evoking subclinical hypomania as a potential autism treatment

18 Pages·2017·0.25 MB·English

by  Krzysiek Nesterowicz

Świerczek M. et al. Medical Research Archives, vol. 6, issue 1, January 2018 issue Page 1 of 18
REVIEW ARTICLE

E
VOKING SUBCLINICAL HYPOMANIA AS A POTENTIAL
-
AUTISM TREATMENT A HYPOTHESIS BASED ON AN
- -
UP TO DATE LITERATURE REVIEW
1
Maciej Świerczek, MPharm , Krzysztof Nesterowicz, MPharm, PhD
2,3
candidate
Authors’ affiliations:

1 Jagiellonian University, Medical College, Faculty of Pharmacy, Krakow, Poland (former)

2 Jagiellonian University, Medical College, Faculty of Pharmacy, Krakow, Poland (former)
3 National University of Public Service, Budapest, Hungary
Corresponding authors: Maciej Świerczek, [email protected] and
Krzysztof Nesterowicz, [email protected]
Abstract
The growing number of children diagnosed with autism spectrum disorder (ASD) urges the scientific
community to find a simple and cost-effective solution to this problem. Before 1990, the general
population prevalence for autism was considered steady at 4–5/10,000 (1/2,000–1/2,500). However,
recent studies on children in the United States have reported an ASD diagnosis in 1/91 3-17 year olds
and 1/110 8 year olds.
A comprehensive literature review of over 700 articles on neurotransmitter levels and brain
performance in autism and other psychiatric conditions was conducted to finally include 83 studies.
The results of the search led us to the conclusion that autism is a state of the brain performance
opposite in many aspects to mania (in particular hypomania), both behaviourally (in particular autism
being characterized by social deficits and hypomania by hypersociability), neurochemically (e.g. low
brain vasopressin, high cortisol in autism vs. high brain vasopressin, low cortisol in mania) and by
activity of key brain areas (e.g. mirror neuron system, amygdala).
We hypothesize that instead of targeting separate neurotransmitter systems in autism, the focus
should be on 'moving and locking' the brain into a subclinical hypomanic state when required. When
in a subclinical hypomanic state, a patient's sociability (the key and most debilitating symptom of
autism) should be massively improved. We have designed experiments which would test the above
hypothesis.
Keywords: autism, mania, hypomania, mirror neuron system (MNS), amygdala

1. Background scientists fearing that some environmental
toxins have emerged to cause an autism
'The growing number of children being
epidemic. Before 1990, the general
diagnosed with autism has raised enormous
population prevalence for autism was
concern from parents, physicians, and
considered steady at 4–5/10,000 (1/2,000–
Copyright 2018 KEI Journals. All Rights Reserved http://journals.ke-i.org/index.php/mra
Świerczek M. et al. Medical Research Archives, vol. 6, issue 1, January 2018 issue Page 2 of 18
1/2,500). Recent studies in the United associated with marked clumsiness. There
States reported the diagnosis of autism is a strong tendency for the abnormalities to
spectrum disorder (ASD) in 1/91 3- to 17- persist into adolescence and adult life.
year olds and 1/110 8-year-old children Psychotic episodes occasionally occur in
[1].’ early adult life [2].’
'Children with classic autism are unable to New diagnostic criteria have been proposed
‘read’ other people, ignoring them and often for ICD-11 beta draft due to be published in
strenuously avoiding eye contact. 2018, merging Kanner's syndrome,
Reciprocal communication, through speech, Asperger's syndrome and Pervasive
gestures, or facial expressions, is impaired. Developmental Disorder – Not Otherwise
Children with autism fail to develop Specified under one umbrella of Autism
friendships with peers and siblings. In Spectrum Disorder. However, due to cited
school, they often stand and watch other articles being published at different times
children from a distance. Some children and the ongoing debate whether that merger
respond to social overtures but take little was a right one, we refer to the diagnostic
social initiative, whereas others seek criteria used in the original studies we cited
interaction but have little sense of how to [3].
proceed toward normal friendships [1].’
