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Home , Catathrenia, Hypnopompic, Parasomnia

REVIEW ARTICLE published: 12 December 2011 doi: 10.3389/fpsyt.2011.00071 and therapy: a review of the literature

Lara Kierlin1,2 and Michael R. Littner 1,2*

1 David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA, USA 2 Pulmonary, Critical Care and Medicine, VA Greater Los Angeles Healthcare System, Los Angeles, CA, USA

Edited by: There exists a varying level of evidence linking the use of antidepressant to Ruth Benca, University of the parasomnias, ranging from larger, more comprehensive studies in the area of REM Wisconsin – Madison School of Medicine, USA sleep behavior disorder to primarily case reports in the NREM parasomnias. As such, prac- Reviewed by: tice guidelines are lacking regarding specific direction to the clinician who may be faced Ruth Benca, University of with a patient who has developed a that appears to be temporally related to Wisconsin – Madison School of use of an antidepressant. In general, knowledge of the mechanisms of action of the med- Medicine, USA ications, particularly with regard to the impact on sleep architecture, can provide some David Plante, University of Wisconsin, USA guidance. There is a potential for selective serotonin reuptake inhibitors, tricyclic antide- *Correspondence: pressants, and serotonin–norepinephrine reuptake inhibitors to suppress REM, as well Michael R. Littner, 10736 Des Moines as the anticholinergic properties of the individual drugs to further disturb normal sleep Avenue, Porter Ranch, Los Angeles, architecture. CA 91326, USA. e-mail: [email protected] Keywords: parasomnias, REM sleep behavior disorder, non-REM parasomnias, selective serotonin reuptake inhibitors,

INTRODUCTION and night terrors (Ohayon et al., 1999; Yeh et al., 2009). Reports Parasomnias are a diagnostic grouping of sleep disorders that also link sleep-related (Winkelman et al., 1999) include abnormal sleep-related behaviors, , or autonomic to antidepressant use. This review will focus on the association changes that manifest during transitions from wakefulness to sleep, and proposed mechanisms of action of selective serotonin reup- or within transitions between sleep stages. Parasomnia suffer- take inhibitors (SSRIs), the serotonin–norepinephrine reuptake ers may complain of unwanted interruptions from sleep, inhibitors (SNRIs), the tricyclic (TCAs), and the to themselves, or to their partner during periods of motor norepinephrine– reuptake inhibitor bupropion to para- activation, and dysphoria relating to the burden of shoulder- somnias. Literature for this review was obtained via systematic ing these negative sequelae. The International Classification of search in PubMed for articles published on or before August 15, Sleep Disorders categorizes parasomnias into (1) disorders of 2010. The terms “antidepressants,”“parasomnias,”“SSRI,”“SNRI,” arousal from NREM (non-rapid eye movement) sleep – these “bupropion,” “REM behavior disorder,” “,” “somnam- include somnambulism, , and sleep terrors; bulism,” “confusional arousals,” “sleep terrors,” “,” (2) disorders of REM (rapid eye movement) sleep – these include “hypnagogic ,” and “ hallucinations” REM sleep behavior disorder (RBD), nightmares, and recur- were used. References from relevant articles, as well as from recent rent isolated sleep paralysis; and (3) other parasomnias – these reviews of the literature, were also assessed. include sleep-related , sleep , explod- The reader will also note that the specific effects of antidepres- ing head syndrome, or sleep groaning, hypnagogic or sants on the sleep-related movement disorders are not the focus of hypnopompic hallucinations, sleep-related eating disorders, and this parasomnia-centered review, although there is evidence that parasomnias due to drug, other substance, or medical condi- specific antidepressants may induce and/or tion (Table 1 – note not all of the parasomnias are discussed periodic limb movements of sleep. A review of the most recent in this article given limited existing literature; American Acad- literature on this topic is provided in the references (Hoque and emy of , 2005). Etiologies of the parasomnias vary Chesson, 2010). based upon diagnoses, although some research has suggested cor- relations between specific parasomnias and psychiatric disorders THE SSRIs (Ohayon et al., 1999; Winkelman et al., 1999). This relationship DEPRESSION AND SLEEP ARCHITECTURE becomes less clear with the realization that some of the med- Major depression has been studied by ,with doc- ications used to treat psychiatric disorders may themselves be umentation of decreased sleep continuity, prolonged linked to the onset of parasomnias. The literature supports an latency, increased wake time after sleep onset, decreased sleep association between antidepressant pharmacotherapy and certain efficiency, decreased total sleep time, early morning awakenings, parasomnias, with the greatest amount of data for RBD (Olson reductions in slow wave sleep,and REM sleep disturbances (Kupfer et al., 2000; Winkelman and James, 2004; Teman et al., 2009) et al., 1986; Benca et al., 1992). Reduced REM sleep onset latency, and with some data for NREM disorders such as somnambulism increased REM density, and prolonged time spent in first REM

