Drug-induced changes and disorders of sleep and wake cycles – a narrative review

Overview

Sleep and wake cycle changes are common adverse effects of medications and can be classified into nosological groups of insomnia, hypersomnolence, sleep-related breathing disorders, parasomnias, and sleep-related movement disorders according to the International Classification of Sleep Disorders, 3^rd edition, Text Revision. This review article enumerates which medications can induce sleep-wake cycle abnormalities and diseases and outlines how these adverse effects occur.

Keywords:

sleep – pharmacodynamics – adverse drug reaction – wake

This is an unauthorised machine translation into English made using the DeepL Translate Pro translator. The editors do not guarantee that the content of the article corresponds fully to the original language version.

 

Introduction

Sleep and wakefulness are fundamental functional states of living organisms. The perfection and appropriate alternation of sleep and wakefulness in mammals are ensured by complex brain processes linked to changes in peripheral organs. Exogenous chemicals, including drugs, can interfere with the regulation of sleep and wakefulness. This may be the desired effect of a drug, but it may also be an adverse effect if the drug is administered for a different indication. This review article summarizes the adverse effects of drugs on sleep and wakefulness and presents them in symptom groups as classified in the International Classification of Diseases, 3rd edition, text revision (ICSD-3-TR) [1], omitting circadian disorders.

The adverse effects of drugs on the quality of wakefulness and on the duration and quality of sleep are often taken into account and are also asked about by laypeople, while parasomnias or abnormal sleep-related movements are rarely considered as possible adverse effects. Therefore, the section of this review dealing with parasomnias and movement disorders is more detailed.

The sources of information used in compiling this overview were professional literature and summaries of product characteristics (SPCs) that are not cited. In terms of sleep disorders, the SPCs mainly mention adverse effects manifested by reduced alertness or non-specific sleep disturbances. The generally known and reported data on sleep-related adverse effects in the SPC are based largely on subjective patient reports. Objective measurements, cohort or prospective studies are available to a limited extent, which is probably the reason for the heterogeneity of descriptions of sleep-related adverse effects of some drugs. The information presented in this broad overview does not cover details such as the different probabilities of adverse effects in patients and healthy controls, the different intensities of adverse effects, and the aforementioned heterogeneity of effects on sleep. The overview omits rare case reports, and the authors refer to the more detailed overview sources cited in this regard.

 

Insomnia

Insomnia is the inability to fall asleep and/or stay asleep, including premature awakening under conditions conducive to sleep. Insomnia as a disease is further defined by adverse effects on the patient during the day [1,2].

First and foremost, it should be noted that drugs commonly used to induce sleep, such as hypnotics, sedatives, and anxiolytics, can paradoxically cause insomnia due to tolerance, dependence, or withdrawal syndrome and a decrease in the level of the active substance during the night. Sedative and short-acting hypnotic medications administered too early in the evening or afternoon may cause sleep disturbances in the second half of the night due to a rebound effect of anxiety or a decrease in the hypnotic effect of the prematurely administered medication [1,3].

Insomnia is reported as a side effect mainly in stimulants, antidepressants, antihypertensives, lipid-lowering drugs, anorectics, corticosteroids, antiparkinson drugs, anticonvulsants (anti-seizure medication; ASM), decongestants, and theophylline [3]. The development of insomnia in these cases is promoted by the use of alcohol, caffeine, nicotine, and other recreational addictive substances.

With centrally acting stimulants (methylphenidate, modafinil, atomoxetine, amphetamines, pitolisant, solriamfetol), the development of insomnia is not surprising [3]. When prescribing these drugs, it is therefore necessary to administer the dose in the morning or mid-morning, adhere to the prescribed dosage, and take individual sensitivity into account.

The mechanism of action of antidepressants affects receptor systems that influence both sleep (gamma-aminobutyric acid; GABA) and wakefulness (noradrenaline, acetylcholine, serotonin, histamine, hypocretin, glutamate). The effects of individual groups of antidepressants on sleep or wakefulness are summarized in Table 1. It is important to note that antidepressants may have different effects on sleep in patients with severe depression, mild depression, and in individuals receiving antidepressants for other reasons, and possibly in healthy subjects. Antidepressants generally improve sleep quality in severe depression, but some antidepressants may worsen sleep quality in healthy individuals and, in most cases, alter sleep architecture, particularly by prolonging the latency of rapid eye movement (REM) sleep and shortening its duration. Depression itself can manifest as shortened sleep or, conversely, hypersomnolence, so in depression, shortened sleep and insomnia or hypersomnolence cannot be clearly attributed to the use of antidepressants. Insomnia is most common in patients treated with fluoxetine, bupropion, and venlafaxine [3].

