Conservative estimates suggest that one-third of the US population has a sleep

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1 Reltionships Between Polyphrmcy nd the Sleep Cycle Among Active-Duty Service Memers R. Gregory Lnde, DO Cynthi Grgnni, PhD From the Psychitry Continuity Service t Wlter Reed Ntionl Militry Medicl Center in Bethesd, MD. Finncil Disclosures: None reported. Support: None reported. The views expressed in this rticle re those of the uthors nd do not reflect the officil policy of the Deprtment of Army/ Nvy/Air Force or the Deprtment of Defense. Address correspondence to R. Gregory Lnde, DO, 8901 Rockville Pike, Bethesd, MD E-mil: rglnde@gmil.com Sumitted Novemer 13, 2014; revision received Jnury 12, 2015; ccepted Ferury 5, Context: Sleep disorders re frequent clinicl presenttions, especilly mong ctiveduty service memers. Medictions re one fctor tht cn ffect sleep in mny wys. Ojective: To determine the effect of incresing numers of medictions on the sleep cycle of ctive-duty service memers. Methods: Medicl records for ctive-duty service memers who completed enhnced sleep ssessments t the Psychitry Continuity Service t Wlter Reed Ntionl Militry Medicl Center from Octoer 1, 2010, through Novemer 30, 2013, were retrospectively reviewed. Dt were collected on home sleep study findings, sleep-relted self-report instrument scores, nd ctive medictions. Results: A totl of 135 medicl records were reviewed. One hundred ptients (74.07%) hd n ctive prescription for psychoctive drug. Among ll ptients, the men (SD) numer of ctive medictions per prticipnt ws 2.52 (2.09), with 118 ptients (82.96%) hving n ctive mediction for depression or insomni. As the numer of prescried medictions incresed, the percentge of the sleep cycle in deep sleep decresed (P=.049), the percentge of light sleep incresed (P=.016), the percentge of rpid eye movement sleep decresed (P=.083), nd the first episode of deep sleep ws delyed (P=.056). An incresed numer of medictions hd no significnt impct on totl sleep time (P>.05). Conclusion: An incresing numer of medictions did not influence totl sleep time ut negtively ffected the sleep cycle. J Am Osteopth Assoc. 2015;115(6): doi: /jo Conservtive estimtes suggest tht one-third of the US popultion hs sleep disorder, ccounting for its frequent clinicl presenttion. 1 Insomni hs een reported s the most commonly cited prolem mong service memers returning from comt deployment. 2 In our experience, sleep prolems re prticulrly prevlent mong ctive-duty service memers with comt-relted posttrumtic stress disorder (PTSD). According to Rieiro et l, 3 insomni is risk fctor for suicidl tendencies mong recent militry veterns. Becuse roughly hlf of ll individuls with chronic insomni hve psychitric disorder, 4 prescription medictions re lso common in this ptient popultion. Medictions cn ffect sleep in mny wys; even those tht re prescried for insomni cn produce unhelpful side effects. Commonly prescried sedtive hypnotics such s temzepm, trizolm, nd zolpidem reduce totl rpid eye movement (REM) sleep. 5 Among other psychotherpeutic medictions, commonly prescried selective serotonin uptke inhiitors reduce slow wve sleep, reduce totl REM sleep, reduce totl sleep time, nd im- 370 The Journl of the Americn Osteopthic Assocition June 2015 Vol 115 No. 6

2 pir sleep continuity. 6 Tricyclic ntidepressnts nd trzodone increse slow wve sleep nd totl sleep time, with trzodone lso promoting sleep continuity. 7 Antihistmines such s diphenhydrmine increse slow wve sleep while lso reducing totl REM sleep. 5 Some of these sme medictions lso cuse nightmres or especilly vivid drems. 8,9 Multiple sedting medictions my lso ffect respirtion during sleep. 