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Table 1 | ICSD-II parasomnias. with other SSRIs, including paroxetine, sertraline, citalopram, and escitalopram (Geyer et al., 2009). Disorders of Arousal (From Non-) 1. Confusional arousals TCAs and SNRIs 2. The neurophysiologic effect of REM sleep suppression has been 3. Night terrors observed with TCAs (Kupfer and Spiker, 1982; Armitage, 1996). Parasomnias Usually Associated With REM Sleep TCAs (and SNRIs) act predominantly as serotonin and norepi- 1. REM sleep behavior disorder (including parasomnia overlap disorder and nephrine reuptake inhibitors. As serotonergic agents, they might status dissociatus) be expected to affect sleep similar to SSRIs. In addition, norepi- 2. Recurrent isolated sleep paralysis nephrine, originating from the locus ceruleus, has an inhibitory 3. disorder effect on pontine “REM-on” neurons (Semba, 1993). The TCAs, Other Parasomnias more so than the SNRIs, also have anticholinergic properties of 1. Sleep-related dissociative disorder varying degree and contribute to the reduction of REM sleep on 2. Sleep Enuresis this basis (possibly by reducing the effects of acetylcholine in the 3. Sleep-related groaning (catathrenia) basal forebrain during REM sleep). Acetylcholine potentiates REM 4. via activation of“REM-on”cells in the pontine tegmentum (Berger 5. Sleep-related hallucinations and Riemann, 1993). Further sleep-related effects of the TCAs 6. Sleep-related eating disorder occur through their antagonism at histamine receptors (primarily 7. Parasomnia, unspecified H1 and H2). Central histamine at H1 and H2 receptors is wake- 8. Parasomnia due to drug or substance promoting, and inactivation has been shown in animal models to 9. Parasomnia due to medical condition result in an increase in NREM sleep (Lin et al., 1988).

International classification of sleep disorders, 2nd edition. Bupropion Bupropion may reduce REM less than other antidepressants. sleep period have been described in depressed patients (Kupfer Bupropion prolongs REM sleep latency and increases REM density et al., 1981). Several hypotheses have been proposed, including a (a measure of the number of eye movements in the period) and relative deficiency in sleep homeostasis (sleep drive) with a shifting activity during the first REM sleep period (Ott et al., 2004). Oth- forward of the circadian cycle (Borbely and Wirz-Justice, 1982), ers have found an increase in overall REM sleep percentage with versus alterations in cholinergic, serotonergic, and noradrenergic bupropion (Nofzinger et al., 1995). Bupropion’s primary mecha- neurotransmission typically seen in subjects with mood disorders nism is thought to be via action as a dopamine reuptake inhibitor, (Thase, 1998). Further detailing of the causes of sleep changes in though it also acts as a norepinephrine receptor antagonist (Ascher mood disorders is beyond the scope of this review, but may be et al., 1995). Its lack of REM sleep suppression may be due to found elsewhere in the literature. absence of an effect on serotonin reuptake.