The antipsychotics aripiprazole, fluphenazine, perphenazine, and haloperidol often lead to complaints of insomnia, but this is sometimes a consequence of induced restless legs syndrome (RLS). The potential of antipsychotics to cause insomnia is shown in Table 2 and is related to the profile of the receptors they occupy, their half-life (short-acting ones are more sedative) and the dose of individual preparations [3].

Antihypertensive drugs often list insomnia in their SPCs. It is most commonly induced by β-blockers and angiotensin-converting enzyme inhibitors. β-blockers cause insomnia by reducing melatonin secretion [4], with the more lipophilic ones –⁠ propranolol, less metoprolol and pindolol –⁠ having the greatest potential to cause insomnia and the effect being negligible in others [5]. Angiotensin-converting enzyme inhibitors do not directly affect sleep regulation, but they cause dry cough, which disturbs sleep. Despite this information and clinical experience, a recent large study and a recent systematic review did not confirm the effect of antihypertensive medication on total sleep time, REM sleep, or sleep efficiency [6,7].

SPCs for lipid-lowering agents indicate an increased risk of sleep disorders, including insomnia, but reviews do not describe changes in sleep duration and efficiency or sleep latency. There are even reports that statins reduce the number of awakenings and the time spent awake after falling asleep [3,8,9].

Anorexigenics prescribed/recommended/indicated in previous periods contained caffeine and other stimulants and could cause insomnia. Some older anorectics, such as mazindol, were even indicated for the treatment of excessive daytime sleepiness in narcolepsy. The promotion of noradrenaline release, typical of earlier obesity drugs, induces insomnia. Glucagon-like peptide-1 (GLP-1) receptor agonists (semaglutide, liraglutide, ozempic, and tirzepatide), currently used in the treatment of type 2 diabetes and obesity, have adverse effects on sleep. GLP-1) (semaglutide, liraglutide, ozempic, and tirzepatide) currently used in the treatment of type 2 diabetes and obesity do not have an adverse effect on sleep.

Corticosteroids can interfere with falling asleep in the evening, even when administered at the time of the natural morning secretion peak. Corticosteroids reduce melatonin secretion [10], inhibit GABA release, and have adrenergic and probably also glutamatergic effects. Corticosteroid-induced insomnia is common with long-term use and higher doses and is an unpleasant side effect for patients [3]. Insomnia can also occur with the use of inhaled corticosteroids.

In Parkinson's disease, insufficient dopaminergic signaling is replaced by levodopa and dopamine agonists. Low doses of dopaminergic therapy tend to improve nighttime sleep, while higher doses may disrupt it [11]. Pramipexole and ropinirole may worsen sleep but also increase daytime sleepiness. Selegiline improves daytime alertness but in some cases leads to insomnia [12]. Insomnia has been reported after amantadine [13,14].

Opioids are associated with improved sleep, but this is due to a reduction in pain that disturbs sleep. Opioids themselves disrupt sleep architecture—they shorten N3 sleep (the deepest sleep important for brain regeneration) and REM sleep and impair sleep efficiency. Opioid dependence worsens insomnia and is worsened by insomnia [15,16].

The effect of antiseizure medications (ASMs) on sleep and the development of insomnia is mentioned in SPCs and reviews in monographs, but a recent comprehensive review article concludes that ASMs in patients with epilepsy are not a risk factor for insomnia, with the exception of topiramate (Table 3) [3,17]. Information on the effect of ASMs on sleep and wakefulness is therefore conflicting, and there are likely to be multiple factors involved in the effect of ASMs on sleep.

Bronchodilators from the β2 adrenergic agonist group in combination with corticosteroids may induce insomnia.

Over-the-counter decongestants and cough suppressants containing pseudoephedrine, caffeine, and the synthetic opioid dextromethorphan have a stimulating effect and may contribute to insomnia.

Methylxanthines (caffeine and theophylline) act as adenosine antagonists and may cause irritation, restlessness, and difficulty falling or staying asleep.

