The effect of guanfacine treatment on ocular parameters in pediatric and adolescents patients with attention-deficit/hyperactivity disorder

Abstract

Background

This study aimed to evaluate the effects of guanfacine on the anterior and posterior segments of the eye.

Methods

This prospective study included 32 children and adolescents with Attention-deficit/hyperactivity disorder (ADHD). The participants underwent a detailed ophthalmologic evaluation before and 6 months after the beginning of guanfacine treatment. The following data were recorded for each participant: refraction error, intraocular pressure (IOP), anterior chamber depth (ACD), central corneal thickness (CCT), corneal aberrations using corneal topography, retinal nerve fiber layer (RNFL) analysis of seven quadrants (central, nasal, naso-superior, naso-inferior, temporal, temporo-superior, temporo-inferior), central macular thickness (CMT), and choroidal thickness (CT). Assessments were made of these parameters obtained from images using an optical coherence tomography (OCT) instrument.

Results

A significant increase in total root mean square (RMS) (p = 0.029*), RMS low-order aberration (LOA) (p = 0.014*), Coma 0° (p < 0.001*), and Coma 90° (p = 0.037*) corneal aberrations was observed at the sixth month of guanfacine treatment in comparison with the baseline examination. Other ocular parameters demonstrated no significant change from the baseline examination findings at the sixth month of guanfacine treatment. (p > 0.05, for each).

Conclusion

Oral guanfacine in the treatment of ADHD had no effect on ocular structures such as the retina, choroid, optic nerve, refraction, or corneal thickness, although it increased corneal aberrations. The results require support through further studies with extended follow-up and a larger patient group.

Introduction

Attention-deficit/hyperactivity disorder (ADHD) is a persistent neurodevelopmental condition identified by impulsivity, hyperactivity, and inattention [1]. This diagnosis is the most prevalent among school-age children in the field of psychiatry [2]. The prevalence of ADHD in children and adolescents has been reported to range from 5.9 to 14% [3].

Stimulant (methylphenidate, amphetamine) and non-stimulant (atomoxetine and guanfacine) pharmacologic treatments are used in the treatment of ADHD and their effectiveness has been shown in randomized controlled trials and other studies [4]. There has been a notable rise in the use of ADHD medication among both children and adults in recent years [5]. Guanfacine, a nonstimulant used in the management of ADHD, functions as a selective alpha-2 A adrenergic receptor agonist, activating postsynaptic alpha-2 A receptors in the prefrontal cortex (PFC) [6]. It enhances noradrenergic transmission and improves connectivity within PFC networks [7]. The United States Food and Drug Administration (FDA) has approved the extended-release formulation of guanfacine (GEXR) for the treatment of ADHD in children and adolescents aged 6 to 17 years [8].

Optical coherence tomography (OCT) is a noninvasive imaging technique that captures high-resolution cross-sectional images of the retina [9]. In recent years, choroidal vascularity index (CVI) has been frequently used in the evaluation of choroidal diseases [10]. CVI is the ratio of the luminal area (LA), indicative of the vascular component, to the total choroidal area (TCA). The Oculus Pentacam (Optikgerate) uses Scheimpflug photography to obtain several cross-sectional scans of the anterior segment of the eye, including the posterior lens surface. It also estimates central corneal thickness (CCT), assesses corneal wavefront aberrations, and evaluates anterior chamber depth (ACD) [11].

Although the adverse effects of ADHD pharmacotherapy are well documented and the subject of extensive research, there is a deficiency of empirical studies investigating the effects and adverse effects related to the eye. The existing literature is largely limited to case reports and small cross-sectional studies [12]. Studies on ocular structures in the pediatric group are usually disease-based or related to drugs used in the treatment of epilepsy [13, 14]. As far as we are aware, no research has been performed on how guanfacine medication for ADHD affects ocular results. Therefore, the aim of this current study was to evaluate the effects of guanfacine therapy on the anterior and posterior segments of the eye following a 6-month treatment period in children newly diagnosed as having ADHD.

Materials and methods

Study design

The study population comprised children and adolescents aged between 6 and 17 years who were admitted to the Child Psychiatry Department of Kartal Dr Lütfi Kırdar Hospital with a diagnosis of ADHD. This prospective study received ethical approval from the Ethics Committee of Haydarpaşa Numune Training and Research Hospital (HNEAH-KAEK 2023/KK/167) and was conducted in accordance with the Declaration of Helsinki. The participants had been receiving methylphenidate treatment for at least 1 year; however, it was insufficient, therefore guanfacine treatment was added. Following a pediatric psychiatric evaluation, the children were subsequently evaluated by an ophthalmologist. Guanfacine treatment was initiated following the completion of the ophthalmologic evaluation. The children who continued regular follow-up visits were re-evaluated by the ophthalmologist after an evaluation by a child psychiatrist at the sixth-month follow-up. The procedures were fully explained to the participants, the goal of the study was elucidated, and written informed consent was collected from all subjects and their parents prior to enrollment. Patient admission to the research and follow-up processes proceeded between May 2023 and June 2024.

