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Drug Therapy in Autism A Present and Future Perspective
Drug Therapy in Autism A Present and Future Perspective
Drug Therapy in Autism A Present and Future Perspective
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Department of Neurology, Postgraduate Institute of Medical Education and Research, Chandigarh – 160012, India
Abstract:
Autism is a neurodevelopmental disorder, with a multifactorial etiology, characterized by severe abnormalities in communications,
social awareness and skills, and the presence of restrictive and stereotyped patterns of behaviors. It is traditionally considered
a “static” encephalopathic disorder without any specific cure and few effective biomedical interventions. There are various factors
which are involved in the etiopathogenesis of autism or autism spectrum disorder (ASD) such as impaired immune responses, neuro-
inflammation, abnormal neurotransmission, oxidative stress, mitochondrial dysfunction, environmental toxins and stressors. The
autism is often associated with a number of genetic disorders such as fragile X syndrome, tuberous sclerosis, epilepsy and Down syn-
drome. The recent approaches to autism treatment included various non-pharmacological and pharmacological therapy such as food
supplementation, detoxification, treatment of neuroinflammation, immunologic treatments and psychotropic medications, which
are found to be effective in treating various behavioral symptoms of autism. In current practice, there is no curative treatment for
autism but the recommended treatment for autism involves educational therapies: speech therapy, sensory integration therapy, audi-
tory therapy. There are classes of different pharmacological agents which are found to be effective in improving behavioral symp-
toms of ASD such as neurotransmitter reuptake inhibitors (fluoxetine), tricyclic antidepressants (imipramine), anticonvulsants
(lamotrigine), atypical antipsychotics (clozapine), acetylcholinesterase inhibitors (rivastigmine), etc. New classes of drugs with
novel mechanisms of action should be there so that this disorder will become less prevalent in the future.
Key words:
autism, ASD, behavior, clinical studies, drugs
mitochondrial dysfunction without the classic fea- Lemli-Opitz syndrome [122], FG syndrome [101] and
tures, which shows less severity [118]. This dysfunc- reduced adenosine deaminase activity [106].
tion might also be contributing to many symptoms of Genomic and mutational studies have identified
autism, such as cognitive impairment, language defi- a number of known genes which are supposed to be
cits, increased oxidative stress, and others [114]. The involved in the pathogenesis of autism and that are
inability to neutralize reactive oxygen species and also implicated in excitatory and inhibitory neuro-
free radicals during mitochondrial respiration lead to transmission [1]. For example, GABA has been linked
increased oxidative stress. Oxidative stress is also to chromosome 15 which is implicated in autism [91].
known to be involved in various neurodegenerative This inhibitory neurotransmitter is involved in early
diseases in humans. Increasing evidence suggests brain development; impairments in this neurotrans-
a role of oxidative stress in the development and clini- mitter are likely to have a negative effect on the matu-
cal manifestation of autism [25]. It is suggested that ration of local circuits which are involved in informa-
autism may result from an interaction between ge- tion processing as well as complex cognitive behavior
netic, environmental, and immunological factors, with [10]. Atypical GABAergic signaling have also been
oxidative stress as a mechanism linking these risk fac- found in different brain regions of persons with
tors [24]. Mitochondrial dysfunction could further autism, which indicates that this disorder is wide-
lead to oxidative stress and lower glutathione levels. spread in their brains and may be implicated in the
Impaired energy production and oxidative stress in- cognitive deficits present in these patients [46]. There
duced release of glutamate leads to excitoxicity. Many are more than ten genes that contribute to the underly-
industrial toxins, including pesticides, can inhibit mi- ing genetic risk of developing autism [91]. Autism-
tochondrial function. Again, a diet high in antioxi- associated mutations of neuroligins (NLGN3, NLGN4)
dants, organic raw, fresh fruits and vegetables seems cell-adhesion molecules are also proposed as candi-
appropriate for reducing oxidative stress in autistic date genes implicated in neural alteration affecting in-
patients [118]. formation processing in autism [10].