If a medication is known to cause insomnia, it should be administered at the correct time and the patient should be advised to follow good sleep hygiene practices.

 

Hypersomnolence

Hypersomnolence has three manifestations, which are usually combined:

a)
excessive daytime sleepiness (EDS) –⁠ inability to remain adequately alert during the day;

b)
hypersomnia in the narrow sense –⁠ prolonged sleep duration during a 24-hour cycle;

c)
sleep inertia –⁠ difficulty waking up.

 

Of these three manifestations, EDS is the most common side effect of medication, which can take the form of falling asleep during the day (sometimes imperative), reduced alertness and attention, or automatic behavior when falling asleep during activity. Pharmacogenic reduction in the ability to maintain alertness is mentioned in the SPCs of many drugs.

Drugs induce EDS mainly through GABA and histamine receptors. These include ASMs, including benzodiazepines, antipsychotics, antidepressants, and opioids.

Anticonvulsants are represented by many groups of drugs that act on the central nervous system in various ways, and their relationship to alertness is documented in varying detail. The effect of ASMs on daily alertness is shown schematically in Table 3. The basic ASM levetiracetam is generally well tolerated but may lead to EDS and fatigue, depending on the dose. However, the only objective study did not find a correlation between subjectively perceived EDS and multiple sleep latency [18].

Gabapentin and pregabalin are primarily ASMs, but are often used as (co)analgesics and mood stabilizers. Gabapentin is a lipophilic structural analogue of GABA, easily crosses the blood-brain barrier, and reduces alertness. Pregabalin modulates calcium entry into neurons in the central nervous system and slightly reduces alertness [19].

Antipsychotics are divided into typical and atypical. Typical antipsychotics are further divided into sedative (chlorpromazine, levomepromazine, chlorprothixene, flupenthixol, zuklopentixol), which significantly induce all forms of hypersomnolence, and incisive (haloperidol, melperone, fluphenazine), in which the sedative effect is less pronounced, which is probably related to weak antagonism of the H₁receptor antagonism. Of the easily dosed and relatively safe atypical antipsychotics, quetiapine, which is an H1 receptor antagonist and also induces sleep by inhibiting histamine synthesis, most commonly causes EDS. Quetiapine is therefore sometimes indicated off-label for the treatment of resistant insomnia. EDS in acute psychosis may be a temporarily welcome effect of the drug and therefore only formally falls into the undesirable category. Hypersomnolence, including EDS, is most commonly induced by clozapine, chlorpromazine, and thioridazine (Table 2).

Antidepressants affect sleep and wakefulness, as shown in Table 1. It should be noted that the information is schematic, as the effect on sleep or wakefulness is dose-dependent in some antidepressants (mirtazapine has a strong hypnotic effect at low doses and little effect at higher doses). Of all commonly used antidepressants, amitriptyline, mirtazapine, and trazodone have the most hypnotic effect, which is used off-label in the treatment of insomnia. These antidepressants should be administered in the evening, even if they are not indicated for improving sleep. The duration of their hypnotic effect may still extend into the daytime. Amitriptyline reduces the reuptake of noradrenaline and serotonin, but also significantly affects other receptors. Mirtazapine has a hypnotic effect through its strong antagonistic action on H1 receptors, while trazodone acts antagonistically on several different receptors (5-HT-2A, H1, and alpha1) [3].

Sodium oxybate is an agonist of GABA B and specific oxybate receptors. It is indicated for the treatment of narcolepsy. It is administered at night to improve sleep and daytime alertness. Incorrect daytime administration leads to drowsiness and also to dependence [20].

Baclofen has a similar mechanism of action to sodium oxybate. When administered at night, it improves nighttime sleep, but when administered during the day, it induces drowsiness [21].

First-generation antihistamines (H1 receptor antagonists, more precisely H1 receptor inverse agonists) (bisulepin, dimetinden, promethazine, hydroxyzine) are lipophilic and cross the blood-brain barrier, blocking histamine receptors in the periphery and in the brain. Their penetration into the central nervous system manifests itself as EDS. These drugs are sometimes used off-label to treat insomnia. Second-generation antihistamines (cetirizine, levocetirizine, loratadine, desloratadine, bilastine) are not lipophilic and act almost exclusively on the periphery, so they rarely cause EDS [22].

