Risperidone is the only antipsychotic drug with Food and Drug Administration approval for treating aggressiveness and stereotypic and self-injurious behaviors in ASD.25 This class of drugsalso includes haloperidol and the newer ‘‘atypical’’ compounds.26,27 Aripiprazole is an atypical anti-psychotic approved for treating irritability in children with ASD.28 A review of 21 randomizedplacebo-controlled trials using psychopharmacologic agents29 showed that only risperidone foraggressive behavior30,31 and methylphenidate for hyperactivity32 produced significant improvementin more than one study.29 A recent systemic review of medical treatments for children with ASDconcluded that only risperidone and aripiprazole had some benefit, but they had significant adverseeffects.33 For instance, they result in significant weight gain, whereas haloperidol use is limitedowing to higher risks of extrapyramidal effects and tardive dyskinesia. Another study of childrenwith ASD from a national registry showed that 35% of children with ASD received psychotropicmedications, but adding a second-generation antipsychotic to the stimulant did not have any sig-nificant additional benefit on any of the parameters studied.34 Moreover, the long-term safety ofantipsychotics in children remains unknown.23 Many children with ASD are also prescribed antidepressants, especially selective serotonin reuptake inhibitors (SSRIs).9 However, 2 recent reviews concluded that there is insufficient evidencefor any benefit of SSRIs or other psychotropic drugs in ASD.33,35 In fact, the results of a recent trial From the *Molecular Immunopharmacology and Drug Discovery Laboratory, Department of Molecular Physiology andPharmacology, and Departments of †Biochemistry, ‡Internal Medicine, and §Psychiatry, Tufts University School of Medi-cine, ||Department of Pharmacy, Tufts Medical Center, Boston, MA.
Reprints: Theoharis C. Theoharides, BA, MS, MD, PhD, Molecular Immunopharmacology and Drug Discovery Laboratory, Department of Molecular Physiology and Pharmacology, Tufts University School of Medicine,136 Harrison Avenue, Boston, MA 02111, USA (e-mail:
Copyright * 2012 by Lippincott Williams & WilkinsISSN: 0271-0749DOI: 10.1097/JCP.0b013e31825e00e4 Journal of Clinical Psychopharmacology & Volume 32, Number 4, August 2012 Copyright 2012 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Journal of Clinical Psychopharmacology & Volume 32, Number 4, August 2012 FIGURE 1. Diagrammatic representation of some of the most important interactions commonly seen among treatment of ASD.
NSAIDs, nonsteroidal anti-inflammatory drugs.
indicate that one SSRI, citalopram, not only was not effective for This broad category of flavonoids also includes the subgroups children with ASD but may actually be detrimental.36 These of flavonols (quercetin) and flavones (luteolin).51 Oral absorption findings highlight the fact that psychotropic agents have different and bioavailability of flavonoids are limited.54 These substances have varying antioxidant and anti-inflammatory properties, mostlydue to the degree of hydroxylation of their phenolic rings.51 The main metabolism of a flavonol such as quercetin is by glucur- Autistic children seem to have decreased capacity to sul- onidation (quercetin-3¶-glucuronide) and sulfation (quercetin-3¶- foconjugate acetaminophen and therefore are unable to effec- sulfate).55,56 Some children with ASD seem to be intolerant to tively metabolize particularly phenolic amines such as polyphenols, presenting with increased hyperactivity. Not all dopamine, tyramine, and serotonin.38 Some authors even hy- phenolic compounds carry the same potential risk. For instance, pothesized that the increased rate of ASD may be at least pycnogenol from pine bark has 15 hydroxyl groups and naringin partly due to acetaminophen39 through decrease of glutathione has 8 hydroxyl groups, as compared to quercetin’s 5 hydroxyl levels (Fig. 1).40 In view of this, parents have been shifting to groups and luteolin’s 4 hydroxyl groups. More detailed informa- ibuprofen. However, a recent study reported that using nonste- tion on interactions in general can be found elsewhere.53,57 roidal anti-inflammatory drugs, such as ibuprofen, with SSRIsreduces the antidepressant effect of the latter41 while increasing the risk of GI bleeding with SSRIs (Fig. 1).42 Quercetin