Sleep Disturbances

19


Sleep Disturbances


Hypersomnia and Sleep Attacks


General Recommendations


Sleep attacks may occur, although rarely, with several psychotropic agents, most notably certain dopamine agonists (e.g., pramipexole, ropinirole) and MAOIs. Antihistaminergic psychotropic drugs often cause insomnia at treatment initiation, which may or may not diminish with continued use. Consideration should be given to the role of sleep studies to assess excessive daytime sleepiness, particularly if noniatrogenic etiologies (e.g., sleep apnea, narcolepsy) are suspected. Adjunctive stimulants, or wakefulness-promoting agents such as modafinil or armodafinil, may be of value to counteract excessive daytime somnolence or suspected sleep attacks. Persistent symptoms that disrupt or imperil normal daytime functioning may require drug cessation.



Sleep attacks may involve sleep-onset REM periods and may be a manifestation of narcolepsy when accompanied by sleep paralysis upon falling asleep or waking, cataplexy, and hypnagogic hallucinations. Narcolepsy per se affects about 0.02% of the population, usually first arising in adolescence or young adulthood. DQB1*06:02 genotyping is a sensitive but not specific laboratory test to gauge the likelihood of narcolepsy when it is clinically suspected, with the DQB1*06:02 genotype being present in 90% or more of the individuals who manifest both sudden sleep attacks plus cataplexy (but in fewer than half of those with sleep attacks alone).


A limited number of psychotropic drugs have been reported to cause sleep attacks, which may include falling asleep while driving. The most well known among these drugs are dopamine agonists (e.g., pramipexole and ropinirole) when used in patients with Parkinson’s disease, producing an approximate 5-fold increased risk for somnolence as compared with placebo across several randomized trials. It is unknown whether this risk similarly pertains to other patient groups (e.g., those with restless legs syndrome or bipolar depression) who may take these medicines. (Notably, patients with restless legs syndrome typically have intrinsic sleep architecture disturbances that neither pramipexole nor ropinirole directly alters, either beneficially or adversely, apart from improving nighttime sleep quantity and adequacy.) In a retrospective review of patients with Parkinson’s disease who took dopamine agonists, sleep attacks were identified in 6.6% of patients without significant differences across agents (Homann et al. 2002). It is unknown whether dosage reductions can ameliorate sleep attack events; therefore, caution favors the discontinuation of such agents if sleep attacks cannot otherwise be explained, with caution against driving until sleep attacks fully resolve.


Case reports exist of excessive daytime sleepiness with MAOIs. Traditional psychostimulants such as amphetamine or methylphenidate pose sympathomimetic risks that complicate their use to counteract MAOI-related sedation, although case reports do describe the safe use of carefully monitored amphetamine plus MAOIs without consequent hypertension or hyperthermia. Alternatively, the wakefulness-promoting agent modafinil (or its enantiomer, armodafinil) lacks pressor effects and thus may be more compatible with MAOI treatment.


Modafinil or armodafinil have been used broadly in “off label” fashion to counteract excessive daytime sedation caused by other psychotropic drugs, including FGAs, SGAs, and SSRIs. In the case of clozapine-induced sedation, it is noteworthy that one small (N=35) double-blind, placebo-controlled trial failed to demonstrate an advantage for modafinil (up to 300 mg/day) in improving wakefulness/fatigue (Freudenreich et al. 2009). Additionally, modafinil has been reported to increase serum clozapine levels, potentially via its inhibition of CYP2C19, with resultant decreased metabolic clearance of clozapine, leading to paradoxical worsening of sedation, dizziness, and gait unsteadiness (Dequardo 2002).


If amphetamine or methylphenidate is prescribed, in general, clinicians should bear in mind that cessation can sometimes trigger rebound increases in non-REM sleep, which in turn may increase daytime fatigue and somnolence.



Insomnia


General Recommendations


Insomnia, whether arising as a symptom of a psychiatric disorder or as a condition by itself, can be difficult to treat. The clinician must rule out other contributing medical causes (e.g., obstructive sleep apnea, restless legs syndrome, pain, substance withdrawal) or psychiatric etiologies (e.g., mania, depression). Initial conservative approaches for managing simple insomnia caused by psychotropic drugs involve modifying drug dosing schedules and assuring sleep hygiene. Iatrogenic insomnia is often transient but may warrant treatment with sedative-hypnotics or other soporific agents; its persistence, particularly after resolution of other psychiatric symptoms being treated, may signal the presence of an independent sleep disorder that merits independent evaluation.