Herbert [59] states that environmental toxins and Although autism has been considered as neurode-
stressors might cause or trigger autism, implying that velopmental disorder caused by various structural and
we have to look at the whole person and whole body genetically based neurochemical alterations, different
affected by these stressors. This involves shifting markers of chronic inflammation and oxidative stress
from autism as a genetically determined brain disor- has also been found in autistic patients [58, 61]. Re-
der to a newer and more inclusive model that consid- cent studies suggested that many autistic children
ers autistic behavior one of many effects of genetic have also been accompanied with many other medical
and environmental impacts on the whole body, includ- problems (Tab. 1) such as increased oxidative stress
ing the brain. A recent report suggested that close [67], mitochondrial dysfunction [114], increased
relatives of children with autism (who themselves do metal toxicity burden [2], immune dysregulation with
gastrointestinal disturbances and immune activation
not meet criteria of autism) can have autism-related
of glial cells in the brain [69, 125], combined with
symptoms, milder social and communication deficits
central nervous system (CNS) hypoperfusion or ab-
and stereotyped behaviors [35].
The autism syndrome is often associated with
a number of genetic disorders such as FXS, tuberous
Tab. 1. Various biomedical problems observed in ASD [15]
sclerosis, Rett syndrome, epilepsy, Asperger syn-
drome and Down syndrome [12, 33, 43, 121]. FXS is
the most common chromosomal abnormality associ- Biomedical problem Autistic spectrum disorder
(ASD)
ated with autism and about 2–5% of autistic children
also has this syndrome. At least 15% of males with Oxidative stress Yes
FXS fulfill the criteria for infantile autism. Autism Mitochondrial dysfunction Yes
and FXS are neurodevelopmental disorders that Metal toxicity Yes
sometimes manifest shared neurocognitive and be-
Immune
havioral phenotypes [10, 30]. In several studies, it has Yes
dysregulation/inflammation
been reported that about 30% of autistic children have
Cerebral hypoperfusion Yes
epilepsy and other genetic disorders such as Smith-
mia and limited dietary habits. Audiometric and oph- tional intervention and complementary and alternative
thalmic examinations should also be done to check medicine (CAM) approaches are highly prevalent
whether there is any hearing and visual deficits or any (about 74%) among children affected with ASD [56].
communication disorder [47]. The broad heterogeneity of clinical and behavioral
symptoms in autistic children indicates that no single
treatment will benefit every autistic child. Thus, defi-
nition and characterization of subgroups of children
Therapeutic basis who respond positively or negatively to intervention
are necessary to be identified more clearly [66].
Despite these advances in early diagnosis and inter-
vention, no therapy has been yet proven to completely
reverse the core symptoms of autism. In current prac-
tice, there is no specific treatment for autism but the Non-pharmacological therapy
recommended treatment for autism involves educa-
tional therapies: applied behavior analysis, speech
therapy, sensory integration therapy, auditory therapy, There is currently no known ‘cure’ for autism. The
etc. Based on various reports and parent surveys, it only treatment in ameliorating the core behavioral
has been shown that food supplementation and alter- deficits in autistic children is early intensive behav-
native treatments aimed at intestinal healing and de- ioral and educational interventional therapy [70].
toxification also helps in ameliorating the symptoms A team of trained and specialized healthcare profes-
of autism. This has prompted autism research into sionals such as a developmental pediatrician, a child
a different treatment approach that autism should be psychiatrist, an occupational (behavioral) therapist,
treated as a whole body condition [118]. The recent a nutritionist, a speech therapist, a psychologist,
approaches to autism treatment included various a specialist teacher and a social worker [70] are neces-
non-pharmacological and pharmacological therapy sary for the management of autism. There is an im-
such as food supplementation, detoxification, dietary provement in the cognitive, communication, adaptive
intervention, treatment of GI disturbances, treatment and social functioning and reduction in inappropriate
of chronic inflammation (Fig. 1) in the brain and in- behaviors such as aggression, hyperactivity and tem-
testines and immunologic treatments, etc. [60]. Nutri- per tantrums after early (initiated before 4 years of
treating various behavioral symptoms of autism such hypomania, agitation, and hyperactivity [36, 45, 61].
as hyperactivity, lack of attention, agitation, insomnia, Fluvoxamine has also shown the similar potential ef-
aggression, self-injury, irritability, repetitive and com- fects against autistic disorder as those by fluoxetine
pulsive behaviors and anxiety [48]. Although, benefits [78, 132]. In a double-blind, placebo-controlled trial,
have been reported with: (i) atypical antipsychotics fluvoxamine has been found well tolerated in autistic
(risperidone, olanzapine, clozapine) for temper tan- adults and improved compulsive and repetitive behav-
trums, aggression, or self-injurious behavior; (ii) selec- iors and aggression [85]. Other SSRIs, including ser-
tive serotonin reuptake inhibitors (sertraline, citalo- traline [81, 109], paroxetine [108] and escitalopram
pram, fluoxetine) for anxiety and repetitive behaviors; [100], also possessed the same potential benefits and
and (iii) psychostimulant (methylphenidate), opioid an- adverse effects as fluoxetine and fluvoxamine. It has
tagonist (naltrexone) for hyperactivity [3, 89] but the also been reported that the use of venlafaxine in autis-
risk of drug toxicity must always be balanced against tic individuals showed the improvements in their re-
the benefits of reducing interfering behaviors [62, 70]. stricted behaviors, interests, social deficits, hyperac-
There are varieties of different pharmacological agents tivity and communication problems [19].
