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Effect of Methylphenidate as A Dopaminergic Agent on Myopia: Pilot Study

Article  in  International Journal of Clinical Practice · July 2021

DOI: 10.1111/IJCP.14665

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Accepted Article Effect of Methylphenidate as A Dopaminergic Agent on Myopia: Pilot Study
Running Short Title: The effect of methylphenidate on myopia
Ugur GURLEVİK*, Halil KARA**, Erdogan YASAR*,
*: MD, Aksaray University Faculty of Medicine, Aksaray Education and Research Hospital ,
Ophthalmology Department, Aksaray/Turkey
**: MD, Aksaray University Faculty of Medicine, Aksaray Education and Research Hospital ,
Child and Adolescent Psychiatry/Turkey

Corresponding Author: Ugur GURLEVIK

Address: Aksaray University Faculty of Medicine, Aksaray Education and Research Hospital ,
Ophthalmology Department, Aksaray/Turkey
Phone: +00 90 505 442 46 95
E-mail: ugurlevik@hotmail.com

Number of Tables/Graphics:2/0

Disclaimer on financial support (grants): None

Potential conflicts of interest: None
All persons named in the Acknowledgment section have provided me with written permission to
be named.
Our study has not been published anywhere before and the authors declare it.

This article has been accepted for publication and undergone full peer review but has not been
through the copyediting, typesetting, pagination and proofreading process, which may lead to
differences between this version and the Version of Record. Please cite this article as doi:
10.1111/IJCP.14665
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Accepted Article
DR UGUR GURLEVIK (Orcid ID : 0000-0003-2965-481X)

DR ERDOGAN YASAR (Orcid ID : 0000-0001-5129-9397)

Article type : Original Paper

EFFECT OF METHYLPHENIDATE AS A DOPAMINERGIC AGENT ON MYOPİA:PİLOT

STUDY

Abstract:

Purpose: Methylphenidate hydrochloride is used as a first-line treatment for Attention

Deficit Hyperactivity Disorder (ADHD). However, there is concern that this treatment may
be associated with increased risk of refractive disorder. The aim of this study was to
investigate the effect of methylphenidate therapy on myopic shifts in refraction in children
diagnosed with ADHD.

Methods: This study, children with ADHD and meeting inclusion criteria were examined
before the initiation of methylphenidate treatment and 3,6 and 12 months after the initiation
of treatment. Twenty age-gender matched participants who applied to the outpatient
ophthalmology clinic with various complaints were included in the study as a control group.
Cycloplegic refraction examination and detailed eye measurements were performed at each
visit.

Result: Nineteen patients were included in this study and the group consisted of 11 (%57.9)
females and 8 (%42.1) males. The mean age of patients was 11.3 ± 2. (range 8-18) years.
During 12 months of use of mph, the spherical equivalent changed from -0.36 ± 1.08 to -0.39
± 1.05, and this difference was not statistically significant. (p = 0.187) Axial length from
22.92 ± 0.66 There was a change to 22.93 ± 0.62, and this difference was not statistically
significant. (p = 0.076) In the control group, the spherical equivalent changed from -0.43 ±

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 0.62 to -0.56 ± 0.84, and this difference was statistically significant. (p = 0.012) There was a
Accepted Article
change in axial length from 22.97 ± 0.78 to 22.99 ± 0.62, and this difference was statistically
significant. (p = 0.015)

Conclusion: No significant changes spherical equivalent and axial length were detected
during 12-month mph use, but the increase spherical equivalent and axial length in the
control group in the similar age group may indicate that mph may reduce myopic shifts in
refraction progression through dopamine, similar to invivo studies.

Key Words: Axial length, Dopamine, Methylphenidate hydrochloride, Myopia

What’s Known

• Myopia is spreading rapidly in technologically advanced societies.

• There is strong evidence that myopia develops as the axial length of the eye increases as a
result of spending more time indoors and working in close distances in parallel with the
increase in education level.

• Animal studies have shown that decreased dopamine release plays an important role in the
development of myopia.

What’s New

 The effect of dopamine in slowing or stopping myopia in experimental studies has

also been demonstrated in human studies.
 No significant change in spherical equivalent and axial length was observed in
methylphenidate users compared to control patients of similar age group. A
significant increase in spherical equivalent and axial length was detected in the
control group.
 This pilot study will shed light on future studies on the safe use of dopamine in the
treatment of myopic shifts.