ANTIDEPRESSANTS AND SLEEP ARCHITECTURE SSRIs AND REM SLEEP-RELATED PARASOMNIAS Selective serotonin reuptake inhibitors Patients with depression frequently have disturbances in REM Serotonin neurons, originating from the dorsal raphe nucleus, sleep. SSRIs are known to suppress REM, but are regularly used project to the cholinergic laterodorsal and pedunculopontine to treat depression. Given these facts, it is not surprising that tegmental areas, inhibiting “REM-on” neurons and therefore, REM sleep-related events including parasomnias may occur in inhibiting REM sleep (McCarley and Hobson, 1975; McCarley depressed patients being treated with SSRIs. A recent cross- et al., 1995). In addition to their tendency to suppress REM sleep, sectional study published by Lam et al. (2008) found a higher SSRIs have also been implicated in sleep fragmentation (Sharp- percentage of RBD in subjects with depressive spectrum disor- ley and Cowen, 1995). Despite these effects on sleep architecture, ders who were taking SSRIs. The authors prospectively identified SSRI treatment of depression may result in an improvement of patients with parasomnias using a structured questionnaire, and sleep symptoms in many patients. Some practitioners opt to add then confirmed diagnoses via clinical interview and PSG for those the medication trazodone (which improves sleep efficiency and with recent active parasomnias. Of the 1235 subjects who com- decreases sleep onset latency) as a counter to some of the undesir- pleted diagnostic interview, 276 (22.3%) were positive for som- able sleep changes that may result from SSRI monotherapy (Van nambulism, sleep-related eating disorder, or sleep-related injury, Bemmel et al., 1992). Trazodone is a 5-HT2A receptor antagonist with the latter including REM-related parasomnia as primary that weakly inhibits the 5-HT2C receptor; its sedative proper- cause of injury (66.6% of the 70 subjects with sleep-related injury). ties may be due to its potent α1-adrenergic blockage (Asayesh, REM-related parasomnias included RBD, nightmares, and mixed 1986). Finally, a distinctive effect of the SSRI fluoxetine has been REM and NREM parasomnias. Sleep violence was correlated with described on the polysomnogram (PSG). The term “Prozac eyes” depressive spectrum disorder (78.3% of those with depressive has been used to describe eye movements occurring during all spectrum disorder) but no association was found with bipolar stages of NREM sleep (Armitage et al., 1995a), although the sig- or anxiety spectrum disorders. SSRI use was associated with vivid nificance of this alteration in the PSG is unknown. Of note, recall and loss of REM atonia on PSG in the psychiatric this effect is not exclusive to fluoxetine and has been reported population studied. Subjects taking SSRIs had increased risk of

