© Springer International Publishing Switzerland 2015
Maria de los Angeles Robinson-Agramonte (ed.)Translational Approaches to Autism Spectrum Disorder10.1007/978-3-319-16321-5_1111. Current Therapies
(1)
Department of Experimental Medicine—Division of Pharmacology, Second University of Naples, via S. Maria di Costantinopoli, Caserta, Italy
(2)
Biomedical Centre for Autism Research and Treatment, Bari, Italy
Abstract
Nowadays, autism could be considered as a still untreatable disease. Its very complex nature and the still unclear pathophysiology and pathogenesis create challenges in treating this disorder. Current drug options for autism management are not effective for the treatment of core symptoms of autism.
This chapter describes the state-of-the-art about pharmacological interventions and focuses on novel potential therapeutics, including cell therapies, for autism care.
Keywords
AutismPharmacotherapyCell therapy11.1 Introduction
11.1.1 Autism: A Brief Overview
Autism and autism spectrum disorders (ASDs) are complex heterogeneous neurodevelopmental conditions (American Psychiatric Association 2000). Interaction of genetic and environmental factors contributes to the development of these multifactorial disorders (Siniscalco et al. 2013a) . Dysfunctions in communication skills and social interactions, combined with repetitive, restrictive, and stereotypic verbal and nonverbal behaviors are the common symptoms. Despite extensive research efforts, the etiologic-pathologies of ASDs are still inadequately understood (Siniscalco 2013; Siniscalco and Cubala-Kucharska 2013; Siniscalco et al. 2012b) .
Estimated ASD prevalence is still raising; these disorders are now recognized as urgent public health problems, as their frequency continues to increase dramatically, until present dramatic rates of 1 in 68 children aged 8 years in the USA, according to Center for Disease Control (Baio 2014) .
In addition, ASDs show a negative impact on the quality of life of patients and their families (Siniscalco et al. 2013b) . Increased stress and mental and physical health problems have been reported in parents of autistic children compared with parents of typically developing children (Karst and Van Hecke 2012) .
Health system has also been affected, as the estimated total lifetime societal cost of caring one autistic patient is US $ 3.2 million (Siniscalco 2013) . Indeed, autism is a pathology that persists throughout the entire existence, hence autistic individual needs, throughout their life, continuous protection, comprehensive and accessible health care services, and prolonged specialized assistance and opportunities for independent adult life by the family (Siniscalco et al. 2013b; Zablotsky et al. 2014) .
For a molecular point of view, several cellular and biochemical events are associated with ASDs: cellular oxidative stress; endoplasmic reticulum stress; decreased methylation capacity; limited production of glutathione; mitochondrial dysfunction; intestinal dysbiosis; increased toxic metal burden; immune dysregulation; immune activation of neuroglial cells (Siniscalco et al. 2012b) .
The very complex nature of autism and the still unclear pathophysiology and pathogenesis create challenges in treating these disorders. However, there is no effective pharmacological intervention for the treatment of core symptoms of ASDs (Siniscalco and Antonucci 2013a)] .
11.2 Autism: Current Therapies
First of all, it must be pointed out that many autism clinician practitioners agree that an early, intensive, individual-designed, and multitreatment program will greatly improve the condition of most young autistic children. Several treatments could be enrolled; however, a combination of techniques is to be preferred. Current available treatments for autism can be divided into: behavioral, nutritional, psychotherapeutical, and pharmacological approaches—even if a defined standard approach does not exists. The most used approaches include: psychological intervention, occupational and physical therapy, speech-language therapy, medications and sensory integration , and vision therapy (http://umm.edu/health/medical/ency/articles/autism Siniscalco and Antonucci 2013b) .
Nowadays, it is well recognized that once a child is diagnosed with autism, the psychological intervention is a priority (Siniscalco et al. 2013b) . The widely used and the most effective psychological treatment is the applied behavior analysis (ABA). This program uses a one-on-one teaching approach useful for reinforcing the practice of various skills and is usually performed in the child’s home under the supervision of a behavioral psychologist. With the use of this program, psychologists try to reach the goal of getting the child close to normal developmental functioning.