Opioids primarily impair sleep, but they can also impair daytime alertness [15,16].

The antiparkinsonian drug levodopa and, in particular, dopamine agonists cause EDS depending on the dose. The use of dopamine agonists can lead to narcolepsy-like symptoms –⁠ so-called sleep attacks were first described in the late 1990s with pramipexole and ropinirole [23].

Cannabis is associated with improved sleep, although information on the effects of cannabis on sleep is mixed. It is acknowledged that in certain situations it can lead to sleepiness [24], which should be considered an adverse effect in the case of medical cannabis.

 

Sleep-disordered breathing

Breathing is controlled centrally from the brain stem, where information from baroreceptors in the lungs and chemoreceptors in the blood vessels is received. Breathing during sleep is influenced by circadian, endocrine, mechanical, and chemical factors. The voluntary component of breathing during sleep disappears, but during REM sleep, respiratory activity is partially influenced by the cerebral cortex. Medication can suppress respiratory activity during sleep, but it can also promote it [25] and, by increasing weight, may secondarily increase the likelihood of sleep-disordered breathing [26].

The ICSD-3-TR divides sleep-disordered breathing into four basic groups: obstructive sleep apnea (OSA), central sleep apnea (CSA), hypoventilation disorders, and hypoxemic disorders [1].

Benzodiazepines (diazepam, clonazepam, flunitrazepam, flurazepam, lormetazepam, nitrazepam, oxazepam, temazepam, midazolam, triazolam) act on GABAA receptors in the brain. In addition to other effects on the central nervous system, they affect sleep architecture and breathing during sleep, and the extent of this effect is dose-dependent. Low doses are safe for healthy people in terms of sleep breathing. Increased caution is necessary in patients with OSA, CSA, obstructive pulmonary disease, neuromuscular diseases, and when combined with opioids, antihistamines, alcohol, or other depressants. Individual benzodiazepines differ in the significance of their effect on sleep breathing. No adverse effect on sleep breathing has been demonstrated with non-benzodiazepine benzodiazepine receptor ligands (zolpidem, zopiclone, and zaleplon), melatonin receptor agonists (ramelteon, melatonin, agomelatine, and tasimelteon), and dual orexin receptor antagonists (e.g., daridorexant), which are also used to improve insomnia.

Sodium oxybate may worsen breathing during sleep, including worsening OSA, and may induce central sleep apnea by activating GABA receptors in the brain stem. High doses and inappropriate combinations with other sedative drugs or alcohol enhance this effect [20,27,28]. Any OSA must be compensated for by continuous positive airway pressure during oxybate administration.

Opioids suppress respiratory activity by directly affecting the respiratory center in the brain stem via μ-opioid receptors, but also via peripheral chemoreceptors. They may induce or exacerbate existing central or obstructive sleep-disordered breathing. The risk is higher in polymorbid patients and in older patients on polytherapy. In addition to OSA and CSA, excessively high doses of opioids also cause Biot's breathing [15,16,28,29]. Methadone substitution therapy causes both OSA and CSA, according to some studies in up to 70% of treated patients [30].

Pregabalin and gabapentin act via the α2d subunit of presynaptic voltage-gated sodium channels. They may suppress respiratory activity during sleep and cause apnea. Central apnea is thought to be caused by GABA receptors in the brain stem, which occur together with μ-opioid receptors [28,31].

Baclofen has the ability to increase pharyngeal collapsibility and, by reducing respiratory effort during sleep, induce or worsen OSA and hypoventilation, or possibly CSA in a manner similar to that mentioned for gabapentin [28,32].

Antipsychotics and some antidepressants lead to weight gain, which increases the risk of OSA and hypoventilation during sleep.

Atypical antipsychotics –⁠ olanzapine, risperidone, quetiapine –⁠ slightly increase the risk of OSA independently of weight gain [33].

Exogenous testosterone is considered a risk factor for the development or worsening of OSA and accentuates snoring [34].

The risk of inducing central apnea is mentioned in valproate and the antiplatelet agent ticagrelor, and this effect is thought to be related to GABA receptors in the brain stem [28].

 

Parasomnia

The term parasomnia refers to undesirable behaviors or experiences that occur during falling asleep, sleep, or waking up. Paranormia arise from the dissociation of three basic states of central nervous system functioning—waking, NREM, and REM sleep—and are linked either to incomplete awakening from NREM sleep (collectively referred to as NREM paranormaal) or to REM sleep, or they may occur independently of sleep type [1].