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having an active RBD-like disorder (OR = 3.7, 95% CI = 1.6–8.7, disease, , and with Lewy Bodies, p < 0.05) and 5% of those subjects taking SSRIs reported symp- leaves open the possibility that psychiatric symptoms may pre- toms of RBD. Interestingly, the subjects in this study were younger dict a later neurologic disorder, an observation noted by Teman and included more females than are typically associated with et al. (2009). Temancites several studies that demonstrate the asso- the usual demographic for RBD, leading the authors to suggest ciation between depression and Parkinson’s disease (Lieberman, that psychotropic-related RBD may present in those without the 2006) as well as the correlation between RBD and later identifi- expected characteristics of old age, male predominance, or asso- cation of neurodegenerative disorders (Schenk et al., 1996, 2003; ciation with α-. Further, the authors posited that Olson et al., 2000; Boeve et al., 2003). Literature on antidepressants these psychiatric subjects may have been vulnerable to “recurrent and RBD are provided in Table 2. emotionally charged and aggressive dreams” and were perhaps Nightmares are a REM-related parasomnia for which a link more likely to enact RBD-like behaviors in the face of loss of REM to SSRIs has been studied (Table 3). Earlier research demon- atonia. Future studies may help clarify the relationship between strated a relationship between SSRI use and dreaming in general, drug-related RBD and typical RBD, including the mechanisms with some studies finding enhancement of dreams with citalo- underlying each. pram (Koponen et al., 1997) and fluoxetine (Markowitz, 1991; Other authors have found a link between SSRI use and the Armitage et al., 1995b; Lepkifker et al., 1995). Pace-Schott et al. development of RBD symptoms in subjects without known under- (2001) examined the dream effects of paroxetine and fluvoxam- lying neurodegenerative disease, though study designs differ, ine in 14 normal subjects who were randomized to one of the and case reports predominate over higher-level methodologies drugs during 19 days of a 31-day home-based study. While dream (Schenck et al., 1992; Winkelman and James, 2004). Teman et al. recall frequency was diminished during the treatment period, sub- (2009) performed a retrospective case–control chart review in jective report of dreams indicated increased intensity of dreams which 48 idiopathic RBD patients were divided into groups based during both treatment and acute discontinuation. The authors upon age of onset, then were compared to each other and to con- acknowledge that this effect seemed to run counter to the well- trols. Early onset RBD patients had significantly more psychiatric known effects of REM sleep suppression by SSRIs, and offer that diagnoses (OR = 17.0) and antidepressant use (OR = 12.0) than enhanced brain arousal may be associated with aminergic stim- did controls, while late-onset RBD sufferers had similar increase ulation. They cite a possible difference in processes involved in in psychiatric diagnoses without a significant increase in antide- dream initiation and the quality and/or maintenance of already- pressant use. There were more females in the early onset group. occurring dreams, pointing to research by Nofzinger et al. (1995) Similar to Lam et al. (2008) the authors suggested that there may which found an increase in phasic REM activity with fluoxetine be different clinical RBD profiles relative to psychiatric diagnoses, use. An alternative hypothesis by the authors is that late-night antidepressant use, and age. This may indicate that antidepressant cholinergic rebound after serotonergic REM sleep suppression contribute independently to RBD onset, particularly earlier in the night may result in greater dream intensity being in younger patients. As a result, the clinician who is presented with reported. The authors acknowledge that patient reports of wors- a case of RBD in a younger, female patient may be alerted to screen ened nightmares with SSRIs are difficult to study, given the for antidepressant medications as a possible etiology. In an earlier complex relationship of depression-related REM enhancement, study, Schenck et al. (1992) retrospectively reviewed 2650 PSG drug-related REM sleep suppression, depression-related dream reports to identify those treated with fluoxetine or TCAs, finding suppression, and recovery-related dream enhancement. Further in the data a case of fluoxetine-induced RBD that resolved when research is needed to elucidate the mechanisms governing these the medication was discontinued. In addition, there exists one interrelated systems. case report of the SSRI paroxetine associated with RBD at a 30-mg dose (Parish, 2007), though an earlier case series (Yamamoto et al., SSRIs AND REM-RELATED PARASOMNIAS: CLINICAL GUIDELINES 2006) found improvement in RBD symptoms from paroxetine in No formal clinical guidelines exist for the use of SSRIs in RBD, 16 out of 19 participants, with possible REM sleep suppression though there is mention of an adverse relationship in the Best effects as the causal mechanism cited. Practice Guide for the Treatment of RBD published by the Stan- In order to better clarify the relationship between RBD and anti- dards of Practice Committee of the AASM (Aurora et al., 2010a). depressant use, Winkelman and James (2004) performed a chart Data supporting SSRIs as a possible cause of secondary RBD is pre- review that compared clinical and PSG data of 15 subjects taking sented, though no guidance on treatment is provided. Paroxetine serotonergic antidepressants with 15 subjects in an age-matched in particular is mentioned, citing the inconclusive data indicat- control group without a depressive or that was ing its potential efficacy in the treatment of RBD. The authors not taking these medications. The antidepressant group exhibited state that there is little support for such use. A recent review increased tonic submental electromyogram (EMG) activity dur- (Hoque and Chesson,2010) of pharmacologically induced or exac- ing REM sleep compared to controls. The authors hypothesized an erbated RLS,PLMs,and RBD,however,did find strong evidence for effect of serotonin on motor systems at the spinal cord or brain- drug-induced RBD with the TCA clomipramine, the monoamine stem as a possible mechanism. As this study was retrospective and oxidase inhibitors (MAOIs) selegiline and phenelzine, and lower the control group patients did not have a depressive or anxiety levels of evidence for the SSRIs. The authors acknowledged that disorder, it is difficult to separate the effects of SSRIs from the clinicians might opt to modify treatment given the emergence of effects of such underlying disorders. For example, the relation- RBD with the use of certain medications, including switch to an ship of RBD with the , including Parkinson’s alternative medication or withdrawal of the medication if prudent.