Insomnia is among the most common phenomena whose etiologies can be difficult to discriminate among iatrogenic or illness-related causes. In the case of depression, for example, initial, middle, or terminal insomnia may be a target symptom of a depressive episode, a treatment-emergent adverse effect, or both. In the treatment of patients with bipolar mania, experts emphasize the importance of differentiating a loss of the need to sleep from difficulty falling or staying asleep with consequent fatigue the following day. A complaint of insomnia must be assessed as the possible manifestation of a more fundamental psychiatric or medical problem, for which proper remediation requires more effective treatment of the underlying cause.


DSM-5 has eliminated the formal distinction between primary and secondary insomnia but does identify “insomnia disorder” as a condition involving trouble falling or staying asleep at least three nights per week for at least 3 months, which must not simply result from the physiological effects of a substance or medication (American Psychiatric Association 2013). Drug-induced insomnia may occur from a wide range of catecholaminergic, indoleaminergic, and sympathomimetic agents that are alerting or stimulating. The degree to which some psychiatric medicines may cause either insomnia or hypersomnia is often unpredictable. For example, package insert descriptions from FDA registration trials of paroxetine for major depression report insomnia as occurring in 13% of patients but somnolence in 23% of patients. Insomnia rates may also vary substantially with the same agent across different disorders; for example, higher rates of insomnia were seen in FDA trials of fluoxetine for bulimia (33%) or obsessive-compulsive disorder (28%) than for major depression (16%). In the case of sertraline, insomnia rates were highest in obsessive-compulsive disorder (28%) and lowest in major depression (16%).


Depression increases sleep latency, increases waking after sleep onset, decreases REM latency but increases REM density and duration, increases early morning awakenings, decreases stages 3 and 4 (slow-wave) sleep, and shifts REM sleep to earlier in the night. The effects of antidepressants and other psychotropics on sleep architecture vary, as summarized in Tables 19–1 through 19–3. The clinician should be aware of the ways in which the drugs may disrupt sleep latency or continuity, while bearing in mind the effects of depression itself on these sleep parameters. Antihistaminergic drugs generally increase sleep continuity and may have variable effects on other elements of sleep architecture. Anticholinergic drugs as well as many serotonergic, noradrenergic, and dopaminergic binding agents generally suppress REM sleep and increase REM latency. Postsynaptic serotonin type 2A (5-HT2A) antagonists (e.g., SGAs) typically increase sleep continuity and increase slow-wave sleep.


Decreases in slow-wave sleep can interfere with patients’ feeling rested after waking from sleep. Conflicting data exist on the extent to which disruption of REM sleep may interfere with memory consolidation, as had once been more widely assumed. Most antidepressants (with the notable exceptions of bupropion, mirtazapine, and nefazodone) markedly suppress REM in dose-related fashion (presumably via 5-HT1A stimulation) and yet do not adversely affect learning and memory; paradoxically, SSRI- or SNRI-induced REM suppression may even improve verbal memory (Rasch et al. 2008). Antidepressant cessation initially leads to decreased REM latency and increases the percentage of time spent in REM sleep.


Minimal research has specifically examined strategies to counteract iatrogenic sleep disturbances caused by psychotropic medications, as opposed to adjunctive medications to selectively target poor sleep quality as part of the syndrome of depression. Most pharmacotherapy antidotes to iatrogenic insomnia have been extrapolated from use in primary sleep disorders. Perhaps the most obvious interventions when a medication appears to cause insomnia include altering its dosing schedule (e.g., morning instead of evening administration), determining whether any concomitant medications might better account for iatrogenic insomnia, eliminating other factors that may disrupt sleep (e.g., alcohol or caffeine intake), and assuring normal sleep hygiene. To the extent that some SSRIs such as fluoxetine have been shown to cause significant periodic limb movement disorders during sleep, adjunctive sedative-hypnotics that also diminish restless legs (e.g., clonazepam) may be particularly effective as sleep aids. Moreover, depressed patients who begin fluoxetine treatment with adjunctive clonazepam develop less treatment-emergent insomnia and anxiety than do those taking fluoxetine alone (Londborg et al. 2000).






























































































TABLE 19–1.Known effects of antidepressants and anxiolytics on sleep architecture


Agent


REM


REM latency


Slow-wave sleep


Sleep continuity


Benzodiazepines


Suppress


Decrease


Decrease


Increase


Bupropion


Increases


Decreases


No effect


No effect or may impair


Buspirone


No effect


No effect


No effect


No effect


MAOIs


Suppress (virtually abolish)


