Dyskinesia following modafinil administration in a patient with autism spectrum disorder and narcolepsy: a case report

Abstract

Background

In our clinical practice, we encountered a patient with autism spectrum disorder (ASD) and comorbid narcolepsy who developed dyskinesia following the administration of modafinil for excessive daytime sleepiness. Modafinil is widely prescribed as a wakefulness-promoting agent for the treatment of narcolepsy. Although dyskinesia has been reported as a potential adverse effect of modafinil, to our knowledge, no cases have been described in individuals with ASD. We hypothesized that modafinil contributed to the development of dyskinesia in this patient and conducted a literature review to explore the possible underlying mechanisms.

Case presentation

A 24-year-old Japanese woman with ASD was diagnosed with narcolepsy type 2. She had previously been treated with aripiprazole for ASD-related symptoms, but it had been discontinued more than two weeks before the sleep study. Modafinil was initiated at 100 mg/day and increased to 200 mg/day after three weeks because of insufficient efficacy. Two weeks after the dose increase, dyskinesia developed. A literature review was performed to identify potential mechanisms. Dyskinesia may have resulted from dysregulated striatal dopamine release associated with ASD and residual dopamine D2 receptor blockade from prior aripiprazole use, triggered by modafinil.

Conclusion

Dopaminergic agents in individuals with ASD may induce dyskinesia, particularly following dose escalation, underscoring the need for clinical vigilance.

Background

We report a patient with autism spectrum disorder (ASD) and comorbid narcolepsy who developed dyskinesia after modafinil administration. Modafinil is widely prescribed as a wakefulness-promoting agent for narcolepsy. Although the precise mechanism of action of modafinil remains unclear, modafinil is thought to increase dopamine (DA) levels via binding to the DA transporter and inhibition of DA reuptake [1, 2], while enhanced histamine release in the anterior hypothalamus [3] may also contribute to its effects. Common adverse events include headaches (23.2%), thirst, insomnia, and palpitations [4], while dyskinesia occurs in about 2% of cases [5]. Previous reports have described modafinil-induced dyskinesia in a patient with major depressive disorder receiving adjunctive treatment [6], and in a patient with treatment-refractory bipolar depression after dose escalation [7]. However, no cases in individuals with ASD have been reported to our knowledge. We hypothesized that modafinil contributed to the development of dyskinesia in this patient and reviewed the literature to explore potential mechanisms.

Case presentation

A 24-year-old Japanese woman with ASD presented with excessive daytime sleepiness (EDS) to Chutoen General Medical Center in month (X-3), 2023. She had experienced EDS since about age 10. At her initial visit, she was prescribed aripiprazole 9 mg/day and biperiden 1 mg/day for ASD. These medications had been prescribed since childhood, for a duration exceeding 10 years. According to her attending physician, aripiprazole was prescribed to treat irritability associated with ASD, while biperiden was administered to prevent extrapyramidal symptoms induced by aripiprazole. EDS impaired her ability to maintain employment, leading to frequent job changes, although she lived independently. She had no cataplexy, sleep paralysis, or hypnagogic hallucinations. She did not consume alcohol or tobacco. Her body mass index was 23.6, and her Japanese version of the Epworth Sleepiness Scale score was 21.

With the attending physician’s approval, aripiprazole and biperiden were discontinued for more than two weeks before polysomnography (PSG) and multiple sleep latency test (MSLT). She maintained a regular sleep schedule with over 8 hours of nightly sleep during the two weeks preceding the tests. PSG findings showed an apnea–hypopnea index of 1.1, periodic leg movement with arousal index of 0.2, and rapid eye movement (REM) sleep without atonia in 2.0% of REM sleep. A sleep-onset REM period (SOREMP) was not observed. Sleep architecture was preserved, with no abnormalities. MSLT revealed a mean sleep latency of 1.1 minute with two SOREMPs across five nap opportunities. Based on the International Classification of Sleep Disorders, Third Edition (ICSD-3) criteria, narcolepsy type 2 was diagnosed.

Treatment was initiated with modafinil 100 mg/day on day 1 of month (X-1). Aripiprazole and biperiden were not resumed to avoid potential drug interactions. As the treatment for her excessive sleepiness was insufficiently effective by day 21 and no adverse events or laboratory abnormalities (for example, liver dysfunction) were detected, the dose was increased to 200 mg/day. Following this adjustment, sleepiness improved. However, on day 10 of month X, involuntary movements appeared in the orofacial region and right-sided limbs. She presented urgently to our outpatient clinic the following day. The involuntary movements consisted of mumbling and slow twisting movements, resembling tardive dyskinesia (TD). All biochemical findings were normal, with no evidence of liver dysfunction, normal thyroid function, and no electrolyte abnormalities. Although brain magnetic resonance imaging was not performed, she exhibited no symptoms suggestive of structural brain abnormalities other than dyskinesia. Furthermore, she had no psychiatric symptoms. Based on these findings, we excluded metabolic, endocrine, neurological, and psychiatric disorders that could cause involuntary movements, including dyskinesia, and suspected dyskinesia associated with modafinil; therefore, the medication was discontinued. Despite cessation of modafinil, dyskinesia persisted until day 22 of month (X + 1), prompting initiation of Yi-Gan San at 5.0 g/day (administered twice daily before breakfast and dinner). Adherence was good, and no adverse or unanticipated events occurred. Gradual improvement was observed by day 14 of month (X + 2), with complete resolution by day 5 of month (X + 5), five months after symptom onset.