Psychiatric and ophthalmologic evaluation of patients

The same physicians from the outpatient clinic for child and adolescent psychiatry evaluated each patient before and 6 months after the start of ADHD therapy. The assessments were performed following the criteria established in the Current and Lifetime Version of the Schedule for Affective Disorders and Schizophrenia for School-Age Children, Diagnostic and Statistical Manual of Mental Disorders-5 (DSM-5) (K-SADS-PL-DSM-5-T) and were based on the DSM-5 diagnostic criteria [15]. The K-SADS-PL semi-structured interview program was employed to ascertain the clinical diagnosis of ADHD. The T-DSM-IV-S Rating Scale was completed by the parents prior to and 6 months following the commencement of treatment. The T-DSM-IV-S scale helped to assess clinical features and their severity.

Detailed ophthalmic examinations of all participants were recorded. The study included participants who had an intraocular pressure (IOP) of < 21 mm Hg, and a best corrected visual acuity (BCVA) of > 0.6 according to a Snellen chart examination. All participants were orthophoric according to the cover/uncover test, prism, and alternating cover test. Patients with a history of previous eye surgery or trauma, refractive error (RE) outside the + 4/-4D range, psychiatric comorbidity other than ADHD, coexisting glaucoma, corneal, retinal, pathology or systemic diseases such as diabetes mellitus, were excluded from the study.

Each participant underwent slit-lamp examinations, fundus examinations, IOP measurements using non-contact tonometry (Nidek NT-530P Noncontact tono/pachymeter, Hiroishi-Cho, Japan), corneal topography (Oculus Pentacam HR, Germany) for CCT, ACD and corneal aberration (total root mean square (RMS), RMS low-order aberration (LOA), and RMS high-order aberrations (HOA) (including trefoil, coma, and spherical aberration)) measurements, enhanced depth imaging (EDI)-OCT (Spectralis, Heidelberg Engineering, Heidelberg, Germany) for central macular thickness (CMT), retinal nerve fiber layer (RNFL), and choroidal thickness (CT) measurements. The REs of the participants were noted according to the autorefractometry (Topcon, Auto Kerato-Refractometer KR.8100 A, Tokyo, Japan) measurements performed 45 min after two drops of cyclopentolate 1% (Sikloplejin %1, Abdi İbrahim, Turkey) in 5 min intervals. The spherical equivalent refraction measurements of the eyes were recorded. The power of the sphere plus (cylinder power/2) was used to calculate the spherical equivalent. These procedures were performed twice before and 6 months after the onset of guanfacine treatment. Data from the right eyes of all participants were used.

To minimize the potential impact of diurnal fluctuations in CCT, corneal topography images of the subjects were acquired at 11:00 a.m. EDI-OCT scans were performed in a dark room from 10:00 to 11:00 a.m. The RNFL scanning mode automatically analyzed the thickness parameters of the peripapillary RNFL. The CMT was automatically measured and assessed using the OCT software. The CT was assessed by measuring the external surface of the hyper-reflective line, known as the “retinal pigment epithelium” layer, and calculating the distance from this outer surface to the hyper-reflective line of the inner scleral border via EDI-OCT. The caliper contained within the software of the device was used to measure the thickness of the choroid layer at the fovea, 500 μm nasal, 1500 μm nasal, 500 μm temporal, and 1500 μm temporal to the fovea. The CVI was assessed using the ImageJ software (Version 1.50a; National Institutes of Health, Bethesda, MD, USA) (Fig. 1). CVI measurements were calculated by two different experienced ophthalmologists who were blinded to the study and averaged measurements were used.

Fig. 1

CVI calculation with EDI-OCT image binarization. A. EDI-OCT image of a patient. B. The image was binarized using the auto-local threshold from Niblack. C. The color threshold tool was used to select the dark pixels, representing the luminal area (yellow lines)

Statistical analysis

The statistical analysis of the study was conducted using the IBM SPSS version 26.0 software package. The demographic information of the subjects and all ocular characteristics were examined using descriptive statistics (frequency, percentage, median, mean, standard deviation, minimum-maximum values). The paired samples t-test was chosen for normally distributed variables, whereas the Wilcoxon signed-rank test was used for non-normally distributed variables in the comparison of baseline and 6-month data within the ADHD group. The Shapiro-Wilk test was employed to confirm the normality of distribution of the variables. All statistical analyses were conducted at a 95% confidence interval with a significance threshold of p < 0.05.

Results

The study was completed with 32 child and adolescent patients aged 6 to 15 years. Thirty male (93.8%) and two female (6.3%) patients were included in the research group. The mean age of the participants was 9.06 ± 2.2 years. The sociodemographic results of the participants are summarized in Table 1.