Increase


No effect


No effect or may impair


Mirtazapine


No suppression or increase


No effect


No effect or may increase


Improves


Nefazodone


Increases


Decreases


No effect


Improves


SNRIs


Decrease


Increase


No effect or may decrease


Impair


SSRIs


Suppress


Increase


No effect or may decrease


No effect or may impair


TCAs


Suppress


Increase


No effect or may increase


No effect or may improve


Trazodone


No effect or may suppress


Increases


No effect or may increase


Improves


Vilazodone


Suppresses


Increases


Increases


Not reported


Vortioxetine


Suppresses


Increases


No effect


May impair


Note. MAOI=monoamine oxidase inhibitor; REM=rapid eye movement; SNRI=serotonin-norepinephrine reuptake inhibitor; SSRI=selective serotonin reuptake inhibitor; TCA=tricyclic antidepressant.




































































































TABLE 19–2.Known effects of antipsychotics on sleep architecturea


Agent


REM


REM latency


Slow-wave sleep


Sleep continuity


Aripiprazole


Not reported


Not reported


Not reported


Not reported


Asenapine


Not reported


Not reported


Not reported


Not reported


Brexpiprazole


No effect


No effect


Decreasesb


Improves


Cariprazine


Not reported


Not reported


Not reported


Not reported


Clozapine


No effect or suppresses


No effect or increases


No effect or decreases


Improves


Iloperidone


Not reported


Not reported


Not reported


Not reported


Lurasidone


Suppresses


Not reported


Increases


Not reported


Olanzapine


Can either increase or suppress


No effect or increases


No effect or increases


Improves


Paliperidone


Increases


No effect


No effect


Improves


Pimavanserin


Not reported


Not reported


Increases


Improves


Quetiapine


No effect or suppresses


No effect or increases


Increases


Improves


Risperidone


No effect or suppresses


No effect


No effect or increases


Improves


Ziprasidone


Can either increase or suppress


No effect or increases


Increases


Improves


Note. REM=rapid eye movement.


aBased on manufacturers’ product information as well as Monti et al. (2017). Effects on sleep architecture may vary across patients versus healthy control subjects.


bBrexpiprazole diminishes duration of slow-wave sleep but improves latency to slow-wave sleep (Krystal et al. 2016).


























































TABLE 19–3.Known effects of anticonvulsants and lithium on sleep architecture


Agent


REM


REM latency


Slow-wave sleep


Sleep continuity


Carbamazepine


Suppresses


Increases


Increases


Increases


Divalproex


Suppresses


Not reported


Increases


Increases


Gabapentin


Increases


Not reported


Increases


Increases


Lamotrigine


Increases


No known effect


Decreases


No known effect


Lithium


Suppresses


Increases


Increases


Increases


Topiramate


Not reported


Not reported


Not reported


Not reported


Note. REM=rapid eye movement.



Table 19–4 summarizes information on the use and sleep architectural effects of agents that are commonly used to counteract simple insomnia. Often, clinicians find themselves choosing between benzodiazepines and nonbenzodiazepine soporific drugs to counteract insomnia. Nonbenzodiazepine sleep aids increase total sleep time while disrupting sleep architecture less extensively than benzodiazepines. They also generally carry less abuse potential, less often cause rebound insomnia or withdrawal upon cessation, and are often less likely to cause the types of cognitive problems (e.g., retrograde memory impairment) associated with benzodiazepines.


The treatment of apparent iatrogenic insomnia first requires a differential diagnostic assessment. For example, individuals with bipolar disorder who have trouble sleeping require assessment of other possible signs of mania or hypomania, and the use of sedating antidepressants as sleep aids (e.g., trazodone, mirtazapine, TCAs) would be less desirable than nonantidepressant sedative-hypnotics (e.g., benzodiazepines or benzodiazepine agonists) while optimizing patients’ fundamental antimanic regimen. Individuals with sleep problems caused by restless legs syndrome may benefit more from a dopamine agonist (e.g., pramipexole, ropinirole) than a dopamine antagonist (e.g., quetiapine). Individuals with sleep apnea likely would be better served by a continuous positive airway pressure (CPAP) device and possible use of modafinil, armodafinil, or sodium oxybate.


Insomnia that results from nonsedating antidepressants (e.g., SSRIs, SNRIs, bupropion) is often an initial, transient phenomenon. Morning rather than evening dosing may help to minimize the potential for interference with normal sleep. Some reports suggest that independent treatment of antidepressant-induced insomnia with a hypnotic agent (e.g., adjunctive benzodiazepine at night) yields better overall outcomes than when antidepressant-associated insomnia receives no independent treatment.