which are found to be effective in improving behav-
ioral symptoms of ASD.
Tricyclic antidepressants
Atypical antipsychotics
Nortriptyline has been found to be effective in children
Although clozapine has been reported to be effective with ASD as it improved the hyperactivity, aggressive-
in improving hyperactivity and aggression in autistic ness, and ritualized behavior, while imipramine is not
children, adolescents and adults, but has a limited us- well tolerated in autistic children [17, 76]. In a study,
age because of the hematological safety monitoring 58% of autistic subjects have found clomipramine to
that is necessary for patients taking the medication be superior to placebo and the antidepressant desi-
and a potential lowering of the seizure threshold in pramine in improving autistic symptoms, anger, and
patients [26, 52, 133]. Ziprasidone possessed some compulsive and ritualized behaviors [53]. In another
beneficial effects for patients with autism spectrum study, clomipramine has produced adverse effects such
without any significant weight gain or other adverse as sedation and a worsening of behaviors like aggres-
effect [84]. sion, irritability, and hyperactivity [117].
McDougle et al. found [83] that risperidone is bet-
ter than placebo in treating irritability, repetitive be-
havior, aggression, anxiety, depression and nervous- Anticonvulsants
ness. In addition to this, risperidone has also been
shown to possess neuroprotective effect, modulate In epileptic children, lamotrigine treatment has shown
important astroglial functions and increase the anti- a decrease in autistic symptoms in 62% of the autistic
oxidant and neuroprotective activity in brain disorders subjects [123]. However, no significant difference be-
such as ASDs [112]. Risperidone is well tolerated, tween placebo-treated and lamotrigine-treated pa-
showing no evidence of extrapyramidal side effects tients has been found in a double-blind, placebo-
(EPS) or seizures except mild sedation [83]. Other controlled study of 35 patients with autistic disorder.
side effects with use of risperidone include increased Divalproex sodium (sodium valproate + valproic acid,
appetite, fatigue, dizziness and drowsiness [80]. 1:1) has shown beneficial effects in patients with
autism spectrum disorders (ASDs) and PDDs [60].
Neurotransmitter reuptake inhibitors Several other reports from clinical studies have also
shown that divalproex sodium produced clinical im-
Fluoxetine (selective serotonin reuptake inhibitor, provements in the various symptoms of autistic pa-
SSRI) has shown several possible benefits, including tients such as receptive language, affective instability,
reductions in rituals, stereotyped and repetitive behav- aggression, and social skills [6, 60, 63]. Rugino and
iors in children and adolescents with autistic spectrum Samsock found that levetiracetam may be useful in
disorders (Fig. 1). However, fluoxetine has also pro- reducing hyperactivity, impulsivity, aggression, and
duced some sort of adverse effects like disinhibition, affective lability [116].
Methylphenidate is a stimulant that is commonly indi- Loss of neuronal functions of certain brain areas in
cated for autistic children and adolescents. In some autism further leads to the development of behavioral
controlled studies, methylphenidate was found to be and sensory complications such as attention deficits,
effective in improving the behavior symptoms like hyperactivity, mood instability, aggressiveness, agita-
hyperactivity, impulsivity and attention but it also tion, etc. The present scientific research directs us to
produces some initial side effects such as anorexia, a few things. One is being the plasticity of brain tis-
aggression, and insomnia [38, 55]. sue, the second being nerve tangling in the brain and
the third being uneven production of serotonin, all
Clonidine which may have a significant effect on evolution and
degree of severity of autism in any particular individ-
Oral or transdermal administration of selective a-2 ual. Apart from this, there are many other pathologi-
agonist, clonidine, have shown improvement in hy- cal changes occurred in autism such as gastric distur-
peractivity, mood instability, aggressiveness and agi- bances, oxidative stress, chronic inflammation and
tation in autistic individuals. The side effects were immunological problems.
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