In ICD-11 beta, 'Autism spectrum disorder
ICD-10 defines childhood autism is characterized by persistent deficits in the
(Kanner's syndrome) as follows: ‘A type ability to initiate and to sustain reciprocal
of pervasive developmental disorder that is social interaction and social commu-
defined by: (a) the presence of abnormal or nication, and by a range of restricted,
impaired development that is manifest repetitive, and inflexible patterns of
before the age of three years, and (b) the behaviour and interests. The onset of the
characteristic type of abnormal functioning disorder occurs during the developmental
in all the three areas of psychopathology: period, typically in early childhood, but
reciprocal social interaction, symptoms may not fully manifest until
communication, and restricted, stereotyped, later, when social demands exceed limited
repetitive behaviour. In addition to these capacities. Deficits are sufficiently severe to
specific diagnostic features, a range of other cause impairment in personal, familial,
non-specific problems are common, such as social, educational, occupational or other
phobias, sleeping and eating disturbances, important areas of functioning and are
temper tantrums, and (self-directed) usually a pervasive feature of the
aggression [2].’ individual’s functioning observable in all
settings, although they may vary according
Asperger's syndrome is classed as a
to social, educational, or other context.
milder form of autism and defined as: 'A
Individuals along the spectrum exhibit a full
disorder of uncertain nosological validity,
range of intellectual functioning and
characterized by the same type of
language abilities [4].’
qualitative abnormalities of reciprocal
social interaction that typify autism, On the other hand, ICD-10 defines
together with a restricted, stereotyped, hypomania (a milder form of mania) as ‘a
repetitive repertoire of interests and disorder characterized by a persistent mild
activities. It differs from autism primarily in elevation of mood, increased energy and
the fact that there is no general delay or activity, usually marked feelings of well-
retardation in language or in cognitive being and both physical and mental
development. This disorder is often efficiency. Increased sociability,
Copyright 2018 KEI Journals. All Rights Reserved http://journals.ke-i.org/index.php/mra
Świerczek M. et al. Medical Research Archives, vol. 6, issue 1, January 2018 issue Page 3 of 18
talkativeness, over-familiarity, increased Scholar with the use of search keywords
sexual energy, and a decreased need for (neurotransmitter name OR brain part
sleep are often present but not to the extent name) AND (autism OR mania / manic) for
that they lead to severe disruption of work each combination (e.g. vasopressin +
or result in social rejection. Irritability, autism; vasopressin + mania; amygdala +
conceit, and boorish behaviour may take the autism; amygdala + mania). The study DID
place of the more usual euphoric sociability. NOT involve people, human tissues,
The disturbances of mood and behaviour medical records or death certificates even
are not accompanied by hallucinations or retrospectively, therefore no approval from
delusions [2].’ the bioethical commission was needed. The
search resulted in over 700 articles, of
We present references on how main
which 83 most relevant are cited below. The
neurotransmitters (acetylcholine, nor-
review is non-systematic as a systematic
adrenaline, cortisol, dopamine, hista-
one would have had a very high volume,
mine, NMDA ligands, opioids, oxytocin,
and a very high volume is not necessary to
serotonin, testosterone, vasopressin) have
present our idea. We selected the most
opposing (low/high compared to controls)
representative articles to include in this
levels in autism and mania. The fact that
publication based on quality of the
there is opposing activity of the mirror
publication and the research centre the
neuron network (low in autism, high in
study was conducted at. Mania is not so
mania), different emotional biases
heavily researched. Aside from a few
(towards negative emotions in autism
studies (e.g. mirror neuron activity, cortisol
and towards positive emotions in mania),
levels), the articles are usually case reports
opposing amygdala activation in autism
of hospitalized patients after being initiated
and mania (high to neutral and sad faces
on certain medication. The results of the
in autism, low to sad and high to happy
search provided us with sufficient
faces in mania) supports our hypothesis
arguments to hypothesize that autism is the
that evoking a subclinical hypomanic
opposite state of the brain performance to
episode using commercially available
mania in many aspects, in particular hyper-
pharmacological agents in adolescents
sociability, therefore triggering a subclinical
and adults with autism (in particular
hypomanic state should abolish autism
mild autistics / Asperger's syndrome
symptoms for the duration of hypomanic
patients) would help these individuals in
state and the idea of conducting the
improving their social skills, the key and
experiment in attempt to test the hypothesis
most debilitating symptom of autism. We
is justified in our opinion.