A fundamental issue in choosing from among sedative-hypnotics involves the relative advantages or disadvantages of using a benzodiazepine versus a nonbenzodiazepine. With benzodiazepines, the patient incurs greater potential disruption to sleep architecture, a potential for rebound insomnia and withdrawal, the possibility for developing dependence and tolerance over time, the potential for abuse, a risk for respiratory suppression (particularly among individuals with underlying pulmonary disease), and the risk for daytime cognitive impairment and retrograde memory impairment; nonbenzodiazepine sedatives, such as zolpidem, zaleplon, ramelteon, and eszopiclone, carry relatively lesser risks in these domains (Wagner and Wagner 2000).




















































TABLE 19–4.Pharmacological strategies for psychotropic-induced insomnia


Agent


Comments


Benzodiazepines


Promotes more time in light sleep (stage 2), reduction in slow-wave sleep and REM; potential for tolerance, abuse, and rebound insomnia after cessation


Chloral hydrate


Decreases sleep latency


Eszopiclone


Does not alter slow-wave sleep or REM


Gabapentin


Increases slow-wave sleep


Melatonin


Causes minimal disruption of sleep architecture


Mirtazapine


Decreases sleep latency; increases total sleep time and sleep efficiency; increases time spent in stage 2 sleep, REM sleep, and slow-wave sleep (Schittecatte et al. 2002; Winokur et al. 2000)


Ramelteon


Increases REM and slow-wave sleep; ~10-fold higher binding affinity to M1 and M2 melatonin receptors than melatonin itself


Suvorexant


Plasma half-life ~12 hours; increases REM> non-REM sleep


Tasimelteon


Plasma half-life ~1.3 hours; improves sleep latency and sleep efficiency and reduces awakenings after sleep onset


Trazodone


Decreases sleep stages 1 and 2, increases slow-wave sleep, has little effect on REM sleep; few efficacy studies focusing on insomnia, although some suggestion of a lesser reduction in sleep latency than zolpidem for primary insomnia; no known studies on use in counteracting psychotropic-induced insomnia


Zaleplon


Plasma half-life ~1 hour; better for sleep initiation than maintenance


Zolpidem


Preserves slow-wave sleep


Note. REM=rapid eye movement.



In 2014, the FDA approved suvorexant, a dual orexin receptor antagonist (DORA), for the treatment of initial or middle insomnia dosed at 10, 15, or 20 mg at bedtime. Although not yet formally studied specifically to counteract insomnia caused by psychotropic medications, suvorexant represents a promising alternative to traditional (GABAergic or antihistaminergic) sedative-hypnotics. It is contraindicated in people with narcolepsy because of their preexisting low levels of CNS orexin. Although not known to cause physical dependence, tolerance, or withdrawal, suvorexant is a Schedule IV drug—a decision made by the FDA based mainly on its “likability” among individuals with substance use disorders and consequent potential for abuse.


Nightmares and Vivid Dreams


General Recommendations


Nightmares and vivid dreams may occur at any point during treatment with a variety of antidepressants and other psychotropic drugs. It is unknown whether the phenomenon may be dose related, and presumptive mechanisms are not well understood. Abnormal dreams are medically benign, but if they create substantial distress, then a causal agent may need to be stopped if dosage reductions alone prove ineffective.



Vivid dreams have been reported as a relatively uncommon, medically benign adverse effect associated with dopaminergic agents (including bupropion and antiparkinsonian drugs) and with many serotonergic or serotonergic-noradrenergic antidepressants. Other psychotropic drugs with which vivid or abnormal dreams have been identified as possible adverse effects include lamotrigine, gabapentin, quetiapine (2% incidence in FDA registration trials), and lurasidone (<1% incidence in FDA registration trials).


Serotonergic agents have been shown to suppress REM sleep in a dose-related fashion and, correspondingly, would be expected to diminish (or disrupt) dream activity. Over time, tolerance to antidepressant-associated REM suppression may account for the development of vivid dreams as treatment progresses. Some authors have suggested that 5-HT2 receptor agonism may also lead to vivid dreams or nightmares and noted the potential value of 5-HT2 antagonists (e.g., trazodone, mirtazapine, SGAs, or cyproheptadine) to counteract nightmares. On the basis of extrapolations from the literature on nightmares associated with posttraumatic stress disorder (PTSD), α2-adrenergic agonists such as guanfacine (0.5–1 mg at bedtime) or clonidine (0.1–0.3 mg at bedtime), or the α1-blocking agent prazosin (dosed from 1–4 mg at night, or potentially as high as 10 mg/day as studied in PTSD-related nightmares among combat veterans [Raskind et al. 2003]), may help to diminish nightmares by providing a soporific effect at bedtime as well as by reducing noradrenergic hyperactivity. Blood pressure monitoring by the prescriber is advisable to assure the absence of clinically meaningful hypotension.