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Table 2 | Antidepressants and parasomnia: RBD.

Parasomnia Antidepressant Reference Methods/design Findings medication(s)

RBD SSRIs/SNRI, fluoxetine, Winkelman and James Chart review, n = 15 on Antidepressant group had increase in tonic EMG paroxetine, citalopram, (2004) SSRIs, n = 15 controls, PSG during REM compared to controls sertraline, venlafaxine data included SSRIs, TCAs, Mixed Teman et al. (2009) Retrospective, case–control, Early onset RBD patients exhibited more psychi- Mechanism, bupropion chart review, 48 idiopathic atric diagnoses [OR = 17.0 (3.5–83.4)] and anti- RBD patients, compared depressant use [OR-12.0 (2.7–53.3)] than non- with controls RBD controls SSRIs, TCAs Olson et al. (2000) Retrospective chart review Lack of strong causal relationship between anti- of 93 consecutive patients depressants and RBD, however patient mean with RBD age of RBD onset = 60.9, 2 of 11 on antidepres- sants developed RBD with use of medication SSRIs Lam et al. (2008), Ott Prospective, cross-sectional SSRIs increased RBD risk [OR = 3.7 (95% et al. (2004) study, n = 1235 psychiatric CI = 1.6–8.7, p < 0.05)], younger patients, female outpatients; questionnaire, patients experienced more medication-related structured interview, PSG RBD SSRI – fluoxetine Schenck et al. (1992), Single case in retrospective Fluoxetine-induced RBD resolved with discon- Nofzinger et al. (1995) review of n = 2650 PSGs tinuation of medication SSRI – paroxetine Parish (2007), Lam et al. Case report Paroxetine 30 mg was associated with RBD-like (2008) symptoms SSRI – paroxetine Yamamoto et al. (2006), Case series; n = 19 Paroxetine improved RBD symptoms in 16/19 Schenck et al. (1992) studied SSRIs, TCAs, MAOIs Hoque and Chesson Review Higher-level of evidence for TCA- and MAOI- (2010), Markowitz (1991) related RBD than SSRIs

Table 3 | Antidepressants and parasomnia: nightmares.

Parasomnia Antidepressant Reference Methods/design Findings medication(s)

Nightmares Fluoxetine Lepkifker et al. (1995), Case series Four patients experienced nightmares on fluoxetine Schenk et al. (2003) monotherapy Nightmares Bupropion Balon (1996), Gaillard Case report 55-year-old female with nightmares following increase et al. (1994) in bupropion from 75 to 150 mg/day Dream Fluoxetine, Pace-Schott et al. (2001), 14 Normal subjects randomized Subjects reported increase in dream intensity during intensity paroxetine Armitage et al. (1995b) to fluoxetine or paroxetine SSRI phase Dream Citalopram Koponen et al. (1997), Open pilot study Dream enhancement in 6% of subjects enhancement Boeve et al. (2003)