 

NREM parasomnias after hypnotics and other medications

NREM parasomnias include three basic clinical entities: confusional arousal, somnambulism (sleepwalking), and night terrors. Somnambulism is characterized by motor activation with complex automatisms and automatic behavior, including leaving the bed and other more complex activities. A variant of somnambulism is sleep-related eating disorder (SRED), in which the behavioral manifestation is the preparation and consumption of food [1]. NREM parasomnias most often occur in association with the N3 sleep stage. A common feature of NREM parasomnias is difficulty in waking up during an episode and subsequent partial or complete amnesia. NREM parasomnias usually begin in childhood and gradually disappear with age, but may persist into adulthood or manifest only in adulthood [3,35].

The pathophysiology of NREM parasomnias is primarily based on the simultaneous presence of sleep and wakefulness activity in different areas of the CNS during the transition between sleep and wakefulness. This leads to the dissociated activation of some cortical circuits, while sleep activity persists in other cortical circuits. The pathophysiology of NREM parasomnias involves instability of deep NREM sleep, sleep inertia (gradual, rather than physiologically immediate, activation of brain areas during the transition from sleep to wakefulness), and activation of central generators of movement patterns, which are responsible for complex motor symptoms [36].

A number of medications can trigger these parasomnic episodes in predisposed individuals (Table 4).

 

Benzodiazepine receptor agonists and other modulators of GABAergic transmission

Most cross-sectional studies confirm a link between zolpidem use and the occurrence of somnambulism or its variant SRED. In adults, zolpidem-induced somnambulism affects 0.5–1.1% of individuals, 2.2% of adolescents, and as many as 5.1% of patients receiving psychiatric treatment [3,35]. Although in some cases these problems occurred at supratherapeutic doses of zolpidem, this adverse effect was more commonly observed at usual doses [37]. Surprisingly, patients with zolpidem-induced NREM parasomnia have no history of somnambulism without zolpidem; therefore, this is not a reactivation of childhood parasomnia, but the induction of new symptoms. Zolpidem, probably due to its binding to GABA receptors throughout the nervous system, disinhibits central movement generators associated with evolutionarily conserved motor patterns such as walking or food intake [38]. In contrast to the extensive literature on zolpidem and NREM parasomnias, only two case reports describe somnambulism in connection with zaleplon and zopiclone [35]. The onset of NREM parasomnia during administration of clonazepam, a commonly used drug for NREM parasomnias, was paradoxical and rare [39].

 

Antidepressants and lithium

NREM parasomnic episodes have been reported in connection with the administration of various antidepressants, especially tricyclics, and particularly amitriptyline. In the case of tricyclic antidepressants, the key effect in triggering abnormal motor activity during sleep is an increase in synaptic serotonin concentration. Bupropion is another antidepressant that induces NREM parasomnias. It increases synaptic concentrations of norepinephrine and dopamine by inhibiting their reuptake, has little effect on serotonin levels, and also blocks nicotinic cholinergic receptors. Lithium is widely used in the treatment of bipolar disorder, but its mechanism of action is not yet fully understood. However, it is known to affect serotonin and dopamine and to enhance GABAergic transmission. The specific mechanism underlying the induction of NREM parasomnic episodes by lithium is unclear.

 

Antipsychotics

The mechanism by which first-generation antipsychotics (chlorprothixene, thioridazine) induce somnambulistic manifestations is unknown. Modern atypical antipsychotics, which have been reported to be associated with sleepwalking (olanzapine, quetiapine, risperidone, aripiprazole), act like first-generation antipsychotics as antagonists of dopamine receptors, but also show affinity for serotonin receptors. Alterations in central serotonergic activity are likely to play a role in triggering NREM parasomnic episodes. SRED may be related to the effects of atypical antipsychotics on 5-HT2C receptors, which regulate mood, anxiety, and food intake, among other things [40]. In addition, quetiapine, olanzapine, risperidone, and ziprasidone show high affinity for histamine H1 receptors. Blockade of H1 receptors may also increase the incidence of periodic limb movements in sleep (PLMS), which can lead to dissociated awakenings from N3 sleep and subsequently to a somnambulistic episode or SRED episode.