Introduction

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 Myopia is the state where parallel rays from distant objects are focused in front of the
Accepted Article
retina. It is known that there has been a significant increase in the prevalence of myopia in
the last decade.1 Prevalence of myopia is expected to be around 2.5 million by 2025.2
Melatonin secreted by daylight is responsible for the circadian rhythm. In the inner retina,
melatonin regulate dopamine release. Dopamine mediates light adaptation and circadian
changes in visual sensitivity, entrains circadian rhythms of gene expression in photoreceptors,
retinal pigment epithelium, and retinal ganglion cells. 3-6 In recent years, Dopamine (DA) has
7
appeared as a molecule emphasized in the development of myopia. DA is an important
neurotransmitter in the retina, and it mediates multiple functions including retinal
development, perception of visual signals and development of the refractive mechanism.8 As
shown by some studies following up child development, there is a close inverse relationship
between exposure to daylight and development of myopia.9-10 There is also a close biological
relationship between exposure to light and dopamine release. In this respect, the relationships
between dopamine and myopia have been studied several times.

While it is important to discuss the retina-related effect of an agent with dopaminergic

activity in the brain in terms of myopia, the effects of MPH on the development of myopic
eye have not been prospectively studied in detail. Dopamine and its primary metabolite 3,4-
dihydroxyphenylacetic acid have been shown to reduce the development of myopia by
inhibiting ocular growth in experimental animals. This effect can be reversed by using a
dopamine antagonist. Almost all of the studies conducted are experimental animal studies. To
our knowledge, this is the first study to investigate the relationship between axial length and
MPH, which is the most important parameter in myopic progression. MPH appears as the
most frequently used dopaminergic agent during childhood. The aim of the study is to follow
up patients diagnosed with ADHD for 1 year in pre- and post- MPH treatment process and to
study the effects of treatment on myopia to determine the effect of DA on the
pathophysiology of myopia.

Methods

In this prospective, single-center study, 19 patients with ADHD (19 eyes) who had
indication for methylphenidate treatment were included. Twenty (20 eyes) age-gender
matched participants who applied to the outpatient clinic with various complaints were
included in the study as a control group. After providing the approval of local committee of

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 Clinical and Laboratory Research Ethics, patients between the age of 6- 18 years were
Accepted Article
admitted to the clinic. The study group was selected from 6-18 years old patients who had
ADHD and were indicated for, informed about and consented to receive oros-
methylphenidate therapy.

Patients who have a history of sensitivity or allergy to methylphenidate and who have
already used dopaminergic or anti-dopaminergic agent were excluded from the study.
Methylphenidate therapy was initiated at a average dose of 1.1 mg/kg body weight and the
dose of methylphenidate during the whole therapy was the same for every patient. Treatments
lasted for at least twelve months. Patients were followed up montly or bimontly during the
pscychitric treatment.

Exclusion criteria for the patients were strabismus or amblyopia, a presence of eye
diseases( corneal, lens, macular, retinal disase) that may affect refractive error, a presence of
ocular infection, a history of ocular surgery or refractive surgery, a history of systemic
disease or drug use that may affect refractive error. In addition, patients who was detected
drug-induced side-effect during methylphenidate use and who did not regularly come
controls during the use of drug were excluded from the study.

Demographic data of all patients were obtained. The pupilla of both eyes were dilated with
one drop of cycloplegic drops. After pupillary dilation, the anterior segment and fundus were
examinated in all cases. Axial length and lens thickness were measured by an optical
biometer (Lenstar APS, Haag- Streit Koeniz, Switzerland). Central corneal thickness, anterior
chamber depth measurements were performed with corneal topography device (Cirrus,
Costruzione Strumenti Ophthalmic, Florence, Italy). Then, central retinal thickness and
central choroidal thickness measurements were performed with OCT (Optovue Inc., Fremont,
CA, USA). The subfoveal choroidal thickness was defined as the distance from the outer
border of the retinal pigment epithelium line to the hyperreflective line behind the large
vessel layers of the choroid, which is presumed to be the choroid sclera interface. Subfoveal
choroidal thickness measurements were performed in a masked fashion by 2 experienced
physicians. After the refraction measurement with the autorefractometer (TONOREF ™ III,
Nidek Co. Ltd. Japan), visual acuity examination was performed with Snellen the next day
and the results were noted. The same visual acuity examination, bimicroscopic examination
and measurements were repeated at thirdt month, sixth month and twelve month after the
start of the drug.