Careful assessment of the risks and benefits of such a move should REM-RELATED PARASOMNIAS: OTHER ANTIDEPRESSANTS occur given the individualized experience of each patient. Most non-SSRI antidepressants have not been extensively Recently, the AASM standards of practice committee published researched for their role in the genesis of REM-related parasom- its Best Practice Guide for the Treatment of nias. As discussed earlier, those with aminergic properties, such in Adults (Aurora et al., 2010b). These recommendations indicate as the SNRIs, have been thought to behave similarly to SSRIs that non-SSRI medications such as trazodone, fluvoxamine, and due to their inhibitory effect on REM-on neurons in the pons. the TCAs “may be considered for treatment of PTSD-associated The reader is referred to Gaillard et al. (1994) for a further dis- nightmares, but the data are low grade and sparse.” Nefazodone is cussion of this mechanism. As discussed, the TCAs, which have also mentioned, but not recommended, due to potential for hepa- aminergic properties, have been implicated for their potential to totoxicity. The authors also cite research studying the effect of the induce RBD (Mahowald et al., 2007). Anticholinergic effects of SNRI venlafaxine on PTSD-related nightmares, noting no signif- the TCAs may be responsible for reduced cholinergic atonia in icant difference between the medication and placebo. As a result, REM sleep (Schenck et al., 1992). Research detailing the effects venlafaxine is not suggested for the treatment of PTSD-associated of specific SNRIs or bupropion on REM-related parasomnias, nightmares. however, is lacking. In the Teman et al. (2009) study discussed

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earlier, one of the early onset RBD subjects studied was tak- mentioned previously, sedative antidepressants were being used ing a combination of amitriptyline and paroxetine, and in three by 34.5% of the 29 psychiatric subjects who were diagnosed with others, bupropion was given in combination with another antide- somnambulism (p < 0.05). In their study, “sedative antidepres- pressant. None of the subjects in the late-onset RBD group was sants” included TCAs, trazodone, and the tetracyclic mianserin. taking bupropion. This data is obviously limited, however, and SSRIs, SNRIs, and noradrenergic and specific serotonergic antide- no conclusions about the medications and RBD can be made. pressants were also used in those with somnambulism,but without There is one case report of bupropion inducing nightmares, with statistical significance. The authors noted that while the TCAs cessation of the nightmares once the medication was discontin- in particular are not noted for alterations in NREM sleep, their ued (Balon, 1996). In total, though, there is not a preponder- antihistamine and anticholinergic effects might negatively impact ance of literature describing this phenomena in subjects using arousal. Though the topic is not within the scope of this arti- bupropion. cle, it can be briefly mentioned that Lam et al. (2008) also found increased sleepwalking in those using non- hyp- DEPRESSION AND NREM SLEEP PARASOMNIAS notics such as zolpidem and zopiclone, medications thought to The NREM parasomnias are disorders of arousal from NREM alter slow wave sleep and possibly leading to arousal disturbances sleep, with impaired sleep–wake transitions that can result in in NREM sleep due to this property. The literature regarding activation of physiologic systems. Somnambulism, confusional antidepressants and NREM sleep parasomnia is summarized in arousals, and sleep terrors may occur when the transition from Table 4. slow wave sleep to wakefulness is disrupted. Research has described In summary, the literature concerning NREM sleep parasom- several factors that may contribute to the development of a NREM nias and antidepressants is limited, with a number of case reports parasomnia, including genetic susceptibility, , sit- that do not as of yet demonstrate a compelling pattern link- uational , psychiatric conditions, medication, and substance ing the medications used to treat depression with these sleep use (Pressman, 2007). NREM sleep abnormalities have been stud- disorders. Some of the medications may, in fact, be helpful in ied in depressed subjects,with an early study by Buysse et al. (1997) the treatment of NREM parasomnias, though there are no large finding a shift in slow wave delta activity to the initial part of the randomized controlled studies to support this. NREM sleep para- sleep period in depressed subjects following treatment with inter- somnias may be related to the underlying psychiatric condition, personal psychotherapy. Subjects who experienced a recurrence of with depression having been studied for NREM abnormalities that depression exhibited less baseline slow wave activity compared to may predispose one to dysfunctional transitions between sleep those still in remission at 1 year follow-up. These findings suggest and wake, particularly in the early part of the sleep period. Future that depressed patients may themselves be predisposed to NREM investigations might utilize CAP analysis to better describe the sleep disturbance both pre- and mid-treatment Lopes et al. (2007). specific NREM abnormalities present in depressed subjects, and performed further research into the nature of NREM sleep distur- determine what pharmacologic interventions may target these bance in depressed subjects, using analysis of cyclic alternating abnormalities. pattern (CAP) as a measure of NREM variability. The PSGs of 15 subjects with major depressive disorder were compared to those ANTIDEPRESSANTS AND OTHER PARASOMNIAS of 20 controls. Researchers found depressives had greater distur- The third category of parasomnias, classified as “other parasom- bances in phase A1 of CAP, a period of NREM sleep that may nias,” includes sleep-related dissociative disorder, sleep enuresis, indicate an impending shift from NREM stage 2 to NREM stage 3 exploding head syndrome, catathrenia or sleep groaning, hypna- sleep. This study represents one of the first attempts to clarify the gogic or hypnopompic hallucinations, sleep-related eating disor- nature of specific NREM sleep disturbance in depressed subjects, ders, and parasomnias due to drug, other substance, or medical and may point to a relationship between somnambulism, which condition. Of these, sleep-related eating disorder may have a rela- tends to occur in the first third of the night during the great- tionship to depression in that depressives are frequently treated est period of slow wave sleep, and NREM sleep abnormalities in with non- such as zolpidem for , and depressives. these medications may result in an increase in complex sleep- related behaviors. Zolpidem has also been studied for its relation- ANTIDEPRESSANTS AND NREM PARASOMNIAS ship to somnambulism and sleep driving (Hoque and Chesson, There are numerous case reports linking specific antidepres- 2009). Hwang et al. (2010) studied 125 psychiatric outpatients sants to the various NREM sleep parasomnias, including reports taking hypnosedatives, and found that 15.2% reported complex of somnambulism with bupropion (Khazaal et al., 2003; Oulis sleep-related behaviors (including sleep-related eating). Of these, et al., 2010), the noradrenergic and specific serotonergic tetra- all were taking zolpidem, and there was a tendency toward younger cyclic mirtazapine (Yeh et al., 2009), paroxetine (Kawashima and age (p = 0.023), female gender (p = 0.011), and use of higher dose Yamada, 2003), and the norepinephrine reuptake inhibitor rebox- of zolpidem (>10 mg/day; p < 0.001). Sleep-related eating dis- etine (Künzel et al., 2004). In contrast, there is one case report order must be distinguished from nocturnal eating syndrome, a detailing the successful treatment of somnambulism and night disorder typified by a circadian delay in the timing of eating that terrors with paroxetine (Lillywhite et al., 1994), and an earlier can be effectively treated with the SSRI sertraline (Stunkard et al., report demonstrating efficacy from the tricyclic imipramine (in 2006). In sleep-related eating disorder, the patient may not be fully combination with diazepam) in the treatment of somnambulism awake during eating, and may have little or no recall for the event and night terrors (Cooper, 1987). In the Lam et al. (2008) study the next day.