Discussion and conclusions

Dyskinesias are commonly classified as TD or L-DOPA-induced dyskinesia (LID). TD typically develops after antipsychotic use for more than three months and is characterized by involuntary orofacial movements. Although the pathophysiology of TD remains incompletely understood, the most widely accepted theory is DA receptor hypersensitivity [8]. Specifically, antagonism of D2 dopamine receptor (D2R) leads to compensatory overexpression in the striatum, rendering the system susceptible to dyskinesia via excessive DA stimulation [8]. Conversely, LID is thought to result from enhanced DA surges following L-DOPA administration in the context of nigrostriatal DA depletion due to Parkinson’s disease. A recent study proposed a mechanism in which repetitive DA fluctuations under reduced D2R signaling lead to hypertrophy of striatal neuron terminals, manifested as vesicular GABA transporter (VGAT) overexpression [9]. This mechanism has been reported that it may be shared by both TD and LID [9]. Our patient had neither Parkinson’s disease nor recent D2R-blocking therapy at dyskinesia onset. Moreover, modafinil is known to act as a dopaminergic agent rather than a D2R inhibitor [5]. Therefore, TD and LID were initially considered unlikely to be caused by modafinil.

On the other hand, recent studies suggest that dysregulation of striatal DA release may contribute to behavioral inflexibility in ASD. In the elF4E transgenic ASD mouse model, impaired nicotinic acetylcholine receptor function on DA axons leads to striatal DA deficits [10]. Although the precise relationship remains unclear, increased striatal D2R expression has been suggested in prior report [11]. Furthermore, activation of phasic DA signaling in the striatum by modafinil has been proposed as an important mechanism underlying its clinical efficacy [12]. Taken together, these findings suggest—at a supportive and hypothetical level—that modafinil may influence DA release dynamics in the striatum and facilitate excessive motor activity, such as dyskinesia, in highly sensitive individuals, including those with ASD.

In addition, chronic aripiprazole use may also have contributed. Sustained D2R blockade could induce VGAT overexpression, and subsequent dopaminergic stimulation by modafinil might unmask a latent aripiprazole-related dyskinesia. Although aripiprazole was discontinued more than twelve weeks before onset, preclinical data show persistent D2R occupancy for up to six months after haloperidol cessation [13]. While the effects of aripiprazole cannot be directly equated with haloperidol, the possibility of long-term receptor alterations cannot be excluded. The ‘neurodegenerative’ hypothesis which is neuronal damage and degeneration caused by neurotoxic mechanisms such as the production of lipid peroxidation and free radical formation by chronic antipsychotics, including aripiprazole, use is also thought as the mechanism of TD [14].

Regarding the management of dyskinesia in this patient, we referred to the Manuals for management of individual serious adverse drug reactions issued by the Japan’s Ministry of Health, Labour and Welfare [15]. In addition, we sought advice from an external pharmacology expert (the second author). Because a diagnosis of TD could not be confirmed at the initial stage, valbenazine tosylate was not administered. Instead, Yi-Gan San was prescribed as an alternative therapy, and gradual improvement of symptoms following its administration suggests a potential therapeutic benefit. An open-label trial of Yi-Gan San for TD suggested that this agent could normalize excessive DA function through serotonin 2A antagonism [16].

Regarding the mechanism underlying refractory dyskinesia, alterations in ‘re-wired’ brain system—such as maladaptive synaptic plasticity [17, 18]—as well as the ‘neurodegenerative’ hypothesis [14] have been proposed. Consequently, persistent dyskinesia may occur even after withdrawal of the presumed offending agents, as recovery of the endogenous DA system can require a prolonged period, ranging from several weeks to several years.

In conclusion, patients with ASD, dyskinesia risk may be heightened by DA dysfunction in the striatum and prior chronic D2R blockade by aripiprazole. Dopaminergic agents such as modafinil may provoke dyskinesia, particularly during dose escalation, suggesting the need for vigilance.

Abbreviations

ASD

Autism spectrum disorder

EDS

Excessive daytime sleepiness

PSG

Polysomnography

MSLT

Multiple sleep latency test

REM

Rapid eye movement

SOREMP

Sleep-onset REM-sleep period

ICSD-3

International Classification of Sleep Disorders, Third Edition

TD

Tardive dyskinesia

LID

L-DOPA-induced dyskinesia

DA

Dopamine

D2R

D2 dopamine receptor

VGAT

Vesicular GABA transporter

Author contributions

KN treated the patient in consultation with KK and was a major contributor to the manuscript. All authors reviewed and approved the final manuscript.

Funding

Not applicable.

Data availability

The data and materials of this study are available from the corresponding author upon reasonable request.

Declarations

Ethics approval and consent to participate

Ethical Committee Permission: The Chutoen General Medical Center Clinical Research Ethics Committee approved this case report (approval number: 1299250129).

Consent for publication

Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.

Competing interests

The authors declare that they have no competing interests.