Research progress on melatonin, 5-HT, and orexin in sleep disorders of children with autism spectrum disorder

Sleep disorders in children with ASD may be related to neuropathological mechanisms, particularly dysfunction of the hypothalamic–pituitary–adrenal axis that regulates circadian rhythms [10]. This dysfunction may lead to abnormal metabolic pathways of related neurotransmitters, especially the metabolic pathway of melatonin [11]. In children with ASD, the electroencephalogram (EEG) during rapid eye movement (REM) sleep exhibits abnormalities, such as spindle-shaped EEG waves and EEG activity unique to premature infants and infants aged 3–8 months, while lacking the slow-wave activity and REM burst activity observed in typical children during REM sleep [12]. These abnormalities indicate that children with ASD have issues with the composition and maturation of sleep brainwaves. Additionally, children with ASD may experience increased muscle activity during the REM phase, which may lead to periodic limb movement syndrome and REM sleep behavior disorders, further suggesting abnormalities in factors related to sleep–wake regulation [13]. These factors may include monoamine pathways, neurotransmitters, synapses, and abnormal development of nervous system components [14].

Beyond abnormalities in sleep–wake regulation, gene mutations related to circadian rhythms are also an important mechanism of sleep disorders in children with ASD [15]. Genes known to regulate human circadian rhythm include the PERIOD gene family (such as PER1 and PER2), TIMELESS, NPAS2, and Cryptochromes (such as CRY1 and CRY2). Some gene mutations may simultaneously affect the development of the nervous system and sleep, such as mutations in the NRXN1 and SHANK3 genes, which may influence sleep in children with ASD by affecting synaptic health in the central nervous system (CNS) and peripheral nervous system (PNS) [16, 17].

The core symptoms of ASD mainly include social communication disorders and stereotyped, repetitive behaviors, interests, or activities. These symptoms affect the daily lives of affected children to varying degrees, including their sleep patterns. Firstly, social disorders may lead to difficulties in understanding social cues and routines in children with ASD, including sleep-related daily habits and nonverbal cues expected by parents [18]. For example, they may struggle to recognize or respond to signals from their parents indicating bedtime, such as dimming lights or reducing evening activities, making it difficult to transition smoothly to sleep.

Secondly, children with ASD often exhibit stereotyped and repetitive behaviors that may be out of sync with their internal physiological rhythms, leading to disruptions in the sleep–wake cycle [19]. They may have a strong dependence on certain daily activities or environmental factors, and changes to these factors may disrupt their sleep patterns. Additionally, children with ASD often show resistance to new experiences or changes, making it challenging to alter their sleep habits or adapt to new sleep environments [20]. They may have strict requirements for pre-bedtime routines, and any changes can lead to anxiety and sleep disturbances. Children with ASD may also experience difficulties in emotional regulation, which can result in heightened anxiety and excitement at night, making it hard to calm down and fall asleep [21]. They may need more time to relax and unwind from daytime activities, posing a barrier to sleep onset. Finally, communication barriers with parents may also affect the sleep of children with ASD. Due to challenges with language and nonverbal communication, they may struggle to express their feelings or needs, including issues related to sleep, making it difficult for parents to identify and address specific problems impacting their child’s sleep.

Melatonin is an endogenous neurohormone produced by the pineal gland in mammals, which regulates the sleep–wake cycle by providing photoperiod information to the body [22]. In mammals, melatonin biosynthesis mainly uses tryptophan as a substrate and involves four synthesis steps (as shown in Figure 3): The first step is the formation of 5-hydroxytryptophan (5-HTP) under the catalysis of tryptophan hydroxylase (TPH). In the second step, 5-HTP is catalyzed by L-aromatic amino acid decarboxylase (AAAD) to form serotonin. In the third step, serotonin is acetylated by serotonin N-acetyltransferase (SNAT) or arylalkylamine N-acetyltransferase (AANAT) to produce N-acetyl-5-hydroxytryptamine. Finally, N-acetylserotonin is methylated by N-acetyl-5-hydroxytryptamine-O-methyltransferase (ASMT) or hydroxyindole-O-methyltransferase (HIOMT) to synthesize melatonin [23]. Once synthesized, melatonin is rapidly released into the systemic circulation, reaching central and peripheral target tissues and exerting physiological functions [24]. While most tissues and organs in the body can secrete melatonin, only the pineal gland and retina exhibit circadian rhythms in melatonin synthesis. The circadian rhythm of melatonin is characterized by low levels during the day and high levels at night, peaking approximately 2 h before habitual sleep time, reaching a plateau during the night, and decreasing upon waking [25].