Another used program is the Treatment and Education of Autistic and Related Communication Handicapped Children (TEACCH). TEACCH uses picture schedules and other visual cues that help the child work independently, and organize and structure their environments. Unlike ABA programs, TEACCH programs try to improve child’s adaptation and skills, and also accept the problems associated with autism without trying to overcome them.
11.2.1 Drugs
Pharmacological treatments only target secondary neuropsychiatric symptoms (i.e., irritability, depression, anxiety, and obsessive-compulsive behaviors) coassociated with ASDs, without addressing the core symptoms (social interaction and communication deficits, restricted and repetitive behaviors) (Farmer et al. 2013) . Several drugs are prescribed: psychostimulants, alpha-2 agonists, beta blockers, lithium, anticonvulsant mood stabilizers, atypical antipsychotics, traditional antipsychotics, selective serotonin reuptake inhibitors (SSRIs), antidepressants, and antipsychotics. Developing new drugs for autism has been challenging because of a limited understanding of its pathophysiology, difficulties in establishing efficacious models of the disease and the heterogeneity of symptoms (Ghosh et al. 2013) . However, in the past years several drugs have been evaluated and due the lack of efficacy have been eliminated as possible treatments for the core symptoms of autism. In example, the indirect serotonin (5-hydroxytryptamine) agonist fenfluramine (a drug approved in the USA to treat obesity) has been proposed for treating autism , due to its potential to decrease blood levels of serotonin (Cook and Leventhal 1996) . The serotonin system is involved in autism and many autistic patients show elevated levels in blood. However, no therapeutic effect of fenfluramine on autistic core symptoms was achieved. In addition, several adverse effects on learning and, above all, warnings on associated cardiac valvular disease led to the removal of fenfluramine from the market in 1997 (Farmer et al. 2013) .
Anticonvulsant mood stabilizers were frequently used, likely to treat epilepsy-associated symptoms (Farmer et al. 2013) . Several clinical studies, however, demonstrated the lack of effects in treating autism core symptoms for divalproex sodium, lamotrigine, and levetiracetam (Hollander et al. 2010; Belsito et al. 2001; Wasserman et al. 2006) . Although valproate sodium (VPA) and other mood stabilizers were considered safe and well-tolerated and could be effective for the coassociated symptoms, such as irritability and aggression, as result of the studies, this class of drugs does not treat the autism core symptoms. In addition, it is very important to consider that, on the other hand, VPA is used as autism triggering drug in animal models (Patterson 2011) . VPA is also a potent neurobehavioral and neurocognitive teratogen for humans and should be strictly avoided during pregnancy (Martin and Manzoni 2014; Gentile 2014) .
Among the atypical antipsychotic drugs, the most prescribed for autism is risperidone (Systematic IUPAC name 4-[2-[4-(6-fluorobenzo[d]isoxazol-3-yl)-1-piperidyl]ethyl]-3-methyl-2,6-diazabicyclo[4.4.0]deca-1,3-dien-5-one). Early approved by US Food and Drug Administration (FDA) for schizophrenia, it is now used to treat irritability, violent meltdowns, tantrums, aggression, and self-injury in autistic patients. Together with aripiprazole, it is the unique atypical antipsychotic drug approved by FDA for using in children and adolescents (McKinney and Renk 2011) . Risperidone was also approved by the European Medicines Agency for use in ASDs. Risperidone is a selective postsynaptic monoaminergic antagonist with high affinity for serotonin 5-HT2A and dopamine D2 family receptors, as well as the D1 receptors. Adverse effects are impressive, whereas long-term effects are not clear. The most commonly reported included some extrapyramidal symptoms, somnolence, fatigue, anxiety, increased prolactin, upper respiratory tract infection, tremor, dystonia, hyperglycaemia, drowsiness, nasal congestion, increased saliva, dry mouth, enuresis, diarrhea/constipation, weight gain, and increased appetite (Baribeau and Anagnostou 2014) . The increase in weight could be linked to its antagonistic actions also at the 5-HT2C receptor. Risperidone is also able to bind α1 (hypotensive effects and sedating effects) and α2 adrenergic receptors and histamine H1 receptors (sedation and reduction in vigilance) (Brunton et al. 2010) . While the short-term benefit of risperidone in ameliorating severe disruptive behavior, such as irritability, in autistic children is well established (Troost et al. 2005) , suggesting its use at low dose as emerging drug for the treatment of irritability associated with autistic disorder in children and adolescents (Scott and Dhillon 2008) ; caution should be given for its adverse effects and unknown long-term effects. Several clinicians believe that the ratio benefits/side effects is not enough to justify this medication in ASDs management.