compare autism to mania, and in particular
to hypomania, because hypomania is
3. Review results
characterized by hypersociability and can
be evoked by commercially available
3.1. Neurotransmitters
medications [6, 7, 16, 17]. We hypothesize
that hypomania can be evoked in autistics Neurotransmitters, also known as chemical
as well, therefore evoking it would alleviate messengers, are endogenous chemicals that
autism symptoms. transmit signals across a chemical synapse,
such as a neuromuscular junction, from
one neuron (nerve cell) to another "target"
2. Review Method
neuron, muscle cell, or gland cell. Neuro-
The massive search was carried out using transmitters are released from synaptic
search engines Pubmed, Scopus, Google vesicles in synapses into the synaptic cleft,
Copyright 2018 KEI Journals. All Rights Reserved http://journals.ke-i.org/index.php/mra
Świerczek M. et al. Medical Research Archives, vol. 6, issue 1, January 2018 issue Page 4 of 18
where they are received by receptors on the increased levels of a major noradrenaline
target cells. metabolite (MHPG) were found in CSF
fluid of patients with acute mania and the
Neurotransmitters are used by brain cells
levels correlated with severity of the
(neurons) to 'communicate' with each other.
episode (YMRS score) [15]. Atomoxetine
(noradrenaline re-uptake inhibitor) [16],
Below we present comparison of available
and venlafaxine (serotonin/noradrenaline
data about levels of main neurotransmitters
re-uptake inhibitor) [17] are known to
in the brain and central nervous system in
induce manic switch. The efficacy of
both autism and mania.
clonidine in mania (α-2 agonist lowering
3.1.1. Acetylcholine noradrenaline levels) [18] is well
documented.
Binding of nicotine agonist epibatidine to
granule cells and Purkinje cells is 3.1.3. Cortisol
significantly reduced in autistics [5],
In a number of studies, elevated cortisol
whereas activation of nicotinic receptors
levels have been found in plasma of autistic
either directly through their agonists, e.g.
children and they correlated positively with
varenicline [6], or indirectly by increasing
the severity of autism symptoms [19, 20],
the level of acetylcholine by acetyl-
whereas during the first ever manic episode
cholinesterase blockade (donepezil) can
in drug naive patients cortisol levels were
induce a manic episode [7]. Nicotinic
significantly lower compared to controls
agonists (mecamylamine) and acetyl-
and correlated negatively with severity of
cholinesterase inhibitor galantamine have
manic episode [21].
anti-autistic properties in humans [8, 9].
3.1.4. Dopamine
3.1.2. Adrenergic system
There is conflicting evidence in regards to
The levels of acute noradrenaline were
HVA concentration in CSF autistics with
found elevated in autistics, however,
some studies presenting evidence of
various studies have demonstrated
increased concentration, while others
decreased noradrenaline over a 24-hour
reporting similar levels in autistics and
period in autistics using urinary 3-methoxy-
controls [22]. In an interesting research, an
4-hydroxyphenethylene glycol (MHPG), a
eye blink rate (a reliable indicator of
metabolite of noradrenaline [10], and have
dopamine level in prefrontal cortex) was
also shown decreased levels of salivary α-
positively correlated with the theory of
amylase [11] which is an indicator of
mind performance in autistics [23]. In
noradrenergic tone. Interestingly, it has
BTBR mice (model of autism) dopamine
been found that autism symptoms diminish
re-uptake inhibition failed to elicit
during fever which is believed to be due to
mesolimbic and striatal reward responses
increased activity of the locus coeruleus, a
and also significant psychomotor activation.