10 For the current study, we investigted the effect of commonly prescried medictions, oth lone nd in comintions, on the sleep rchitecture of ctive-duty service memers referred for psychitric tretment. To our knowledge, we re the first to report findings of enhnced sleep ssessments for this ptient popultion. We hypothesized tht medictions would hve negtive impct on ptient s sleep rchitecture. severl stndrdized self-dministered ssessment instruments. For the present study, we exmined ptients enhnced sleep ssessment findings, s well s those ptients concurrent medictions on the dy the home sleep study ws conducted. PCS Enhnced Sleep Assessment Mesures Epworth Sleepiness Scle The Epworth Sleepiness Scle (ESS) consists of 8 questions tht sk ptients to rte their chnce of dozing during specific situtions using 4-point Likert-type scle rnging from 0 ( no chnce of dozing ) to 3 ( high chnce of dozing ). 12 Questions include situtions such s [s]itting nd reding, [w]tching TV, or [s]itting inctive in pulic spce. Scores of 10 or greter suggest dytime sleepiness. Methods Medicl records were retrospectively reviewed for ctive-duty service memers with sleep prolems treted t the Psychitry Continuity Service (PCS) t Wlter Reed Ntionl Militry Medicl Center in Bethesd, Mrylnd, from Octoer 1, 2010, through Novemer 30, The study ws reviewed y the Wlter Reed Ntionl Militry Medicl Center s institutionl review ord nd deemed exempt. Ptients scoring ove 20 on the Pittsurg Insomni Rting Scle (PIRS) were included in the study. The PIRS is 20-item self-report instrument tht ssesses person s sleep over the preceding 7-dy period. 11 Scores on the PIRS rnge from 0 to 60, with scores ove 20 suggesting insomni. Typicl questions on the PIRS include, From the time you tried to go to sleep, how long did it tke to fll sleep on most nights? nd If you woke up during the night, how long did it tke to fll ck to sleep on most nights? In ccordnce with the PCS stndrd of cre, ptients who scored ove 20 on the PIRS received n enhnced sleep ssessment, which included home sleep study nd Pre-Sleep Arousl Scle The Pre-Sleep Arousl Scle contins 16 questions with response options on 5-point Likert scle rnging from 1 ( not t ll ) to 5 ( extremely ). 13 The Pre-Sleep Arousl Scle hs 2 suscles somtic nd cognitive. Somtic questions sk respondents out issues such s jittery, nervous feeling in your ody, wheres the cognitive questions sk out issues such s worry out flling sleep. Scores for ech of the suscles rnge from 8 to 40. The Pre-Sleep Arousl scle does not hve threshold scores, ut higher scores indicte greter rousl efore flling sleep. The clinicin or resercher correltes higher scores with incresing somtic or cognitive fctors tht interfere with sleep initition. Zung Self-Rting Scles The Zung Self-Rting Scles re 20-item self-report instruments in which respondents nswer questions regrding depression or nxiety. For oth instruments, respondents cn choose mong 4 descriptions for ech question little of the time, some of the time, good prt of the time, nd most of the time scored The Journl of the Americn Osteopthic Assocition June 2015 Vol 115 No

3 Chronic sleep prolems cn e frustrting chllenge for oth the clinicin nd the ptient, prticulrly when medictions, either lone or in comintion, do not produce n optimum outcome. Sedtive-hypnotic medictions my help person fll sleep nd my even promote n ins 1, 2, 3, nd 4, respectively. Typicl questions on the Zung Self-Rting Depression Scle include I feel downherted nd lue nd Morning is when I feel the est. The Zung Self-Rting Anxiety Scle includes questions such s, I feel more nervous nd nxious thn usul nd I fll sleep esily nd get good night s rest. Scores ove 50 on the Zung Self-Rting Depression Scle suggest cliniclly significnt depression, nd scores ove 45 on the Zung Self-Rting Anxiety Scle suggest cliniclly significnt nxiety. PCL-M The PCL-M is 17-item self-report instrument in which respondents choose mong 5 descriptions (ie, not t ll, little it, modertely, quite it, nd extremely, scored on sliding scle of 1 through 5) in nswering questions regrding stressful life experiences. 