and its structural analog luteolin are generally Taking multiple drugs increases the risk of adverse reac- safe.58,59 In addition, a number of papers report protective effects tions, especially in children and neonates.43 In a recent study of quercetin and luteolin both in the brain and liver.60,61 For ex- of spontaneous reporting of adverse drug-drug interactions ample, quercetin prevented liver toxicity induced by acetamino- in Italy, the incidence was 9.8% for 2 drugs but increased to phen62 and reduced haloperidol-induced dyskinesia in rodents.63 88.3% for 8 drugs or more.44 There is less information on drug- Quercetin also prevented methylmercury-induced DNA damage,64 supplement interactions. However, it was reported that 33.4% of whereas luteolin prevented mercury and thimerosal-induced in- patients using antipsychotics also took traditional Chinese med- flammatory mediator release from immune cells.65 Luteolin was icine concurrently; 7.2% of these patients had worse outcomes recently shown to inhibit microglial activation and is also neu- compared to 4.4% of those using antipsychotics alone.45 roprotective.66Y72 In fact, a luteolin analog was shown to mimic Risperidone is metabolized and can contribute to numer- the activity of brain-derived neurotrophic factor.73 A recent re- ous drug interactions because it is metabolized by CYP3A4, port also indicated that phenols in olive leaf extract can prevent the most common drug-metabolizing enzyme.46 Many children blood-brain barrier disruption,74 which has been proposed as have GI problems47 and are given numerous medications that a key pathogenetic factor in ASD.18,75 Formulations containing change the GI flora. In particular, they are often given antifungal luteolin in olive kernel extract are, therefore, likely not only to medications,16,17 such as fluconazole, which is a CYP3A inhib- permit higher absorption of luteolin in the brain but also provide itor and can affect the metabolism of many drugs (Fig. 1).48 the additional benefit of blood-brain barrier protection.
Moreover, concurrent use of fluconazole and amitriptyline has re- Patients may still develop idiosyncratic reactions through sulted in syncope49 and in serotonin toxicity presenting with de- activation of a unique immune cell, the mast cell, found in all lirium when given together with citalopram.50 tissues and responsible for allergic and inflammatory reactions.76The likelihood of idiosyncratic reactions may, therefore, be in- creased in the subgroup of patients with ASD who seem to have Treatment approaches for ASD have featured the use ‘‘allergic-like symptoms’’ 77 that involve mast cell activation by of polyphenolic compounds such as anthocyanidins, curcumin, pycnogenol (pine bark extract), green tea, and ginseng extract.
Given the high percentage of children with ASD being All of these are natural polyphenols present in plants, fruits, treated with multiple pharmacologic and nonpharmacologic in- vegetables, and tea.51 Oral administration of curcumin led to terventions, attention to interactions is a vital, but often overlooked, decreased intestinal P-glycoprotein and CYP3A and increased aspect of clinical management. Awareness of efficacy, safety, and serum levels of their respective substrates celiprolol and mid- unwanted interactions could increase the benefits of treatment azolam (Fig. 1).52 The main polyphenolic ingredients of grape- fruit juice, the coumarins, also inhibit the liver enzyme CYP3A,affecting the metabolism and/or activation of numerous drugs and natural substances, whereas the main polyphenolic flavonoid TCT is the inventor of US patents Nos. 6,624,148; 6,689, naringin can inhibit the organic anion-transporting polypeptide 748; 6,984,667, and EPO 1365777, which cover methods and family responsible for the transport of many hormones and drugs.53 compositions of mast cell blockers, including flavonoids; US Copyright 2012 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Journal of Clinical Psychopharmacology & Volume 32, Number 4, August 2012 patents 7,906,153 and 12/861,152 (allowed) for treatment of medication in child and adolescent psychiatric treatment in Denmark.
neuroinflammatory conditions, as well as US patent applications A cross-sectional survey. Nord J Psychiatry. 2008;62:472Y480.
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