major noradrenergic nucleus in brain during
Furthermore, pre-synaptic and post-synaptic
febrile episodes [12]. Atomoxetine
activity of D2 receptors was significantly
(selective noradrenaline re-uptake inhibitor)
impaired in BTBR mice with D1 receptors-
[13] and venlafaxine (serotonin-
mediated response left intact [24]. Fluorine-
noradrenaline re-uptake inhibitor) both have
18-labelled fluorodopa accumulation in the
been found to alleviate the autism
anterior medial prefrontal cortex was 39 %
symptoms including social deficits
lowered compared to controls, suggesting
(venlafaxine) [14]. On the other hand,
lowered dopamine activity in that part of
Copyright 2018 KEI Journals. All Rights Reserved http://journals.ke-i.org/index.php/mra
Świerczek M. et al. Medical Research Archives, vol. 6, issue 1, January 2018 issue Page 5 of 18
brain in autistics [25]. Atypical impairment [40].
antipsychotics: olanzapine [26] and
On the other hand, plasma levels of both
aripirazole [27] have been found to be
glutamate and glycine (which have co-
effective in ameliorating autism symptoms.
agonist sites at the NMDA receptor) were
They are thought to increase cortical
increased during manic episodes [41].
dopamine release through partial dopamine
Furthermore, glutamine levels were
agonism (aripiprazole), direct 5-HT1A
significantly increased in the dorsolateral
receptor agonism (risperidone) or indirect
prefrontal cortex during the manic phase
5-HT1A receptor stimulation once 5-HT2A
[42]. Memantine, an NMDA receptor
receptors are blocked (olanzapine,
antagonist has been found effective in
clozapine) [28].
treatment of manic episodes [43].
Contrary to autistics, manic subjects
displayed increased homovanillic acid 3.1.7. Opioids
concentrations in cerebrospinal fluid
Patients taking morphine for long time
compared to controls [29]. Many drugs with
display similar characteristics to autistic
dopamine-related mechanism of action
patients including a reduced need for social
(levodopa, dopamine receptor agonists like
contact and insistence on sameness [44]. It
ropinirole and pramipexole) are known to
has been found that β-endorphin levels in
induce mania [30, 31]. Surprisingly,
the CSF and plasma of people with autism
atypical antipsychotics which are D2-
are higher compared to controls [45].
receptor antagonists have been reported to
Naltrexone, a µ-opioid receptor antagonist,
induce manic symptoms (olanzapine,
has been found to be effective in improving
risperidone, aripiprazole) [28, 32-34],
social withdrawal, irritability, hyperactivity
hypothetically through the mechanism
and self-injurious behaviour in people with
mentioned above [28].
autism [46].
3.1.5. Histamine
On the other hand, numerous studies report
the development of manic episodes after the
Histamine receptor antagonists (H1 -
withdrawal of opioids [47].
niaprazine [35] and H2 - famotidine [36])
have demonstrated promising clinical
3.1.8. Oxytocin
improvements in autistics, however, they
have also been reported to induce manic In a recent study, oxytocin nasal spray led
symptoms (H1 - pheniramine [37]), H2 - to significant improvements in social
famotidine [38]). responsivity in autistic children [48].
Moreover, MDMA/Ecstasy, a drug with
3.1.6. NMDA receptors
known pro-social effect correlating with
oxytocin release, has been reported to exert
D-cycloserine, an NMDA receptor agonist
pro-social effects in autistics as well [49].
has been found to be effective in
ameliorating autism symptoms in both
On the other hand, serum oxytocin levels
laboratory animals and humans [39].
were found to be increased in bipolar
Combined concentration of glutamate and
patients with an active manic phase when
glutamine (naturally occurring NMDA
compared to depressive and remission
receptor agonist in brain) in the basal
groups [50].
ganglia was lowered in autistics compared
to controls and the reduction was
significantly correlated with social
Copyright 2018 KEI Journals. All Rights Reserved http://journals.ke-i.org/index.php/mra
Świerczek M. et al. Medical Research Archives, vol. 6, issue 1, January 2018 issue Page 6 of 18
3.1.9. Serotonin the CSF compared to other psychiatric
patients [63]. Also, basal plasma
Low brain serotonin concentration (as per
vasopressin-neurophysin was significantly
5-Hydroxyindoleacetic acid (5-HIAA)
higher in the patients with manic
levels in the CSF) has been associated with
schizophrenia compared to other patients
pervasive developmental disorder – not
[64].
otherwise specified (PDD-NOS) [51].