18 A typicl question from the PCL-M sks the service memer if they re hving physicl rections when something reminded you of stressful militry experience from the pst. Scores ove 49 suggest symptoms consistent with the clinicl dignosis of PTSD. Home Sleep Studies The WtchPAT 200 (Itmr Medicl) ws used to conduct the home sleep study portion of the enhnced sleep ssessment This medicl device, pproved y the US Food nd Drug Administrtion, clcultes sleep pne severity using 3 mesurements: the pne/ hypopne index (AHI), the oxygen desturtion index (ODI), nd the respirtory disturnce index (RDI). The WtchPAT lso reports vlues for ody mss index nd the sleep cycle in terms of percentge of the cycle in deep sleep, in light sleep, in REM sleep, nd wke. Sttisticl Anlysis SPSS sttisticl softwre (version 20; SPSS Inc) ws used to nlyze the dt using descriptive, frequency, correlte, nd comprison sttistics. A P vlue less thn.05 ws considered sttisticlly significnt. Results A totl of 135 medicl records of ctive-duty service memers were reviewed. Approximtely two-thirds of ptients were men (87 [64.4%]), with medin ge rnge of 26 to 30 yers. Men (SD) findings were s follows: PIRS score, (10.52) (n=135); totl sleep time, 6.12 (1.57) hours (n=134); percentge of the night in deep sleep, 20.8% (6.09%) (n=119); nd percentge of the night wke, 21.25% (12.69%) (n=134). The clinicl chrcteristics of the study ptients were consistent with those of ptients experiencing depression, PTSD, nd nxiety (Tle 1). In terms of medictions, pproximtely threequrters of ptients (100 of 135 [74.07%]) hd n ctive prescription for psychoctive drug, with men (SD) of 2.52 (2.09) ctive medictions per ptient. Of 135 ctive medictions tht comprised >5% of the identified drug, the mjority (112 [82.96%]) were for depression, sleep prolems, or oth (Tle 2). Results showed tht s the numer of prescried medictions incresed, the percentge of the sleep cycle in deep sleep significntly decresed (P=.049), the percentge of light sleep incresed (P=.016), the percentge of REM sleep decresed (P=.083), nd the first episode of deep sleep ws delyed (P=.056). Incresing the numer of medictions did not significntly lter the mount of time wke, the numer of rousls through the night, the totl time slept, or sleep ltency (P>.05) (Tle 3). The numer of ctive medictions (ie, 1-6) did not hve sttisticlly significnt effect on totl sleep time (Tle 4). Discussion 372 The Journl of the Americn Osteopthic Assocition June 2015 Vol 115 No. 6

4 Tle 1. Enhnced Sleep Assessment Findings Among Active-Duty Service Memers (N=135) Tle 2. Current Medictions of Active-Duty Service Memers for Depression nd Sleep Prolems Mesure Men (SD) Mediction No. (%) PIRS (10.52) Epworth Sleepiness Scle 8.96 (5.44) Pre-Sleep Arousl Scle Somtic 18 (6.57) Cognitive (7.56) Totl (12.72) Zung Self-Rting Scle Anxiety (13.76) Depression (11.76) PCL-M (18.13) BMI c (4.28) Sertrline hydrochloride 24 (17.78) Trzodone hydrochloride 23 (17.0) Przosin hydrochloride 18 (13.33) Clonzepm 12 (8.89) Zolpidem trtrte 10 (7.41) Fluoxetine hydrochloride 10 (7.41) Quetipine fumrte 8 (5.93) Eszopiclone 7 (5.19) Tle lists only medictions comprising >5% of the identified drug. A totl of 135 medictions met the >5% threshold. Most prticipnts hd more thn 1 current mediction. Sleep Time, % REM sleep d (8.35) Deep sleep d (6.09) Light sleep d (11.14) Awke (12.69) Time to Sleep, min e (15.60) Totl Sleep Time, min (93.61) Sleep Apne Severity f n=134 n=122 c n=133 d n=119 e n=118 f n=123 AHI 3.78 (4.60) ODI 1.66 (2.69) RDI (6.49) Arevitions: AHI, pne/hypopne index; BMI, ody mss index; ODI, oxygen desturtion index; PCL-M, Posttrumtic Stress Disorder Checklist Militry Version; PIRS, Pittsurg Insomni Rting Scle; RDI, respirtory disturnce index; REM, rpid eye movement. crese in totl sleep time. On wkening, however, the person my feel unrefreshed, tired, or groggy. In ddition to sleep prolems, ptients in the present study ll hd vrying degrees of nxiety nd depression, common clinicl finding. The enhnced sleep ssessments reveled tht n incresed numer of psychoctive medictions did not improve chronic insomni nd my hve produced unintended, dverse effects. For exmple, the study showed tht s the numer of prescried medictions incresed, the percentge of deep sleep decresed, the percentge of light sleep incresed, the percentge of REM sleep decresed, nd the first episode of deep sleep ws delyed. Our study lso found tht incresing the numer of medictions did not significntly reduce the numer of intrusive rousls through the night. In similr finding, multiple medictions did not improve the totl time sleep. It is importnt to note tht the medictions prescried to the ptients in this study re typicl for ptients with The Journl of the Americn Osteopthic Assocition June 2015 Vol 115 No

