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Cases That Test Your Skills

A veteran who is suicidal while sleeping Piyush Das, MD, and Taru Dutt, MBBS

Mr. R, age 28, is a veteran with major depressive disorder and How would you PTSD. One night while asleep, he puts an unloaded gun in his handle this case? mouth and pulls the trigger. What could be causing this behavior? Answer the challenge questions throughout this article

CASE Suicidal while asleep The authors’ observations Mr. R, age 28, an Iraq and Afghanistan veteran are -wake transition with major depressive disorder and posttrau­ disorders classified by the sleep stage matic disorder (PTSD), is awoken by his from which they arise, either NREM or wife to check on their daughter approximately rapid eye movement (REM). NREM para- 30 minutes after he takes his nightly regimen of somnias could result from incomplete , 10 mg, , 6 mg, and hydroxy­ awakening from NREM sleep, typically zine, 20 mg. When Mr. R returns to the ­ in Stage N3 (slow-wave) sleep.1 DSM-5 room, he appears to be confused. Mr. R grabs describes NREM parasomnias as an unloaded gun from under the mattress, disorders in which the disturbance is not puts it in his mouth, and pulls the trigger. Then attributable to the physiological effects of Mr. R holds the gun to his head and pulls the substance; substance/-induced trigger while saying that his wife and children , type, is when will be better off without him. His wife takes the disturbance can be attributed to a sub- the gun away, but he grabs another gun from stance.2 The latter also can occur during his gun box and loads it. His wife convinces him REM sleep. to remove the ammunition; however, Mr. R gets NREM parasomnias are characterized the other unloaded gun and pulls the trigger by abnormal behaviors during sleep with on himself again. After his wife takes this gun significant harm potential.3 Somnambulism away, he tries cutting himself with a pocket­ or and sleep terrors are the knife, causing superficial cuts. Eventually, 2 types of NREM parasomnias in DSM-5. Mr. R goes back to bed. He does not remember Sleepwalking could involve complex behav- these events in the morning. iors, including: • eating What could have caused Mr. R’s nighttime • talking suicidal behavior? Dr. Das is Staff Psychiatrist and Somnologist, VA Medical Center, a) severe with suicidal ideations Grand Island, Nebraska, and Assistant Clinical Professor of b) , Creighton University School of Medicine, Omaha, Nebraska. Dr. Dutt is Research Fellow, Department of Neurology, c) non -rapid eye movement (NREM) sleep Mayo Clinic College of Medicine, Rochester, Minnesota. arousal disorder/NREM parasomnia Disclosures The authors report no financial relationships with any company d) substance/medication -induced sleep whose products are mentioned in this article or with manufacturers Current Psychiatry disorder, parasomnia type of competing products. Vol. 16, No. 4 43 Cases That Test Your Skills