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 Statistical analysis was performed using the Statistical Package for Social Sciences
Accepted Article
(SPSS)version 23.0 for Windows (SPSS Inc., Chicago, IL. The normality of the data
distribution was evaluated by the Shapiro- Wilk test. Paired samples t-Test was used to
compare the averages of the observed values of a variable in two different conditions. Linear
regression analysis was used to estimate the linear relationship between continuous variables.
The p-value was statistically significant at 0.05 or smaller.

Results
Nineteen patients were included in this study and the group consisted of 11 (%57.9) girls
and 8 (%42.1) boys. The mean age of patients was 11.3 ± 2. (range 8-18) years. The control
group consisted of 11(%55) girls and 9(%45) boys, mean age of this group 12.2 ± 2.7 (range
8-17) years.
During 12 months of use of MPH, the spherical equivalent changed from -0.36 ± 1.08 to -
0.39 ± 1.05, and this difference was not statistically significant. (P = 0.187) Axial length from
22.92 ± 0.66 There was a change to 22.93 ± 0.62, and this difference was not statistically
significant. (P = 0.076) The comparison of pre-drug and post drug 1st, post drug 3rd, post-
drug 6th month and 12th month eye parameters are presented in table 1. No significant
changes were observed in any other parameters in the third, sixth, twelve month in study
group (table 1)

In the control group, the spherical equivalent changed from -0.43 ± 0.62 to -0.56 ± 0.84,
and this difference was statistically significant. (p = 0.012) There was a change in axial
length from 22.97 ± 0.78 to 22.99 ± 0.62, and this difference was statistically significant. (P =
0.015) The comparison of control group 0 and 1st, 3rd, 6th month and 12th month eye
parameters are presented in table 2. No significant changes were observed in any other
parameters in the third, sixth, twelve month in DEHB group (table 2)

Discussion
In this study, pre and post-drug 3rd month, 6th month and 1st year refractive error,
axial length, and antero-posterior segment parameters were measured in patients using MPH
and no significant changes were found in any parameters(p>0.05). On the contrary, In control
group, there were statistically significant differences between pre- and 1st-year control in

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 terms of spherical equivalent, axial length(p=0.012, p=0.015, respectively). In addition, no
Accepted Article
significant change was detected in any parameters in the control group at 3 and 6 months.
It is well known that changes in rhythmicity, intensity, or spectral composition of light
can affect the emmetropization process in animal models. For example, prolonged rearing of
chicks under continuous light or constant darkness results in excessive vitreal cavity
20
lengthening. Melatonin and dopamine are both under circadian control, and have
antagonistic effects in the retina, with melatonin relase in darkness, and dopamine release in
18
response to light. Dopamine (DA) is an important neurotransmitter in retina, mediating
several functions like retinal development, perception of visual signals and development of
the refractive mechanism.8 Retinal DA is synthesized and released by the subtypes of
amacrine and interlexiform cells. Dopamine is synthesized from tyrosine amino acid in two
phases. First, L-tyrosine is converted into 3,4-dihydroxy-L-phenyalanine (L-DOPA) through
tyrosine hydroxylase (TH) enzyme; then L-DOPA is converted into DA through DOPA
decarboxylase enzyme. The presence of light augments DA synthesis and hence, its release
through tyrosine hydroxylase. DA released in synapses is transported by specific dopamine
transporter (DAP) back to DA neurons. It can be re-packed in synaptic vesicles within the
cell or can be metabolized with monoamine oxidase to form the primary metabolite of DA,
i.e. 3,4-Dihydroxyphenylacetic acid (DOPAC). When the changes in DOPAC levels in retina
and vitreous body are considered to be reflecting DA release and cycle, it could be noted as
important. Dopamine can also be converted into homovanilic acid in an extra-neuronal
manner.19 Data obtained from various tests conducted on different species suggest that DA
acts as a growth signal during eye growth. Researches have been conducted on DOPA and/or
DOPAC with the HPLC method in primates, chickens and guinea pigs. Most of the research
on different species has shown the relationship between retinal change and myopia.20