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Table 4 | Antidepressants and NREM parasomnias.

Parasomnia Antidepressant Reference Methods/design Findings medication(s)

Somnambulism Mirtazapine Yeh et al. (2009) Case report 40-year-old female with new-onset somnambu- lism × three nights with increase in mirtazapine from 30 to 45 mg; somnambulism terminated with cessation of medication Somnambulism Bupropion Oulis et al. (2010), Case report 63-year-old female with somnambulism in con- Buysse et al. (1997) text of adjunctive bupropion for depression Somnambulism Bupropion Khazaal et al. (2003), Case report 33-year-old male using bupropion 150 mg BID Lopes et al. (2007) for smoking cessation; developed somnam- bulism and sleep-related eating with use – resolved with discontinuation Somnambulism Paroxetine Kawashima and Yamada Case report 61-year-old female with somnambulism onset (2003), Oulis et al. (2010) 1 week after initiation of paroxetine 20 mg; ceased with discontinuation Somnambulism Paroxetine Lillywhite et al. (1994), Case report 46-year-old female with somnambulism and night terrors Kawashima and Yamada night terrors successfully treated with paroxe- (2003) tine 40 mg Somnambulism Reboxetine (SNRI) Künzel et al. (2004), Case report 19-year-old female with depression and history Khazaal et al. (2003) of somnambulism in childhood had recurrence with use of reboxetine Somnambulism “Sedative Lam et al. (2008), Ott Prospective, cross-sectional Sedative antidepressants being used by antidepressants,” et al. (2004) study, n = 1235 psychiatric 34.5% of the 29 patients with somnambulism TCAs, trazodone, outpatients; questionnaire, (p < 0.05) tetracyclic, mianserin structured interview, PSG