• cooking initial 20 mg.9 Because the patient remem- • shopping bered the suicidal thoughts, the authors • driving believed that the patient attempted suicide • sexual activity. while under the influence of zolpidem. The Zolpidem, a receptor authors did not believe the incident to be agonist, is a preferred agent for sleep-related suicidal behavior, because it because of its low risk for abuse was uncertain if he attempted suicide while and daytime sedation.4 However, the asleep. has been associated with NREM parasom- Mr. R does not remember the events nias, namely somnambulism or sleepwalk- his wife witnessed while he was asleep. ing, and its variants including sleep-driving, To our knowledge, Mr. R’s case is the first sleep-related , and rarely sleep-related pseudo-suicidal behavior case Clinical Point sexsomnia (sleep-sex), with anterograde resulting from zolpidem, 10 mg/d, with- for the event.5 Suicidal behavior out concurrent use in an adult male Zolpidem is preferred that occurs while the patient is asleep with veteran with PTSD and no suicidal ideation for insomnia because next-day amnesia is another variant of som- while awake. of its low risk for nambulism. There are several reports of abuse and daytime suicidal behavior during sleep,6,7 but to our HISTORY sedation; however, knowledge, there are only 2 previous cases Further details revealed implicating zolpidem as the cause: Mr. R says that in the days leading to the it is associated with • Gibson et al8 described a 49-year-old incident he was not sleep-deprived and was NREM parasomnias man who sustained a self-inflicted gunshot getting at least 6 hours of restful sleep every to his head while asleep. He just had night. He had been taking zolpidem every started taking zolpidem, and in the weeks night. He has no childhood or family history of before the incident he had several episodes NREM parasomnias. He says he did not engage of sleepwalking and sleep-eating. He had in intense exercise that evening or have a fever consumed alcohol the night of the self- the night of the incident and has abstained inflicted gunshot wound, but had no other from alcohol for 2 years. psychiatric history. His wife says that after he took zolpidem, • Chopra et al4 described a 37-year-old when he was woken up, “He was not there; man, with no prior episodes of sleepwalk- his eyes were glazed and glossy, and it’s like ing or associated complex behaviors, who he was in another world,” and his speech and was taking zolpidem, 10 mg/d, for chronic behavior were bizarre. She also reports that insomnia. He shot a gun in the basement of his eyes were open when he engaged in this his home, and then held the loaded gun to behavior that appeared suicidal. his neck while asleep. The authors attrib- Three months before the incident, Mr. R had uted the event to zolpidem in combination reported with enactment with other predisposing factors, including behaviors, hypervigilance on awakening and dehydration after intense exercise and alco- during the daytime, irritability, and anxious and hol use. The authors categorized this type of depressed mood with neurovegetative symp­ Discuss this article at event as “para-suicidal amnestic behavior,” toms, and was referred to our clinic for medica­ www.facebook.com/ although “sleep-related pseudo-suicidal tion management. He also reported no prior or CurrentPsychiatry behavior” might be a better term for this current manic or psychotic symptoms, denied type of parasomnia because of its occurrence suicidal thoughts, and had no history of suicide during sleep and non-deliberate nature. attempts. Mr. R’s medication regimen included In another case report, a 27-year-old man tramadol, 400 mg/d, for chronic knee pain; took additional zolpidem after he did not fluoxetine, 60 mg/d, for depression and PTSD; Current Psychiatry 44 April 2017 experience desired effects from an and propranolol ER, 60 mg/d, and propranolol, Cases That Test Your Skills

10 mg/d as needed, for . He was started sleep-related suicidal behavior related to on prazosin, 2 mg/d, titrated to 4 mg/d, for zolpidem, 10 mg at , concomitant medication management of nightmares. dehydration and alcohol use were impli- Mr. R also was referred to the sleep labora­ cated as facilitating factors. Dehydration tory for a polysomnogram (PSG) because of could increase serum levels of zolpidem reported loud and witnessed apneas, resulting in greater CNS effects. Alcohol especially because can cause use was implicated in the Gibson et al8 nightmares and dream enactment behav­ case report as well, and the patient had iors. The PSG was negative for sleep apnea or multiple episodes of sleepwalking and excessive periodic limb movements of sleep, sleep-related eating. However, Mr. R was but showed increased electromyographic not dehydrated or using alcohol. (EMG) activity during REM sleep, which was An interesting feature of Mr. R’s consistent with his report of dream enactment case is that he was taking fluoxetine. Clinical Point behaviors. Two months later, he reported Cytochrome P450 (CYP) 3A4 is involved improvement in nightmares and depres­ in metabolizing zolpidem, and norfluox- Gabapentin, which sion, but not in dream enactment behaviors. etine, a metabolite of fluoxetine, inhib- is known to increase Because of prominent anxiety and irritabil­ its CYP3A4. Although studies have not the depth of sleep, ity, he was started on gabapentin, 300 mg, 3 found pharmacokinetic interactions was added to Mr. R’s times a day. between fluoxetine and zolpidem, these regimen a month studies did not investigate fluoxetine before the event What increased the likelihood of parasomnia dosages >20 mg/d.11 The inhibition of in Mr. R? CYP enzymes by fluoxetine likely is dose- a) high zolpidem dosage dependent,12 and therefore concomitant b) concomitant use of other sedating agents administration of high-dosage fluoxetine c) (>20 mg/d) with zolpidem might result in d) dehydration higher serum levels of zolpidem. Mr. R also was taking several sedating agents (gabapentin, hydroxyzine, melato- The authors’ observations nin, and tramadol). The concomitant use of Factors that increase the likelihood of para- these sedative-hypnotic agents could have somnias include: increased his risk of parasomnia. A review • zolpidem >10 mg at bedtime of the literature did not reveal any reports • concomitant use of other CNS depres- of gabapentin, hydroxyzine, melatonin, sants, including sedative hypnotic or tramadol causing parasomnias. This agents and alcohol observation, as well as the well-known • female sex role of zolpidem5 in etiopathogenesis of • not falling asleep immediately after parasomnias, indicates that the pseudo- taking zolpidem suicidal behavior Mr. R displayed while • personal or family history of asleep likely was a direct result of zolpi- parasomnias dem use in presence of other facilitating • living alone factors. Gabapentin, which is known to • poor pill management increase the depth of sleep, was added to • presence of sleep disruptors such as his regimen 1 month before his parasom- sleep apnea and periodic limb move- nia episode. Therefore, gabapentin could ments of sleep.1,4,5,10 have triggered parasomnia with zolpidem Higher dosages of zolpidem (>10 mg/d) therapy.1,13 have been identified as the predictive risk Conditions that provoke repeated cortical Current Psychiatry factor.5 In the Chopra et al4 case report on (eg, periodic limb movement dis- Vol. 16, No. 4 45 Cases That Test Your Skills