Current studies [26–28] have found that children with ASD exhibit abnormal patterns of melatonin secretion, such as delayed melatonin peaks, decreased amplitude, and reduced nighttime secretion, which may lead to circadian rhythm sleep–wake disorders (CRSWDs) in children with ASD. Studies [28, 29] have reported that mutations in genes encoding melatonin-metabolizing enzymes (ASMT, AANAT, and CYP1A2) and melatonin receptor genes (MTNR1A, MTNR1B, and GPR50) in children with ASD may be the cause of abnormal melatonin metabolism. Mechanistically, melatonin’s role in the sleep of children with ASD involves complex biochemical processes, including the regulation of signaling pathways and cytokines. Melatonin acts through its specific membrane and nuclear receptors, which are expressed in multiple brain regions, including the suprachiasmatic nucleus (SCN), where the main biological clock resides [30]. One of the main signaling pathways of melatonin is through its G protein-coupled receptors MT1 and MT2, which, when activated, can inhibit the production of cyclic adenosine monophosphate (cAMP), thereby affecting various intracellular signaling molecules, such as protein kinase A (PKA) and extracellular signal-regulated kinases (ERK) [31, 32]. Changes in these signaling molecules can regulate neuronal excitability and affect transitions in sleep–wake cycles. On a cytokine level, melatonin has anti-inflammatory effects and can reduce the expression of pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), both of which play important roles in sleep regulation [33, 34]. The anti-inflammatory effects of melatonin help maintain stable sleep structures and reduce sleep disorders.

The treatment of ASD should primarily involve sleep hygiene and behavioral interventions. When these measures do not produce satisfactory results, pharmacotherapy may be considered. Commonly used medications include alpha agonists, antidepressants, and atypical antipsychotics. The sleep problems of children with ASD are often related to abnormal secretion and metabolism of melatonin, so exogenous melatonin supplementation therapy may be effective. So far, the best evidence for the use of melatonin in children is for insomnia caused by circadian rhythm sleep disorders, as it theoretically can shorten sleep onset latency and increase total sleep time [35, 36]. The International Pediatric Sleep Association (IPSA) recommends using sustained-release melatonin for children with ASD who struggle to maintain sleep, while short-acting melatonin is recommended for those who have trouble falling asleep [37]. Schroder et al. [38] found that exogenous melatonin supplementation not only improves sleep but also has a positive effect on externalized behavioral difficulties in children with ASD, significantly improving the quality of life for caregivers. Malow et al. [39] demonstrated that slow-release melatonin can improve the sleep of children with ASD without negatively impacting their growth and development.

5-HT is an important neurotransmitter and local hormone that plays diverse physiological roles in the human body. It is synthesized through the enzymatic reaction of tryptophan, first converted to 5-HTP and then further processed into 5-HT [40]. 5-HT is primarily involved in regulating emotions, sleep, appetite, and pain perception in the brain [41]. It functions by activating different receptor subtypes, which are widely distributed in the central and PNSs, including seven major families: 5-HT1 to 5-HT7 [42]. Signal transmission of 5-HT involves multiple intracellular pathways and can affect nerve transmission and cellular function. In terms of emotional regulation, changes in 5-HT levels are associated with various emotional disorders such as depression [43]. Popova et al. [44] noted in their research that depression, aggression, and suicidal behavior are associated with dysregulation of central 5-HT neurotransmission. In addition, 5-HT plays a central role in regulating the sleep cycle, particularly in promoting sleep and maintaining normal sleep structures [45]. Kang et al. [46] found that regulating the 5-HT pathway can improve fatigue in sleep-deprived mice. The synthesis and release of 5-HT are influenced by light and circadian rhythms, which in turn affect melatonin production and the sleep–wake cycle [47]. Therefore, 5-HT is not only crucial in the nervous system but is also indispensable in maintaining overall physiological balance.

In terms of sleep regulation, 5-HT acts as a neurotransmitter that promotes wakefulness and slow-wave sleep, and its abnormal secretion can directly lead to disturbances in the sleep–wake cycle [48]. Currently, abnormal 5-HT metabolism in children with ASD has been documented, including increased serum levels, decreased 5-HT transporters, and polymorphism of the SLC6A4 gene encoding 5-HT transporters [49–51]. In children with ASD, dysfunction of the 5-HT system is closely associated with the occurrence of sleep disorders. 5-HT affects sleep structure and cycle through its receptors. For example, activation of 5-HT2A receptors is associated with promoting wakefulness, while 5-HT1A receptors are associated with promoting sleep [52, 53]. In children with ASD, changes in the sensitivity or expression levels of 5-HT receptors may lead to an imbalance in sleep–wake cycle regulation. Additionally, 5-HT may indirectly affect sleep by influencing physiological processes, such as thermoregulation, gastric emptying, and intestinal motility. On a molecular level, 5-HT synthesis is catalyzed by TPH, and TPH activity is influenced by gene polymorphisms [54]. Specific TPH gene variations are linked to sleep disorders in children with ASD, potentially by altering the synthesis and availability of 5-HT. The level of 5-hydroxyindoleacetic acid (5-HIAA), a metabolite of 5-HT, in cerebrospinal fluid is also associated with sleep quality in children with ASD [55]. 5-HT also participates indirectly in sleep regulation by affecting other neurotransmitter systems, such as melatonin and dopamine. For example, 5-HT influences melatonin secretion, which is a key hormone in regulating the biological clock and sleep cycle. Interactions between 5-HT and dopamine are also involved in maintaining wakefulness and initiating sleep. In children with ASD, abnormalities in the 5-HT system may be linked to specific behavioral characteristics, such as repetitive behavior and social disorders, which can further affect sleep patterns. For example, repetitive behavior may decrease nighttime wakefulness and sleep efficiency.