 

Other drugs

bCases of somnambulism have been reported after administration of sodium oxybate [35,41]. Somnambulistic episodes as adverse effects have been reported with the beta-blockers propranolol and metoprolol. This is thought to be due to the limited effect of norepinephrine, which plays a key role in awakening. Very rare case studies have linked the occurrence of somnambulistic episodes to the use of the anticonvulsant drug topiramate, the antiasthmatic drug montelukast (a leukotriene receptor antagonist), and the central stimulant methylphenidate.

 

REM sleep-related parasomnias

REM sleep-related parasomnias include REM sleep behavior disorder (RBD), recurrent isolated sleep paralysis, and night terror disorder [1], and these parasomnias may also be induced by medication.

Behavioral disturbance in REM sleep is characterized by the absence of physiological skeletal muscle atonia during REM sleep and the occurrence of dream-like behavior in the form of complex movements and vocalizations. The pathophysiology of RBD lies in the dysfunction of the glutamatergic nucleus subcoeruleus in the pons Varoli and the GABAergic and glycinergic nucleus gigantocelularis ventralis in the medulla oblongata, which in normal REM sleep hyperpolarize peripheral motoneurons via descending pathways [1,42]. RBD occurs in neurodegenerative diseases with the accumulation of pathologically conformed alpha-synuclein (synucleinopathies –⁠ Parkinson's disease, dementia with Lewy bodies, and multisystem atrophy, collectively referred to as synucleinopathies) and in type 1 narcolepsy. RBD also occurs independently and is called isolated (formerly idiopathic) RBD. Isolated RBD affects people over the age of 50 and is considered a prodromal stage of synucleinopathies, as approximately 80% of patients develop manifest synucleinopathies in the following years.

Isolated RBD occurs more frequently in patients with depression and during treatment with antidepressants [43], but RBD is more likely to be causally related to antidepressants [44]. The first mention that sleep behavior corresponding to RBD can be induced by an antidepressant dates back to 1970 and concerns the monoamine oxidase inhibitor phenelzine [45]. Currently, tricyclic antidepressants (e.g., amitriptyline, clomipramine), selective serotonin reuptake inhibitors (SSRIs, e.g., fluoxetine, sertraline, es/citalopram), serotonin and norepinephrine reuptake inhibitors (SNRIs, e.g., venlafaxine), noradrenergic and specific serotonergic receptor antagonists (e.g., mirtazapine), and monoamine oxidase inhibitors (e.g., the aforementioned phenelzine) [46]. Antidepressants increase muscle tone during REM sleep, probably through three mechanisms:

a) increased serotonergic transmission;

b) reduction of cholinergic transmission;

c) disorganization of REM sleep control.

 

A decrease in serotonin, noradrenaline, and histamine is also necessary for muscle atonia during REM sleep, which is prevented by antidepressants [47–49].

RBD without manifest synucleinopathy is classified as isolated RBD even when antidepressants are administered. Only three antidepressants—bupropion, trazodone, and agomelatine—are highly unlikely to induce RBD or REM sleep muscle atonia disorder [44,50–53]. RBD symptoms persist even after discontinuation of antidepressants, and it appears that the induction of RBD by antidepressants is not just a transient consequence of antidepressants, but rather a premature onset or un nd unmasking of a long-term progressive pathological process. Approximately 5% of people who take antidepressants are at risk of RBD [54]. RBD symptoms in patients taking antidepressants begin earlier than in patients not taking antidepressants, and patients taking antidepressants have a lower rate of phenoconversion to manifest synucleinopathy [55].

Case reports have described that, in addition to antidepressants, the acetylcholinesterase inhibitor rivastigmine and the lipophilic b-blockers bisoprolol and propranolol can induce RBD [1,56,57]. Acute RBD can occur during withdrawal from alcohol and barbiturates.