order [PLMD] and sleep apnea) or increase NREM parasomnias with zolpidem com- depth or pressure of sleep (intense exercise pared with .4 in the evening, fever, sleep deprivation) are thought to be associated with NREM Types of parasomnias parasomnias.1-4 However, Mr. R underwent According to DSM-5, there are 2 categories in-laboratory PSG and tested negative for of parasomnias based on the sleep stage major cortical arousal-inducing conditions, from which a parasomnia emerges.2 REM such as PLMD and sleep apnea. sleep behavior disorder (RBD) refers to com- Some other sleep disruptors likely were plex motor and/or vocalizations during involved in Mr. R’s case. Auditory and tactile REM sleep, accompanied by increased EMG stimuli are known to cause cortical arous- activity during REM sleep (Table).2,3 als, with additive effect seen when these The pseudo-suicidal behavior Mr. R Clinical Point 2 stimuli are combined.3,14 Additionally, displayed likely was NREM parasomnia these exogenous stimuli are known to trig- because it occurred in the first third of the REM sleep behavior ger sleep-related violent parasomnias.15 night with his eyes open and impaired recall disorder could be Mr. R displayed this behavior after his wife after the event. Interestingly, Mr. R had RBD explained by use of woke him up. The auditory stimulus of his in addition to the NREM parasomnia likely a selective serotonin wife’s voice and/or tactile stimulus involved caused by zolpidem. This is evident from reuptake inhibitor in the act of waking Mr. R likely played a Mr. R’s frequent dream enactment behav- role in the suicidal and violent nature of his iors, such as kicking, thrashing, and punch- and comorbidity NREM parasomnia. ing during sleep, along with increased EMG with PTSD activity during REM sleep as recorded on What factor increases the risk of NREM the PSG.10 The presence of RBD could be parasomnias with zolpidem compared explained by selective serotonin reuptake with benzodiazepines? inhibitor (fluoxetine) use, and comorbidity a) greater preservation of Stage N3 sleep with PTSD.2,16 b) lesser degree of muscle relaxation c) both a and b Management of parasomnias d) none of the above Initial management of parasomnias involves decreasing the risk of parasomnia-related . Suggested safety measures include: The authors’ observations • sleeping away from windows In general, the mechanisms by which zol- • sleeping in a pidem causes NREM parasomnias are not • sleeping on a lower floor completely understood. The sedation- • locking windows and doors related amnestic properties of zolpidem • removing potentially dangerous objects might explain some of these behaviors. from the Patients could perform these behaviors • putting gates across stairwells after waking and have subsequent amne- • installing bells or alarms on door sia.4 There is greater preservation of Stage knobs.15 N3 sleep with zolpidem compared with Removing access to firearms or other benzodiazepines. Benzodiazepines also weapons such as knives is of utmost impor- cause muscle relaxation while the motor tance especially with patients who have system remains relatively more active easy access during wakefulness. If removing during sleep with zolpidem because of weapons is not feasible, consider disarming, its selectivity for α-1 subunit of gamma- securing, or locking them.15 These consider- aminobutyric acid A receptor. These fac- ations are relevant to veterans with PTSD Current Psychiatry 46 April 2017 tors might increase the likelihood of because of the high prevalence of symptoms, Cases That Test Your Skills