Various antidepressants exerting their action
3.2. Mirror neuron network activity
through increasing brain levels of serotonin
like: mirtazapine [52], clomipramine [53], A mirror neuron is a neuron that fires both
and especially selective serotonin re-uptake when an animal acts and when the animal
inhibitors (SSRI) like fluoxetine [54] and observes the same action performed by
sertraline [55] have been found to be another [65, 66, 67]. Thus, the neuron
helpful in alleviating autism symptoms. "mirrors" the behaviour of the other, as
though the observer were itself acting. Such
On the other hand, numerous anti- neurons have been directly observed in
depressants have been reported to induce
primate species [68]. In humans, brain
mania. These include mirtazapine [56] and activity consistent with that of mirror
in particular paroxetine (SSRI) [57].
neurons has been found in the pre-motor
cortex, the supplementary motor area, the
3.1.10. Testosterone
primary somatosensory cortex and the
inferior parietal cortex [69].
High concentrations of testosterone in
autistics were found during the prenatal
A number of studies confirmed lowered
period and early childhood [58], however,
mirror neuron network activity, a group of
during adolescence male patients with
neurons responsible for the ability to
autism had significantly lower serum
understand and imitate others' behaviours,
testosterone compared to controls [59]. On
in patients with autism. For example, EEG
the other hand, it is well known, that
assessments did not show significant µ
anabolic steroid abusers (testosterone
wave suppression (thus, did not show
analogues) often develop mania or
mirror neuron network activity) during
hypomania as a result of taking doses up to
observed hand movements in autistics [70].
100-fold in excess of therapeutic ones [60].
Also, the transcranial magnetic stimulation
study gave similar results with reduced
3.1.11. Vasopressin
mirror neuron network excitability during
Blood arginine vasopressin concentrations observation of transitive hand gestures in
(which correlated to CSF concentrations) autistics. Interestingly, this correlated
significantly and positively predicted the negatively with self-reported social
theory of mind performance in autistics, but impairments (the lower mirror neuron
failed to do so in non-autistic patients [61]. activity, the greater the impairment) [71].
Moreover, treatment with transcutaneous
On the other hand, during manic states in
electrical accupoint stimu-lation of children
drug naive patients (manic patients are
with autism resulted in increased blood
known to be overfamiliar and have
vasopressin and at the same time alleviated
increased sociability) the mirror neuron
some of the behavioural issues associated
network activity positively correlated with
with autism [62].
the severity of manic symptoms as
Contrary to this, manic patients were found established by Young Mania Rating Scale
to have significantly higher vasopressin in [72].
Copyright 2018 KEI Journals. All Rights Reserved http://journals.ke-i.org/index.php/mra
Świerczek M. et al. Medical Research Archives, vol. 6, issue 1, January 2018 issue Page 7 of 18
3.3. Emotional bias compared to healthy individuals,
hypomanic or manic patients showed higher
The autistic patients displayed hyper-
valence ratings in positive pictures and
vigilance towards faces displaying disgust
associated larger blood-oxygen level-
[73]. Also, adults with ASD occasionally
dependent responses in the left amygdala
misinterpreted happy faces as neutral and
during positive versus neutral picture
attributed negativity to neutral faces in
viewing. This correlated with Young Mania
another study [74].
Rating Scale scores and with euphoria as
opposed to irritable symptom presentation
Contrarily, patients in active manic states
[82].
showed worse recognition of fear and
disgust than controls and showed inverse
correlation of YMRS score with recognition 4. Conclusions
of sadness [75]. In another study, patients
As presented above, mania in many aspects
with mania had attenuated subjective rating
(levels of neurotransmitters, performance of
of sad facial expressions with attenuated
key areas of the brain and most importantly,
activity of corresponding brain areas [76].