Development of myopia associated with the reduction of DA stimulation during eye

growth may assert the need for the augmentation of DA stimulation to inhibit myopia. The
first step to prove such claim is to enhance the common usability of DA by injecting DA
directly into the eye or by using systemic L-DOPA to augment DA synthesis, or by using a
dopamine receptor agonist. Animal experiments have been conducted in parallel with this
view. In these tests, increased levels of DA have been shown to inhibit myopia associated
with form deprivation in guinea pigs, rabbits and rats.21-23 Another approach is to augment
DA signaling by nonselective DA receptor agonists like apomorphine (APO) and 2-Amino-
6,7-dihiydroxy-1,2,3,4-tetrahydronaphtalene hydrobromide (ADTN). Several researches have

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 shown that treatment with APO inhibits myopia associated with form deprivation in various
Accepted Article
animal species including chickens, guinea pigs, monkeys and rats.24-29 However, while daily
injections of APO reduce myopia associated with form deprivation in rats, continuous
infusion of APO by a mini pump is ineffective.28 In this respect it could be noted that
intermittent release of dopamine is more effective in the inhibition of myopia such as it is in
frontal cortex. These researches suggest that DA receptor activation is required for normal
refractive eye growth and that elevation of DA levels in the eye can inhibit myopic growth
signals. Light stimulation is also known to be augmenting retinal dopamine.30,31 The presence
of D1R, D2R, D4R and D5R dopamine receptors in the retina is known.32

Because spending more time in daylight increases dopamine synthesis, it has been
thought to reduce myopic shifts in refraction, and many studies have been conducted on this
topic. Spending more time outdoors is thought to reduce myopic shifts in refraction. Most
33-35
studies support this. Some far east countries (Taiwan, Singapore and mainland China
etc.) have started to increase the outdoor activity time of school age children in the light of
this information. Only a limited number of studies claim that this effect does not exist. 36

The primary effect of methylphenidate (MPH) is that, it is a psychostimulant

involving the increment of noradrenaline (NA) and dopamine (DA) amounts at the frontal
cortex by blocking DA transporter.11 MPH is the primary treatment of Attention Deficit
Hyperactivity Disorder (ADHD).12 The primary pharmacological effect of methylphenidate is
to increase central dopamine and norepinephrine activities. DA is one of the main
neurotransmitters in the brain and retina. Furthermore, it is an important physiological
regulator of cardiovascular, endocrine and immunological functions.13,14 While ocular side
effects of MPH including xerophthalmia, mydriasis, accommodation disorder and blurred
vision are listed in product monography, they are rarely reported.15 The use of
methylphenidate in the presence of glaucoma is contraindicated. The sympathomimetic
activity created by dopaminergic effect increases the risk for a glaucoma crisis by narrowing
the angle.16 In a study with MPH, after 9 months of treatment in children with ADHD, a
decrease in anterior chamber depth, defined as an important indicator of angle-closure
glaucoma, was observed, while ocular symptoms were not evaluated in detail and it was
found that they did not cause myopia.17

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 Activities of methylphenidate at receptor level include the inhibition of dopamine and
Accepted Article
norepinephrine transporter, agonist effect on serotonin type 1A receptor and regulation of
VMAT-2 (vesicular monoamine transporter-2 DA). DA is one of the main neurotransmitters
in the brain and retina and an important physiological regulator of cardiovascular, endocrine
and immunological functions.13,14 Not only we intervene in the dopaminergic effect in the
frontal cortex but also face a dopaminergic effect in the eye with methylphenidate. Therefore,
it is important to discuss an agent with dopaminergic activity in the brain in terms of its effect
on the retina for myopia. In a research conducted with methylphenidate, it was found that it
did not cause myopia in children with ADHD. On the other hand, after a 9-month treatment, a
reduction in the depth of anterior chamber, defined as a significant indicator of angle closure
glaucoma, was observed. However, this is a research with limitations were carried out on 14
children. In addition, retinal changes except for the refractive error were not assessed. 17
Similarly in our research, no significant change in myopia or axial length was observed in
children who were followed up for 1 year with MPH treatment. On the contrary, there was a
significant increase in myopia and axial length 1 year later in a similar age group (p:0.012
and p:0.015, respectively).

Limitations of our study were that the number of patients was relatively low, the
measurements were not repeated after discontinuation of the drug. The variability obtained
from the analysis may be within the device error rate but monitoring this change may still be
important.