Table Distinguishing features between NREM sleep arousal disorder and REM sleep behavior disorder NREM sleep arousal disorder/ Characteristics NREM parasomnia REM sleep behavior disorder Time of the night First third of the night Last half of the night Sleep stage N3 or slow-wave sleep REM sleep Behaviors Simple/complex behaviors Typically gross motor movements (kicking, punching, etc.) related to content of the dream; loud and emotion-laden vocalizations Eye position during the Open Closed episode Sensorium if awakened Confused, disoriented Fully awake, alert, and oriented Clinical Point during the episode Recall after the episode Complete or partial amnesia Often able to recall the dream A review found mentation that sedating Arousal threshold High Low Triggers Sleep deprivation, noise, touch, Alcohol withdrawal, , sleep apnea, PLMD, hypnotic including medications, alcohol use PSG findings Frequent arousals (micro- Increase EMG activity during REM antidepressants, arousals or frank awakenings) sleep can lead to NREM and hypersynchronous delta EEG waves during Stage N3 sleep parasomnias EMG: electromyography; NREM: non-rapid eye movement; PLMD: periodic limb ; PSG: ; REM: rapid eye movement Source: References 2,3

including depression, insomnia, and pain, nia that previously was treated with zolpidem, which require sedating medications.17 A and residual depression. Six months after dis­ review of parasomnias among a large sam- continuing zolpidem, he does not experience ple of psychiatric outpatients revealed that NREM parasomnias, and there are no changes a variety of sedating medications, including in his dream enactment behaviors. antidepressants, can lead to NREM para- somnias.18 Therefore, exercise caution when Summing up prescribing sedating medications, especially Zolpidem therapy could be associated with in patients vulnerable to developing dan- unusual variants of NREM parasomnia, gerous parasomnias, such as a veteran with sleepwalking type; sleep-related pseudo- PTSD and easy access to guns.19 suicidal behavior is one such variant. Several factors could play a role in increas- ing the likelihood of NREM parasomnia TREATMENT Zolpidem stopped with zolpidem therapy. In Mr. R’s case, the Mr. R immediately stops taking zolpidem pharmacokinetic drug interactions between because he is aware of its association with fluoxetine and zolpidem, as well as concom- abnormal behaviors during sleep, and his wife itant use of several sedating agents could removes his access to firearms and knives at have played a role in increasing the likeli- night. Because of his history of clinical benefit hood of NREM parasomnia, with audio- and no history of parasomnias with mirtazap­ tactile stimuli contributing to the violent and Current Psychiatry ine, Mr. R is started on mirtazapine for insom­ suicidal nature of the parasomnia. Exercise Vol. 16, No. 4 47 Cases That Test Your Skills