Paliperidone, an active metabolite of risperidone, approved for schizophrenia and schizoaffective disorders in the USA, was able to decrease the irritability associated with autism in a prospective, 8-week open-label small study conducted in 25 adolescents and young adults with autism (Stigler et al. 2012) .
Aripiprazole (IUPAC name 7-[4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butoxy]-3,4-dihydro-1H-quinolin-2-one), a partial dopamine agonist, is an atypical antipsychotic also used to treat irritability and hyperactivity in ASDs (Ching and Pringsheim 2012) . It is sometimes included in third-generation antipsychotic class, since it is aripiprazole, is a partial agonist at both dopamine D2 and serotonin 5-HT1A receptors and an antagonist at serotonin 5-HT2A, whereas second-generation antipsychotics show several levels of antagonism at the D2 receptors (Farmer and Aman 2011) . Its pharmacodynamics is very particular. Indeed, aripiprazole works as agonist or antagonist in correlation to receptor density and local concentrations of dopamine. It antagonizes the D2 receptor under hyperdopaminergic conditions, and is an agonist under hypodopaminergic conditions (Kikuchi et al. 1995) . It is also a 5-HT2C partial agonist and an inverse agonist at the 5-HT2B receptor. Also for this drug, major adverse effects include weight gain, sleepiness, sedation, drooling, and tremors and long-term safety and effects are unknown (Ching and Pringsheim 2012) . However, some authors reported that there is no weight gain and no significant changes in glucose or lipid metabolism with its use, indicating a significant advantage over risperidone (Greenaway and Elbe 2009) .
The results of clinical trials strongly suggest that the effects of atypical antipsychotics on the core symptoms of autism are very modest. Sometimes, the perceived improvements in the core symptoms are just related to the improvement in irritability and no study has been conducted to evaluate the core symptoms as a primary outcome (Farmer and Aman 2011) . As stated above, the ratio benefits/side effects associated with the atypical antipsychotics does not justify their use and reconsidering the use of atypical antipsychotic in autism care is strongly encouraged (McKinney and Renk 2011) .
The SSRIs are the most commonly prescribed off-label antidepressants for autism. Also for these drugs, their use is for the treatment of autism comorbidity, such as depression, anxiety, and obsessive-compulsive behaviors (Williams et al. 2013) . A huge double-blind, placebo-controlled study on the use of citalopram (IUPAC name (RS)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile) for autism core symptoms showed no effect of citalopram treatment over placebo. On this basis, authors concluded that the results do not support the use of citalopram for the treatment of repetitive behavior in ASD children and adolescent (King et al. 2009) . Clomipramine (IUPAC name 3-(3-chloro-10,11-dihydro-5H-dibenzo[b, f]azepin-5-yl)-N, N-dimethylpropan-1-amine) a tricyclic antidepressant showed no effects on stereotypy (Remington 2001) . The results of several randomized clinical trials agree that the efficacy of SSRIs for the treatment of repetitive behaviors in ASDs is modest and whether or not these drugs are effective is still unclear (Carrasco et al. 2012) . Tolerability and appropriate dose need further studies. In addition, concerns about the association between the use of SSRIs during pregnancy and an increased risk of autism spectrum disorders in the offspring have been raised and need to be evaluated (Hviid et al. 2013; Rai et al. 2013) .