However, axial elongation in patients using MPH showed a more limited progress
compared to patients not using MPH. In conclusion, there was no significant change in
myopia and axial length during 12 months of MPH use, but the increase in myopia and axial
length in the control group in the similar age group may indicate that MPH may decrease the
progression of myopia via dopamine in a similar manner to in vivo studies. Therefore, it
could be stated that it may be protective against the development of myopia in terms of the
long-term effect of MPH.

Funding details : The authors did not receive any financial support from any public
or private source. The authors have no financial or proprietary interest in a product, method,
or material described herein to disclose.

Conflict of Interest: The authors declare that they have no conflict of interest

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 Ethical approval: All procedures performed in studies involving human participants
Accepted Article
were in accordance with the ethical standards of the institutional and/or national research
committee and with the 1964 Helsinki declaration and its later amendments or comparable
ethical standards. This article does not contain any studies with animals performed by any of
the authors. Instution review board/Ethics Committee has approved the study

Informed Consent: Informed consent was obtained from all individual participants
included in the study. The article has not been presented in any conference or meeting

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TABLES

Table 1 . The comparison of pre-drug and post drug 3rd, post drug 6th, post-drug 1st year eye parameters in study group

Parameter Pre-drug Post-drug 3rd month p Post-drug 6th month p Post-drug 1st year p
Mean ± SD Mean ± SD Mean ± SD Mean ± SD

SE -0.36 ± 1,08 -0.36 ± 1,10 1.000 -0.38 ± 1.07 0.163 -0.39 ± 1.05 0.187
AL(mm) 22,92 ± 0,66 22.92 ±0.66 0.187 22.93 ± 0.65 0.104 22.93 ± 0.62 0.076
CCT(µm) 578.1 ±25.3 577.4 ±24.7 0.126 577.3 ± 25.1 0.057 578.4 ± 25.6 0.056
AD(mm) 2.98 ±0.12 2.98 ±0.12 0.755 2.98 ± 0.20 0.561 2.98 ± 0.13 0.107
LT(mm) 3.55 ± 0.13 3.55± 0.12 0.309 3.54 ± 0.26 0.373 3.56 ± 0.12 0.143

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 SCT(µm) 271.4 ± 15.6 272.7 ± 14.6 0.053 272.4± 15.5 0.309 271.8 ± 14.8 0.816
Accepted Article CRT(µm) 257.5 ± 9.2 257.3 ± 9.1 0.878 257.1 ± 9.5 0.469 256.8 ± 12.0 0.541

SE: Spherical equivalent, AL:Axial Lenght, CCT: Central corneal thickness, AD: Anterior depth, LT: Lens thickness, CRT:
Central retinal thickness, SCT: Subfoveal choroidal thickness

Table 2 . The comparison of pre and post 3rd, post drug 6th, post-drug 1st year control eye parameters in control group

Parameter Pre- Post- 3rd month p Post- 6th month p Post- 1st year p
Mean ± SD Mean ± SD Mean ± SD Mean ± SD

SE -0.43 ± 0.62 -0.44± 0.83 0.614 -0.48 ± 0.78 0.214 -0.56 ± 0.84 0.012
AL(mm) 22.97 ± 0,78 22.97 ±0.63 0.262 22.98 ± 0.63 0.111 22.99 ± 0.62 0.015
CCT(µm) 572.8±27.5 572.0±26.9 0.078 572.1 ± 27.5 0.090 572.9 ± 33.8 0.674
AD(mm) 2.95 ±0.15 2.95 ±0.14 0.635 2.96 ± 0.14 0.332 2.94 ± 0.16 0.217
LT(mm) 3.54 ± 0.13 3.54 ± 0.13 0.305 3.53 ± 0.16 0.450 3.55 ± 0.12 0.185
SCT 275.7± 15.5 275.2± 16.2 0.331 274.9 ± 16.8 0.650 275.1 ± 16.0 0.678
CRT(µm) 255.9± 10.4 255.4 ± 11.3 0.408 255.5 ± 9.8 0.852 253.2± 12.4 0.197

SE: Spherical equivalent, AL:Axial Lenght, CCT: Central corneal thickness, AD: Anterior depth, LT: Lens thickness, CRT:
Central retinal thickness, SCT: Subfoveal choroidal thickness

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