the social behaviour) is the opposite state of
brain performance to autism. Therefore, we
3.4. Amygdala activity
claim that instead of focusing on targeting
The amygdala is one of two almond-shaped pharmacologically separate neurotrans-
groups of nuclei located deeply and mitter systems independently, evoking
medially within the temporal lobes of the subclinical hypomanic state in autistic
brain in complex vertebrates, including individuals should invert many autism
humans. It has been shown in research to symptoms, in particular increase sociability
perform a primary role in the processing of (e.g. activate mirror neuron system and
memory, decision-making, and emotional change the performance of amygdala as a
reactions. The amygdalae are considered a result of changed levels of neuro-
part of the limbic system [77]. transmitters) for the duration of subclinical
hypomanic state. According to us, the focus
It was found that youth with ASD had
should be placed on the overall state and the
decreased amygdala habituation to sad and
performance of the whole brain rather than
neutral faces compared with controls.
on separate neurotransmitters.
Moreover, decreased amygdala habituation
correlated with autism severity as measured As many medications known to induce
by the Social Responsiveness Scale [78]. mania exist, the induction of subclinical
Also, autistics relative to control group hypomania should be a matter of finding a
showed greater activation in the amygdala, tolerated medication or their combination in
particularly to sad faces [79]. This was a right dose for each patient. We suspect
confirmed in another study where the ASD that the reason these medications work is
group reported greater social anxiety which simple - they shift the brain state towards
was associated with increased activation in mania.
the right amygdala compared to controls
[80]. Interestingly, some case reports have
documented the abolition of symptoms of
On the other hand, it was found that during Parkinson's disease during a manic episode.
manic episodes, patients had attenuated Parkinson's disease is linked with mental
sensitivity to sad facial expressions and this health disorders and affects motor skills in a
was associated with attenuated amygdala similar but not the same way as autism [83].
response to these sad faces [81]. Also,
Copyright 2018 KEI Journals. All Rights Reserved http://journals.ke-i.org/index.php/mra
Świerczek M. et al. Medical Research Archives, vol. 6, issue 1, January 2018 issue Page 8 of 18
We compared autism to mania and in usually small. With regards to mania, there
particular to hypomania because is a limited number of studies on the
hypomania is characterized by pharmacology of mania and there are often
hypersociability and can be evoked by reports of patients who developed manic
commercially available medications symptoms after being started on a certain
(several reports in the literature exist – medication.
cited in this publication). We hypothesize
Due to the methodology used, some studies
that hypomania can be evoked in
give positive results and some neutral (see
autistics as well, therefore evoking it in
mirror neurons).
autistics would alleviate autism
symptoms.
Our aim is to conduct experiments to check
whether subclinical hypomanic states can
We also hypothesize that this approach
be evoked on purpose in autistics and
should be the most effective in mild autism,
whether during these states the main
in particular among adolescents and adults
symptoms of autism are fully abolished. We
with Asperger's syndrome and would allow
have designed a series of trials in order to
them to develop social skills and confidence
assess whether our hypothesis is correct or
in social situations. We assume that gaining
not.
that experience would rewire the brain in
such a way that pharmacology would no
longer be necessary just like a driving Competing interests:
instructor is no longer needed after several
The authors declare that they have no
hours behind the wheel of the car.
competing interests.
We would like to test this hypothesis in
experiments designed by us.
Acknowledgements:
We thank Joyeeta Roy from Department of
5. Limitations and recommendations for
Anatomy, University of Otago, Dunedin,
future studies
New Zealand for her language corrections
Autism spectrum disorder is a heterogenous and suggestions in the manuscript and Ana
group of similar disorders caused by Scarlat from Maastricht School of
genetic, environmental and social factors. Management, Maastricht, the Netherlands
The pharmacological studies on autistics for her critical content review.
are limited and cohorts of patients used are

Copyright 2018 KEI Journals. All Rights Reserved http://journals.ke-i.org/index.php/mra
Świerczek M. et al. Medical Research Archives, vol. 6, issue 1, January 2018 issue Page 9 of 18
Table 1. Comparison of various aspects of autism and mania.