Data on the comparison of ocular parameters between the ADHD group at baseline and at the sixth month of guanfacine treatment are summarized in Table 2. Therefore, a significant increase in RMS total, RMS LOA, Coma 0° and Coma 90° corneal aberrations was observed at the sixth month of guanfacine treatment in comparison with the baseline examination (RMS total; 1.499 ± 0.61 vs. 1.3 ± 0.4, p = 0.029*, RMS-LOA; 1.44 ± 0.6 vs. 1.22 ± 0.4, p = 0.014*, Coma 0°; 0.18 ± 0.1 vs. -0.13 ± 0.1, p < 0.001*, Coma 90°; 0.07 ± 0.2 vs. 0.01 ± 0.1, p = 0.037*, respectively). Other ocular parameters demonstrated no significant change from the baseline examination findings at the sixth month of guanfacine treatment (p > 0.05, for each).

Table 1 Sociodemographic characteristics of participants

Table 2 Comparison of ocular parameters at baseline and 6 months of guanfacine treatment (minimum maximum values are indicated in brackets)

Discussion

This study was designed to investigate the 6-month follow-up effects of guanfacine, used to treat ADHD, on the anterior and posterior segments of the eye. Consequently, some corneal aberrations increased in the sixth month of guanfacine treatment compared with the pre-treatment period (Fig. 2). Otherwise, there was no significant variation in retina-choroid and RE.

Fig. 2

Statistically significant changes in corneal aberrations after six months of guanfacine use. *Blue color represents the baseline examination and red color represents the 6th month examination

Guanfacine hydrochloride extended-release tablets are used for the treatment of ADHD in children and adolescents aged 6 to 17 years who are not suitable candidates for stimulant medications [15]. In the United Staes of America (USA), guanfacine, a selective agonist of alpha-2 A adrenergic receptors, is used as well as an antihypertensive medication. Brimonidine tartrate is a third-generation alpha adrenergic agonist with high alpha-2 selectivity [16]. In 1996, the FDA approved brimonidine for the treatment of ocular hypertension and glaucoma. Brimonidine reduces the release of catecholamine, adenylate cyclase, and cyclic adenosine monophosphate via stimulating presynaptic alpha-2 receptors in the epithelium of the ciliary body. Thus, it reduces the production of aqueous humor [17, 18]. Because brimonidine and guanfacine are both alpha adrenergic agonists, we considered that oral use of guanfacine might also have an IOP lowering effect. Although the mean IOP was lower in the 6th month findings compared with the baseline results, this decrease did not reach a statistically significant level. This outcome may be related to the mean IOP of the participants being already within normal limits at baseline and none were diagnosed as having glaucoma. In addition, no statistically significant difference was observed between baseline and 6-month RNFL averages from the seven quadrants.

A study in monkeys and rats concluded that oral and topical brimonidine passed the posterior structures of the eye, such as vitreous and retina, and had a greater affinity for melanin pigmented tissues, showing a neuroprotective effect on ganglion cells [19]. A recently published study suggested that brimonidine applied topically, subconjunctivally, and intravitreally in pigs increased blood flow to the eye, thus increased CT and might be used to prevent myopia progression in patients with myopia [20]. Finally, there is a case report in the literature showing that topical brimonidine used after YAG laser capsulotomy in a nanophthalmic eye caused exudative retinal detachment and uveal effusion [21]. In the current study, oral guanfacine had no significant effect on CMT, CT measured at five points, and CVI. These results may be explained by the fact that oral use could not reach the intravitreal retinal dose that may alter CT.

HOAs persist despite optimal spherocylindrical correction and affect retinal image quality and accommodative response. There are many studies showing that HOA and RMS increase linearly between 20 and 70 years of age [22,23,24,25]. Research involving Chinese children revealed a connection between age and HOAs assessed under cycloplegia. In addition, when HOAs were evaluated according to refractive error, no significant difference was found in myopic, hyperopic, and astigmatism groups [26]. Another study in Canadian children found a decrease in HOAs with age up to the fourth decade [27]. However, only 29 children were included in that study, whereas a study conducted in China included more than 1600 children. Our investigation revealed no significant alteration in refractive error throughout the 6-month follow-up period; however, RMS total, RMS LOA, Coma 0° and Coma 90° corneal aberrations exhibited a substantial increase in the 6-month findings compared with baseline. Longer-term follow-up is needed to distinguish whether this change is related to the drug effect or to the 6-month growth period of the children.

The study has limitations. First, we could not analyze guanfacine-only-treated children because it is not regarded as a first-line therapy for ADHD. The research participants were children who had been administered methylphenidate for a minimum of 1 year, had a weak response to the treatment, and then began guanfacine with methylphenidate. Another limitation is the small number of patients and the 6-month follow-up duration. We had patients who could not tolerate the drug and had to withdraw from the treatment due to adverse effects such as irritation-related to the use of guanfacine.

Conclusions

In conclusion, oral guanfacine in the treatment of ADHD had no effect on ocular structures such as the retina, choroid, optic nerve, refraction, or corneal thickness, although it increased corneal aberrations. Therefore, ocular adverse effects should be considered when prescribing guanfacine treatment, and regular ophthalmic examinations should be recommended during guanfacine treatment.