Table 5 | Antidepressants and other parasomnias.

Parasomnia Antidepressant Reference Methods/design Findings medication(s)

Sleep-related Unknown Winkelman et al. (1999) n = 207 depressed subjects in 3.4% of depressed subjects reported symp- eating disorder antidepressant trial were toms of sleep-related eating disorder, thought administered. The inventory of to be higher prevalence than that in general nocturnal eating population Hypnagogic/ Unknown Ohayon et al. (1996), n = 4972 U.K. community sample Increase in hypnopompic hallucinations in sub- hypnopompic Hwang et al. (2010) interviewed by telephone about jects taking antidepressants [OR = 1.4 (95% CI hallucinations sleep disturbances 1–1.9)]

Hypnagogic or hypnopompic hallucinations occur at sleep 1.1–1.8, OR 1.52, 95% CI 1.2–1.8). Of note, the onset or awakening and may be associated with psychiatric authors failed to find an association between the presence of disorders. In research by Ohayon et al. (1996) these phenom- these hallucinations and the use of any psychotropic medica- ena were found to occur more frequently than predicted by the tions in the subjects reporting hypnagogic hallucinations, but use prevalence of , a diagnosis with which hypnagogic of sleep-inducing, anxiolytic, or antidepressant medication did and hypnopompic hallucinations are associated. A community predict an increase in hypnopompic hallucinations (OR = 1.4, sample of 4972 subjects underwent a telephone interview that 95% CI 1.0–1.9). However, as the specific medications used are involved demographic questioning as well as diagnostic analy- not reported in the article, it is difficult to reach meaningful sis of sleep disorders. The subjects were also asked about sleep conclusions regarding antidepressant use and sleep-related hal- habits as well as the presence of psychiatric disorders and the lucinations. Careful diagnosis is essential, as hallucinations may symptoms associated with them. Subjects with anxiety disor- be related to RBD, narcolepsy, or other neurologic or psychi- ders and depression reported a statistically significant higher atric disorder, any of which may have their own propensity to rate of sleep-related hallucinations (hypnagogic: anxiety disor- emerge in the presence of various medications. The literature der OR = 1.4, 95% CI 1.3–1.8; mood disorder OR 1.52, 95% regarding antidepressants and other parasomnias is summarized CI 1.2–1.8 and hypnopompic: anxiety disorder OR 1.4, 95% CI in Table 5.

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CONCLUSION TCAs, and SNRIs to suppress REM, as well as the anticholinergic There exists a varying level of evidence linking the use of anti- properties of the individual drugs to further disturb normal sleep depressant medication to the parasomnias, ranging from larger, architecture. more comprehensive studies in the area of RBD to primarily New research may suggest patterns of NREM disturbances case reports in the NREM parasomnias. As such, practice guide- associated with depression and the medications used to treat lines are lacking regarding specific direction to the clinician who depression. These abnormalities may result in a disturbance of may be faced with a patient who has developed a parasomnia the stability of NREM sleep that may predispose to one or more that appears to be temporally related to use of an antidepres- parasomnias. Understanding the mechanisms that govern the sant. In general, knowledge of the mechanisms of action of the action of these medications, as well as the pathogenesis of depres- medications, particularly with regard to the impact on sleep archi- sion itself, will provide further guidance into the relationship of tecture, can provide some guidance. There is a potential for SSRIs, antidepressant use and the parasomnias.

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