Nightmare disorder is characterized by extremely unpleasant, memorable dreams in which the sleeper is exposed to various threats and suffering. Upon awakening from the dream, the patient is immediately alert and remembers the dream [1]. Drugs that affect noradrenaline, serotonin, and dopamine transmission have the ability to induce nightmares. This is most significant in the case of antidepressants, antihypertensive drugs, and dopamine receptor agonists (levodopa and dopamine agonists). Nightmares can also be induced by substances that affect GABAergic, cholinergic, and histaminergic transmission. A significant inducer of nightmares is varenicline, which blocks nicotinic cholinergic receptors and is used to help people quit smoking. Antidepressants have an ambivalent effect on dreams and nightmares: on the one hand, they reduce dream recall, but on the other hand, SSRIs and SNRIs can intensify dreaming and even induce nightmares. Of the antidepressants, bupropion is the most common cause of nightmares. Discontinuing antidepressants that suppress REM sleep can also induce unpleasant dreams. Nightmares are also caused by bisoprolol and propranolol, donepezil, amphetamines, and modafinil. There are case reports of nightmares after valproate, ciprofloxacin, erythromycin, ganciclovir, digoxin, and amantadine [1,3,57].

Sleep-related hallucinations occur just before falling asleep or after waking up and are mainly visual [1]. They occur in young people, in mood and anxiety disorders, in sleep deprivation, in substance abuse and in alcohol withdrawal, and in narcolepsy. There are reports that they can be triggered by the beta-blockers bisoprolol and propranolol [1,57].

Nocturnal enuresis is a parasomnia unrelated to the stage of sleep. It sometimes occurs during very deep sleep, even in adults. It can be caused iatrogenically by sodium oxybate and other drugs with the ability to deepen sleep in inappropriately high doses.

 

Sleep-related movement disorders

Sleep-related movement disorders are disorders characterized by abnormal motor manifestations that are associated with sleep and may disrupt it. According to the ICSD-3-TR, these disorders include restless legs syndrome (RLS), periodic limb movements in sleep, bruxism, sleep-related rhythmic movements, propriospinal myoclonus during sleep, benign infantile myoclonus, and lower limb cramps [1].

Some sleep-related movement disorders may be exacerbated or induced by medication.

Restless legs syndrome is characterized by an urge to move the lower limbs, which is usually associated with unpleasant sensations in the same location. The symptoms occur at rest, most often in the evening or at night, which is why RLS often delays falling asleep [58]. RLS is often associated with PLMS, which are stereotypical repetitive movements of the limbs (usually the lower limbs), usually of small amplitude, which are sometimes accompanied by a waking reaction. PLMS can thus worsen sleep quality. RLS and PLMS share some pathophysiological features, suggesting that they are a spectrum of the same disorder [59]. The pathophysiology of RLS is based on a hyperdopaminergic state with presynaptic increased synthesis and release of dopamine, leading to secondary postsynaptic receptor downregulation, which is responsible for the relative dopamine deficit at night [60]. Another pathophysiological mechanism of RLS is iron deficiency in neurons. Medications can also contribute to the development of RLS and PLMS symptoms.

 

Antidepressants

The effect of antidepressants on RLS and PLMS appears to be mainly related to increased serotonin levels [3]. Many studies, case reports, and review articles show that antidepressants generally induce or worsen RLS and PLMS. The most significant effects are seen with mirtazapine, SNRIs (especially venlafaxine), and SSRIs (e.g., sertraline and fluoxetine). Mirtazapine at a dose of 30 mg for 7 days induced PLMS in 67% and RLS in 25% of young healthy volunteers. Trazodone, bupropion, and apparently also agomelanin are antidepressants that do not induce RLS symptoms [3,61–64].

 

Antipsychotics

The development of RLS during antipsychotic treatment is mainly related to their antidopaminergic effects. Classic antipsychotics such as haloperidol and phenothiazine derivatives have a high potential to induce or worsen RLS. A number of studies have also reported an association between RLS and the use of atypical antipsychotics such as olanzapine, quetiapine, and clozapine [65], and case reports have also linked it to the use of risperidone.

 

Other drugs

Other drugs that may cause or worsen RLS include antihistamines (H2 blockers) and prokinetics (prochlorperazine, metoclopramide), with the exception of domperidone [66].

 

Augmentation in the treatment of RLS

Augmentation is the worsening of RLS as a result of treatment (mainly dopaminergic). Augmentation manifests itself in more intense RLS symptoms: earlier onset of symptoms, earlier occurrence of symptoms after the onset of rest, involvement of a larger part of the body, and a shorter duration of the drug's effect. Augmentation occurs at doses of dopaminergic treatment that are higher than the recommended low doses, and of all dopaminergic preparations, it is most common with levodopa, which is no longer used for regular treatment of RLS for this reason [67,68].