Of note, when prescribing prazosin, the clinician must be aware of the potential for orthostatic syncope to occur after an initial first dose. Hence, the recommendation is to begin no higher than 1 mg/night for the first few days, with a subsequent increase to 2 mg/day for several days if necessary; dosing may then be increased to 4 mg/day for 1 week if improvement does not occur, followed by an increase to 6 mg/day after 1 week if necessary. Additional dosage increases (by 2 mg/week) have been described such that 2–4 mg are administered in the afternoon followed by up to 6 mg at bedtime (Raskind et al. 2003). Furthermore, the clinician must be cautious not to abruptly discontinue prazosin or other α1-blockers (typically, they are tapered off over days to weeks), in order to minimize the potential for rebound hypertension; patients should be counseled about this potential risk if doses are missed.


Other medications that have been described by the Standards of Practice Committee of the American Academy of Sleep Medicine as generally having potential value for the treatment of nightmares include topiramate, low-dose cortisol, fluvoxamine, triazolam and nitrazepam, phenelzine, gabapentin, and TCAs; notably, venlafaxine is considered inadvisable for the treatment of PTSD-associated nightmares (Aurora et al. 2010). Each of these agents would involve extrapolation to use for the treatment of iatrogenic nightmares.


Parasomnias


General Recommendations


Some antidepressants and nonbenzodiazepine hypnotics (e.g., zolpidem, zopiclone, eszopiclone) carry an increased risk for abnormal REM and non-REM sleep behavior disorders (notably, sleepwalking, sleep-driving, and sleep-related eating disorders). Suspected causal agents should be stopped in patients who report such events.




Parasomnias comprise a series of sleep disorders that occur during transitions from wakefulness and REM or non-REM sleep. REM parasomnias (often also referred to as REM sleep behavior disorders) involve loss of muscle atonia (i.e., loss of paralysis normally associated with REM sleep) that can manifest as the acting out of dreams through uncoordinated movements (e.g., kicking or punching). Non-REM parasomnias occur during slow-wave sleep and involve intact muscle tone, leading to bruxism, restless legs syndrome, and more complex behaviors such as sleepwalking, sleep-related eating disorders, sleep-driving, sexual activity, or conversations. After waking, patients usually are amnestic for parasomnic events. Although parasomnias are not in themselves thought to represent psychopathology, epidemiological studies suggest that they may be more common among people with major depression (but not primary psychotic disorders or bipolar illness) (Lam et al. 2008). Iatrogenic parasomnias most often result from antidepressants or nonbenzodiazepine hypnotics. Antidepressants (notably, fluoxetine, venlafaxine, and TCAs) have been known to induce or worsen preexisting REM sleep behavior disorders (Schenck and Mahowald 2002). Although incidence rates with specific nonbenzodiazepines are not available, manufacturers’ product information for zolpidem and eszopiclone warn of the potential for complex hazardous behaviors such as sleep-driving and advise drug discontinuation if patients report such experiences.


A review of parasomnias among 1,235 psychiatric outpatients found that parasomnias among SSRI recipients typically were associated with sleep-related eating disorders and REM sleep behavior disorders, whereas sedating antidepressants (e.g., TCAs, trazodone) more often involved sleepwalking and sleep-related eating disorders (Lam et al. 2008). Among nonbenzodiazepine hypnotics, zolpidem was linked with both sleepwalking and sleep-related eating disorders, whereas zopiclone led only to sleepwalking. Parasomnia risk was higher among regular versus intermittent nonbenzodiazepine hypnotic users. Complex sleep behaviors associated with zolpidem appear to be linked to doses exceeding the manufacturer’s maximum (Hwang et al. 2010). Coadministration of benzodiazepine agonists with alcohol or other CNS depressants may also increase the risk for REM sleep behavior disorders. FDA registration trials of suvorexant for treatment of insomnia reported no cases of complex sleep behaviors. Interestingly, antipsychotics may be negatively associated with some parasomnias. Benzodiazepines and mood stabilizers have not been reported to cause parasomnias.

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Sep 1, 2019 | Posted by in PSYCHOLOGY | Comments Off on Sleep Disturbances
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