11.2.2 Other Drugs
Cholinergic drugs, such as acetylcholinesterase inhibitors used for dementia treatment, have been proposed to treat autism, based on the fact that nicotinic receptors and M1 muscarinic receptors were found decreased in brain specimens from autistic individuals. Rivastigmine tartrate (IUPAC name (S)-3-[1-(dimethylamino)ethyl]phenyl N-ethyl-N-methylcarbamate), a cholinesterase inhibitor (it inhibits both butyrylcholinesterase and acetylcholinesterase), showed positive effects in ameliorating speech and overall autistic behavior in a 12-week open-label clinical trial on 32 autistic patients (Chez et al. 2004) . However, the anticholinesterase tacrine (IUPAC name 1,2,3,4-tetrahydroacridin-9-amine) showed modest effects in the short-term treatment of irritability in autistic children. Hepatotoxicity makes it not recommended as a helpful drug for autism (Niederhofer 2007) . Donepezil (IUPAC name (RS)-2-[(1-benzyl-4-piperidyl)methyl]-5,6-dimethoxy-2,3-dihydroinden-1-one) decreased irritability and hyperactivity in a small study. No changes in the core autistic symptoms were reported; side effects were gastrointestinal disturbances and mild irritability (Hardan and Handen 2002) . In a later study, donezepil was effective in decreasing rapid eye movement sleep in autistic children; how this sleep state is correlated to cognition and behavior in autism remains to be elucidated (Buckley et al. 2011) . Aggression and inattention were also decreased in an open-label study on the use of galantamine (IUPAC name (4aS,6R,8aS)-5,6,9,10,11,12-hexahydro-3-methoxy-11-methyl-4aH- [1]benzofuro[3a,3,2-ef] [2] benzazepin- 6-ol) (Nicolson 2006) . Safety alerts were released by FDA for its use in mild cognitive impairment after several deaths related to vascular causes (http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm152595.htm). Lastly, mecamylamine (IUPAC name (1S,2R,4R)-N,2,3,3-tetramethylbicyclo[2.2.1]heptan-2-amine), a nonselective and noncompetitive nicotinic receptor blocker, was ineffective in a placebo-controlled pilot trial (Arnold et al. 2012) .
It has been proposed a role for glutamate excitotoxicity in the pathogenesis of autism (Essa et al. 2013) . Language functions and social behavior were improved with the use of memantine (IUPAC name 3,5-dimethyltricyclo[3.3.1.13,7]decan-1amine), a nonselective NMDA receptor blocker, but also a dopamine D2 receptor agonist (Seeman et al. 2008) , in autistic children over a 21-month period (Chez et al. 2007) . No serious side effects were reported. However, an open-label pilot study reported only moderate improvements in cognitive functioning and behavioral symptoms (Owley et al. 2006) .
Taken together, these results highlight that the efficacious and definitive pharmacologic treatment for the core symptoms of autism does not exist (Farmer et al. 2013) . Hence, the lack of effective drugs have led to an increased sense of urgency to identify novel targets and therapies for ASDs (Ghosh et al. 2013) .
11.2.3 Autism: Other Therapies
It has been suggested a therapeutic potential of oxytocin in treating core dimension of autism. Indeed, oxytocin, administered as nasal spray, as it does not cross the blood brain barrier (BBB), was able to improve emotion recognition and social behavior in autistic young people in respect to placebo, opening the way for its use to improve social communication and interaction in ASDs (Guastella et al. 2010) . Oxytocin (IUPAC name 1-({(4R,7S,10S,13S,16S,19R)-19-amino-7-(2-amino-2-oxoethyl)-10-(3-amino-3-oxopropyl)-16-(4-hydroxybenzoyl)-13-[(1S)-1-methylpropyl]-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentaazacycloicosan-4-yl}carbonyl)-L-prolyl-L-leucylglycinamide) is a hormone (nonapeptide) produced by the hypothalamus. Its action is mediated by specific G-protein-coupled receptors (oxytocin receptors). Once released by neurons, it is transported via large neurosecretory axons to the posterior hypothalamus. It has been demonstrated that changes in oxytocin receptor gene or aberrant methylation of the receptor protein, with epigenetic mechanism as protein expression regulators, are related to autism etiology (Jacob et al. 2007; Wermter et al. 2010; Insel 2010) . Oxytocin-treated autistic patients exhibited more appropriate social behavior and affect (Andari et al. 2010) , confirming the results obtained in rodents, suggesting that oxytocin could facilitate social information processing (Hollander et al. 2007) . Further research is necessary to verify potential side effects.