 

Sleep-related bruxism is the name given to rhythmic stereotypical contractions of the masticatory muscles with audible phenomena (teeth grinding) during sleep. It can be triggered or exacerbated by ASM (e.g., barbiturates, benzodiazepines, levetiracetam, carbamazepine, lamotrigine, zonisamide), amphetamines, methylphenidate, SSRIs, SNRIs, and antipsychotics [69].

Lower limb cramps are painful contractions of the calf, foot, or thigh muscles. They occur during sleep or while awake at night. They are caused by diuretics (especially potassium-sparing and thiazides), long-acting inhaled β agonists, statins, oral contraceptives, intravenous iron, donepezil, benzodiazepines, neostigmine, certain cytostatics, and a number of other drugs [70,71].

 

Conflict of interest

The authors declare that they have no conflict of interest in relation to the subject of this paper.

 

Table 1. Effect of antidepressants on nighttime sleep (and possibly inducing insomnia) on daytime alertness (and possibly inducing hypersomnolence).

	Ability to induce insomnia	Ability to induce sleep and somnolence
Monoamine oxidase inhibitors	++	0
Tricyclic antidepressants	imipramine +, nortriptyline +, protriptyline +	amitriptyline +++
Selective serotonin reuptake inhibitors (SSRIs)	fluoxetine +++ fluvoxamine ++ paroxetine ++ sertraline ++ es/citalopram +	fluvoxamine +
Serotonin and noradrenaline reuptake inhibitors (SNRIs)	duloxetine ++ venlafaxine ++	duloxetine +
Noradrenaline and dopamine reuptake inhibitors	bupropion +++	0
serotonin 5-HT2receptor antagonists and serotonin reuptake inhibitors	0	trazodone ++
Noradrenergic and specific serotonergic antidepressants	0	mirtazapine ++
agomelatine	+	+ (gradually during the first 14 days)
vortioxetine	+	0
esketamine	0	+++

+ minor; ++ moderate; +++ significant

 

 

Table 2. Effect of antipsychotics on sleep and wakefulness.

	ability to induce insomnia	ability to induce somnolence and sleep
chlorpromazine	0	+++
flufenazine	+++	+
haloperidol	+++	++
perphenazine	+++	++
thioridazine	++	+++
aripiprazole	+++	+
clozapine	0	+++
olanzapine	++	+++
quetiapine	+	+++
risperidone	++	+++
ziprasidone	+	++

+ small; ++ moderate; +++ significant

 

 

Table 3. Effect of anticonvulsant drugs on sleep and wakefulness.

	Effect on nighttime sleep	Worsening of daytime alertness
perampanel	low incidence of insomnia	++
lamotrigine	insignificant	+/0
valproate	insignificant	+/0
benzodiazepines	shortened sleep latency, improved sleep continuity, shortened N3 and R, excessive daytime sleepiness	+++
phenobarbital	shortening of sleep latency, improvement in sleep continuity, shortening of N3 and R	++
carbamazepine	mild improvement in sleep continuity and prolongation of N3	+/0
levetiracetam	mild improvement in sleep continuity and prolongation of N3, shortening of R	++
phenytoin	mild shortening of sleep latency, shortening of N3 and R	+
pregabalin and tiagabine	shortening of sleep latency, improvement of sleep continuity, prolongation of N3, shortening of R	+
gabapentin	mild deterioration in sleep continuity and shortening of N3	++
primidone	0	++
topiramate	mild to moderate	+

+ mild deterioration; ++ significant deterioration; +++ very significant deterioration; +/0 potential mild deterioration

N1, N2, N3 and R –⁠ sleep stages NREM 1, NREM 2, NREM 3 and REM

 

 

Table 4. Main drug groups causing NREM parasomnic episodes and their representatives.

Drug groups	individual drugs
Benzodiazepine receptor agonists	zolpidem, zaleplon, zopiclone
tricyclic antidepressants	amitriptyline
selective serotonin reuptake inhibitors (SSRIs)	paroxetine, fluoxetine, sertraline
noradrenergic and specific serotonergic antidepressants (SNRIs)	mirtazapine
noradrenaline and dopamine reuptake inhibitor	bupropion
mood stabilizer	lithium
first-generation antipsychotics	chlorprothixene, thioridazine
second-generation antipsychotics	olanzapine, quetiapine, risperidone, aripiprazole
β-blockers	propranolol, metoprolol