Neurotransmitter
/ Performance of Autism Mania
brain areas
Acetylcholine There is evidence that nicotinic signalling Activation of nicotinic receptors either
is lowered in autism [5], directly through their agonist varenicline [6]
or
Nicotinic agonist mecamylamine [8] and
acetylcholinesterase inhibitor galantamine Indirectly by increasing the level of
have anti-autistic properties [9] acetylcholine by acetylcholinesterase
blockade can induce manic episodes [7]
Adrenergic The levels of acute noradrenaline were Increased levels of major noradrenaline
system found to be elevated in autistic, however metabolite (MHPG) were found in the CSF of
studies have demonstrated decreased patients with acute mania and the levels
noradrenaline over a 24-hour period in correlated with the severity of the episode
autism [10], (YMRS score) [15]
This includes the lowered level of salivary Atomoxetine (noradrenaline re-uptake
alpha-amylase [11] which is an indicator of inhibitor) [16] and venlafaxine (noradrenaline
noradrenergic tone re-uptake inhibitor) are known to be able to
induce manic switch [17]
Autism symptoms diminish during fever
due to increased activity of the locus The efficacy of clonidine (alpha-2 agonist
coeruleus, a major noradrenergic nucleus in lowering noradrenaline levels) [18] in
brain during febrile episode [12] treatment of acute mania has been confirmed
Atomoxetine (selective noradrenaline re-
uptake inhibitor) [13] and venlafaxine
(serotonin-noradrenaline re-uptake
inhibitor) both have been found to alleviate
the autism symptoms [14]
Cortisol In a number of studies enhanced cortisol During the first ever manic episode in drug
levels have been found in the plasma of naive patients, cortisol levels were
autistic children and they correlated significantly lower compared to controls and
positively with the severity of autism correlated negatively with severity of manic
symptoms [19, 20] episode [21]
Dopamine There is conflicting evidence with regards Manic subjects displayed increased
to homovanillic acid concentration in homovanillic acid concentrations in the CSF
Copyright 2018 KEI Journals. All Rights Reserved http://journals.ke-i.org/index.php/mra
Świerczek M. et al. Medical Research Archives, vol. 6, issue 1, January 2018 issue Page 10 of 18
Dopamine cerebrospinal fluid in autistics, some compared to controls [29]
evidence in favour of increased
Many drugs with dopamine-related
concentration, whereas others show similar
mechanism of action (levodopa, dopamine
levels as controls [22]
receptor agonists like bromocriptine,
Eye blink rate (a reliable indicator of cabergoline and pramipexole) are known to
dopamine in prefrontal cortex) was induce mania [30, 31]
positively correlated with the theory of
Surprisingly, atypical antipsychotics which
mind performance in autistics [23]
are D2-receptor antagonists have been
In BTBR mice (model of autism) reported to induce manic symptoms
dopamine re-uptake inhibition failed to (olanzapine, clozapine, risperidone,
elicit mesolimbic and striatal reward aripiprazole) [32, 33, 34]. This interesting
response and significant psychomotor effect is thought to be evoked through the
activation as well. Furthermore, presynaptic mechanism mentioned above (indirect
and postsynaptic activity of D2 receptors dopamine release in cortical tissue through 5-
was significantly impaired in BTBR mice HT1A receptor stimulation due to 5-HT2A
with D1 receptors-mediated response left receptor blockade) [28]
intact in BTBR mice [24]
Fluorine-18-labelled fluorodopa
accumulation in the anterior medial
prefrontal cortex accumulation was 39%
lowered compared to controls suggesting
lowered dopamine activity in that part of
brain in autistics [25]
Atypical antipsychotics: olanzapine [26]
and aripirazole [27] have been found to be
effective in ameliorating autism symptoms.
They are thought to increase cortical
dopamine release through partial dopamine
agonism (aripiprazole), or indirect 5-HT1A
receptor stimulation once 5-HT2A
receptors are blocked (olanzapine) [28]
Histamine Histamine receptor antagonists (H1 - Antihistamines can induce manic symptoms
niaprazine [35] and H2 - famotidine [36] (H1 - pheniramine [37] and famotidine [38])
have demonstrated promising clinical
improvements in autistics
NMDA D-cycloserine, NMDA receptor agonist Plasma levels of both glutamate and glycine
has been found effective in ameliorating (it has co-agonist site at the NMDA receptor)
Copyright 2018 KEI Journals. All Rights Reserved http://journals.ke-i.org/index.php/mra