hygiene education and, more importantly, Related Resources cognitive-behavioral therapy for insomnia, • American Academy of . International are preferred. If a patient is already taking classification of sleep disorders. 3rd ed. Darien, IL: American Academy of Sleep Medicine; 2014. zolpidem, nightly dosage should not be • Kryger M, Roth T, Dement WC. Principles and practice of sleep >10 mg. Polypharmacy with other sedat- medicine. 2nd ed. Philadelphia, PA: Elsevier; 2017. ing medications should be avoided when Drug Brand Names possible and both exogenous (noise, pets) Fluoxetine • Prozac Propranolol • Inderal and endogenous sleep disruptors (sleep Gabapentin • Neurontin Tramadol • Ultram Hydroxyzine • Vistaril Trazodone • Desyrel, Oleptro apnea, PLMD) should be addressed. Mirtazapine • Remeron Zolpidem • Ambien, Advise the patient to avoid alcohol and Paroxetine • Paxil Edluar, Intermezzo Prazosin • Minipress remove firearms and other potential weap- ons. Discontinue zolpidem if the patient Clinical Point develops sleep-related abnormal behavior because of its potential to take on violent Advise patients to caution when using CYP enzyme inhibi- forms. avoid exogenous and tors, such as fluoxetine and paroxetine, in References combination with zolpidem. Knowledge of endogenous sleep 1. Howell MJ. Parasomnias: an updated review. disruptors and alcohol, the potential interaction between zolpidem Neurotherapeutics. 2012;9(4):753-775. and fluoxetine is important because anti­ 2. Diagnostic and statistical manual of mental disorders, 5th and remove firearms ed. Washington, DC: American Psychiatric Association; depressants and are commonly 2013. and other potential 3. Zadra A, Desautels A, Petit D, et al. Somnambulism: clinical co-prescribed because insomnia often is aspects and pathophysiological hypotheses. Lancet Neurol. weapons comorbid with other psychiatric disorders. 2013;12(3):285-294. 4. Chopra A, Selim B, Silber MH, et al. Para-suicidal amnestic In veterans with PTSD who do not behavior associated with chronic zolpidem use: implications have suicidal ideations while awake, life- for patient safety. Psychosomatics. 2013;54(5):498-501. 5. Hwang TJ, Ni HC, Chen HC, et al. Risk predictors threatening non-intentional behavior is a for hypnosedative-related complex sleep behaviors: a retrospective, cross-sectional pilot study. J Clin Psychiatry. risk because of easy access to guns or other 2010;71(10):1331-1335. weapons. Sedative-hypnotic medications 6. Shatkin JP, Feinfield K, Strober M. The misinterpretation of a non-REM sleep parasomnia as suicidal behavior in an commonly are prescribed to patients with adolescent. Sleep Breath. 2002;6(4):175-179. PTSD. Exercise caution when using hyp- 7. Mahowald MW, Schenck CH, Goldner M, et al. Parasomnia notic agents such as zolpidem, and consider pseudo-suicide. J Forensic Sci. 2003;48(5):1158-1162. 8. Gibson CE, Caplan JP. Zolpidem-associated parasomnia sleep aids with a lower risk of parasomnias with serious self-injury: a shot in the dark. Psychosomatics. 2011;52(1):88-91. (based on the author’s experience, trazo- 9. Mortaz Hejri S, Faizi M, Babaeian M. Zolpidem-induced done, mirtazapine, melatonin, and gaba- suicide attempt: a case report. Daru. 2013;20;21(1):77. pentin) when possible. Non-pharmacologic 10. Poceta JS. Zolpidem ingestion, automatisms, and sleep driving: a clinical and legal case series. J Clin Sleep Med. treatments of insomnia, such as sleep 2011;7(6):632-638.

Bottom Line Zolpidem has been associated with variants of non-rapid eye movement parasomnia prototype sleepwalking. Suicidal behavior during sleep is one such unusual and life-threatening variant. Exercise caution when prescribing zolpidem in vulnerable patients, such as veterans with posttraumatic stress disorder who have easy access to weapons. Avoid using multiple sedating agents when possible, and consider non-drug therapies such as education and cognitive- Current Psychiatry 48 April 2017 behavioral therapy as first-line treatments for insomnia. Cases That Test Your Skills

11. Hesse LM, von Moltke LL, Greenblatt DJ. Clinically 16. Husain AM, Miller PP, Carwile ST. Rem sleep behavior important drug interactions with zopiclone, zolpidem and disorder: potential relationship to post-traumatic zaleplon. CNS . 2003;17(7):513-532. stress disorder. J Clin Neurophysiol. 2001;18(2): 12. Catterson ML, Preskorn SH. Pharmacokinetics of selective 148-157. serotonin reuptake inhibitors: clinical relevance. Pharmacol 17. Bernardy NC, Lund BC, Alexander B, et al. Increased Toxicol. 1996;78(4):203-208. polysedative use in veterans with posttraumatic stress 13. Rosenberg RP, Hull SG, Lankford DA, et al. A randomized, disorder. Pain Med. 2014;15(7):1083-1090. double-blind, single-dose, placebo-controlled, multicenter, 18. Lam SP, Fong SY, Ho CK, et al. Parasomnia among polysomnographic study of gabapentin in transient psychiatric outpatients: a clinical, epidemiologic, insomnia induced by sleep phase advance. J Clin Sleep Med. cross-sectional study. J Clin Psychiatry. 2008;69(9): 2014;10(10):1093-1100. 1374-1382. 14. Kato T, Montplaisir JY, Lavigne GJ. Experimentally induced 19. Freeman TW, Roca V, Kimbrell T. A survey of arousals during sleep: a cross-modality matching paradigm. gun collection and use among three groups J Sleep Res. 2004;13(3):229-238. of veteran patients admitted to veterans affairs 15. Siclari F, Khatami R, Urbaniok F, et al. Violence in sleep. hospital treatment programs. South Med J. 2003;96(3): Brain. 2010;133(pt 12):3494-3509. 240-243.

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