Research on the treatment of sleep disorders in children with ASD using 5-HT has shown some progress. Due to its central role in regulating emotions and sleep, the 5-HT system has become a potential target for treating ASD-related sleep problems. For instance, selective serotonin reuptake inhibitors (SSRIs) are a class of drugs that increase 5-HT concentration in the synaptic cleft [56]. In children with ASD, SSRIs may help alleviate emotional issues related to sleep disorders, such as anxiety and depression, thereby indirectly improving sleep quality [56]. Some atypical antidepressants, such as trazodone, have an antagonistic effect on 5-HT2A receptors and have been used to treat insomnia. These drugs may also have therapeutic potential for sleep disorders in children with ASD [57]. Additionally, regulating 5-HT through traditional Chinese medicine has been shown to effectively improve sleep quality [58]. It is important to note that when choosing 5-HT-related drugs for treatment in clinical practice, individualized evaluation of patients is necessary to minimize possible complications.

Orexin, also known as hypothalamic secretin, is a group of neuropeptides produced in the hypothalamus that widely affect other areas of the brain. It includes two forms: orexin A and orexin B [59]. These neuropeptides exert their effects by binding to specific G protein-coupled receptors—orexin receptor 1 (OX1R) and orexin receptor 2 (OX2R)—whose distribution in the brain is closely related to physiological processes, such as the sleep–wake cycle, energy metabolism, feeding behavior, and stress response [60, 61]. The activity of orexins is mainly related to promoting wakefulness, reducing sleep, and enhancing feeding behavior [62]. In addition, the orexin system is involved in regulating emotions, cognitive function, and addictive behavior [63]. Abnormal activity of orexin neurons is directly related to various sleep disorders, especially hypersomnia [64]. Excessive secretion of orexins at night can lead to a heightened wakefulness system, making it difficult to transition smoothly to the sleep system, resulting in insomnia. If the activity of orexins at night can be inhibited or the binding between orexins and appetite hormone receptors blocked, it will inhibit the wakefulness-promoting effect of orexins, reduce awakening signals, increase drowsiness, and restore a normal sleep rhythm [65]. The discovery of orexins provides important clues for understanding the neurobiological mechanisms of sleep, wakefulness, and related diseases.

In children with ASD, this neuropeptide may affect sleep patterns through specific neural pathways and genetic mechanisms. Specifically, orexin enhances the activity of arousal-promoting neurotransmitters, such as dopamine and norepinephrine in the brain, while inhibiting sleep-promoting neurotransmitters, such as gamma-aminobutyric acid (GABA) and serotonin (5-HT), thus affecting the sleep–wake cycle [66]. Orexin may also influence the circadian rhythm of the sleep–wake cycle by affecting the circadian function of the SCN [67]. Additionally, the orexin signaling pathway may alter sleep patterns by influencing the expression of genes related to the sleep–wake cycle, such as Clock and Bmal1 [68]. Orexin receptor antagonists (ORAs) help restore a normal sleep rhythm by blocking the binding of orexin to its receptors, reducing arousal signals, increasing drowsiness, and promoting sleep [69]. Orexin may also impact sleep and wakefulness states by influencing pathways related to neural plasticity, such as the expression of brain-derived neurotrophic factor (BDNF) [70]. Therefore, the mechanism of the orexin signaling pathway in sleep disorders in children with ASD is a complex process involving multiple aspects, such as neurotransmitter system regulation, interactions between brain regions, influence on the biological clock, gene expression regulation, and stress response modulation.

In the past two decades, with the growing understanding of the orexin system’s role, particularly in regulating wakefulness, ORAs have shown significant potential as a new type of neurological or psychiatric drug for treating insomnia, making them a hot topic in drug research [71, 72]. Currently, three innovative ORA drugs—suvorexant, lemborexant, and daridorexant—have been approved by the U.S. FDA for treating adult patients with insomnia [73–75]. These three drugs are dual ORAs (DORAs) that can be taken orally. Although no ORA is currently available for treating sleep disorders in children with ASD, regulating orexin system activity may help improve sleep patterns in ASD patients by reducing excessive wakefulness or adjusting the sleep–wake cycle, as orexin mainly promotes wakefulness and inhibits sleep. Additionally, children with ASD often have other mental and neurodevelopmental disorders, such as anxiety, depression, or attention deficit hyperactivity disorder (ADHD). Appetite regulation may also positively impact these comorbid sleep problems.