Bioactive proteins and peptides could provide novel therapeutic applications for autism treatment (Siniscalco and Antonucci 2013b) . Oxidative stress and mitochondrial dysfunction are among molecular changes associated with ASDs, possibly reflecting an impairment in cellular redox homeostasis. The ratio glutathione/glutathione disulfide (GSH/GSSG) is a marker of the redox-dependent cellular functions, as well as of cellular toxicity. It has been proposed that autistic children display a decreased capacity to counterbalance redox damages and detoxification capacity. Indeed, these children show decreased blood levels of total and reduced GSH, while oxidized GSH is significantly increased (Geier et al. 2009) . Glutathione is a sulfhydryl tripeptide (cysteine, glycine, and glutamate) with a strong antioxidant capacity and its supplementation in autistic children, together with daily consumption of cysteine-rich foods, could increase plasma GSH levels (Kern et al. 2011; Witschi et al. 1992; McPherson and Hardy 2011) .
Another interesting potential option for the management of ASD-related behaviors is the vitamin C (McGinnis 2004) . This polypeptide is widely recognized as antioxidant and, together with other antioxidant peptides containing 5–16 amino acid residues, is an inhibitor of lipid peroxidation, scavengers of free radicals and chelators of transition metal ions (Siniscalco and Antonucci 2013b) . Treating ASDs with antioxidant peptides could be an optimal strategy to target the oxidative stress and related autoimmunity (Mostafa et al. 2010) .
11.3 Future Directions: Cellular Therapies
Nowadays, it is widely recognized that stem cell therapy represents the great promise for the future of molecular and regenerative medicine (Siniscalco et al. 2012a) . In principle, stem cells provide a valid approach to curing several untreatable human diseases. Of course, stem cells represent a possibility also for curing ASDs (Siniscalco 2012) . Stem cells are defined by two important and fundamental characteristics: (1) their self-renewal ability: the capacity to generate more identical stem cells; (2) differentiation process: the capacity to give rise to more differentiated cells. In addition, stem cells also show paracrine regulatory functions (Caplan and Dennis 2006) : the capacity to synthesize and release a complex plethora of biomolecules (stem cells as “biopharmacy”), which in turn are able to regulate several key cellular processes, such as cell differentiation, tissue and organ repair, scar formation, apoptosis, mitosis and anti-inflammatory actions in the host recipient. The great appeal (especially in ASDs) of stem cells, however, is due to their strong immunomodulatory capacity (Siniscalco et al. 2013c) . This property is performed through the paracrine activity; by synthesizing and releasing (secretome activity) key molecules (i.e., anti-inflammatory cytokines) stem cells regulate host immune system cells (i.e., B and T cells) . It is noteworthy to consider that autism is related to immune imbalance. It has been demonstrated a strong dysregulation in peripheral blood monocytic cells (PBMCs) or monocytes, the key regulators of the immune response (Siniscalco 2012c) . Monocyte dysfunction could result in long-term immune alterations in autistic children (Enstrom et al. 2010) . Stem cells could restore immune system also through a cell-to-cell contact activation mechanism, through which transplanted stem cells are able to switch proinflammatory macrophages to anti-inflammatory macrophages (Siniscalco et al. 2011) . Through these two mechanisms stem cells could, simultaneously: counterbalance the immune system aberrations, and activate endogenous restorative mechanisms within damaged tissues contributing to recovery of functional deficits.
Related posts:
Autism, Development and Neural Plasticity
Autism Spectrum Disorder. A Clinical Neurophysiology Approach II
The Genetic Basis of Autism Spectrum Disorder
Neuroinflammation in Animal Models of Autism
Understanding on Neuroimmunology in Autism Spectrum Disorder
Epidemiology of Autism Spectrum Disorders
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