5 Tle 3. Correltions Between Totl Numer of Current Medictions nd Sleep in Active-Duty Service Memers (N=135) Person Mesure Correltion P Vlue Sleep Time, % Deep sleep Light sleep REM sleep Awke c Arousls, No. d Time to Sleep, min e Onset of First Deep Sleep, min e Totl Sleep Time, min c Sttisticl tests were 2-tiled. n=119 c n=134 d n=115 e n=118 Arevition: REM, rpid eye movement. Tle 4. Numer of Current Medictions nd Effect on Totl Sleep Time in Active-Duty Service Memers (N=135) Men (SD) Medictions, No. Totl Sleep Time, min n P Vlue (63.65) 35 NA (98.29) (114.63) (119.89) (57.80) (121.19) (75.18) Seven prticipnts hd more thn 6 current medictions (dt not shown). Sttisticl tests were 2-tiled. Arevition: NA, not pplicle. nxiety, depression, nd sleep prolems. As individul drugs, they my ech hve pronounced effects on sleep rchitecture nd s the present study suggests they my hve cumultive effect on the sleep cycle when used in comintion. Our study hd some limittions. For exmple, ptients my hve een tking other unknown psychoctive drugs or not tking their prescried medictions s directed. In ddition, lcohol use is lwys wild crd in the sense tht its use my not e disclosed, ut its pernicious effect on the sleep cycle would only ugment the findings in the current study. 22 Mitigting these concerns re the lrge size of the study nd the 3-yer dt collection time, ut even so, replicting the study with lrger smple size would confirm our findings. Exmining how specific comintions of medictions ffect sleep cycle would e n interesting re for future reserch. In ddition, lthough we did not exclude ny types of mediction in our study, the medictions of our ptient popultion likely differed from those of other popultions. For exmple, ecuse this study ws conducted in psychitry unit, it ws expected tht the prticipnts would e on more psychitric-type medictions. In ddition, our popultion of ctive-duty service memers is young nd tends to e helthier thn similr ge-mtched smple. As such, the ptients in our study likely hd fewer types of medicine (eg, mediction for dietes mellitus is rre in our ptients), which my hve led to less confounding vriles. Thus, dditionl reserch in other ptient popultions is wrrnted. For individuls with chronic insomni, nonphrmcologic tretment interventions, such s sleep restriction or cognitive ehvior therpy, my e useful lterntives. 23 At the very lest, the use of evidencedsed nonphrmcologic tretments for insomni would not increse the potentil risks ssocited with polyphrmcy found in this study. 374 The Journl of the Americn Osteopthic Assocition June 2015 Vol 115 No. 6

6 Conclusion The findings of the present study suggest tht medictions lone my not resolve chronic sleep prolems nd, in some cses, my ctully worsen the condition. On the sis of these findings, clinicins should ressess the risks nd enefits of polyphrmcy nd consider nonphrmcologic tretment options for these ptients. Author Contriutions Both uthors provided sustntil contriutions to conception nd design, cquisition of dt, or nlysis nd interprettion of dt; oth uthors drfted the rticle or revised it criticlly for importnt intellectul content; oth uthors gve finl pprovl of the version of the rticle to e pulished; nd oth uthors gree to e ccountle for ll spects of the work in ensuring tht questions relted to the ccurcy or integrity of ny prt of the work re ppropritely investigted nd resolved. References 1. Sleep nd sleep disorders fct sheet. US Centers for Disese Control nd Prevention wesite. /pulictions/fctsheets.htm. Accessed April 29, McLy RN, Klm WP, Volkert SL. Insomni is the most commonly reported symptom nd predicts other symptoms of post-trumtic stress disorder in U.S. service memers returning from militry deployments. Mil Med. 2010;175(10): Rieiro JD, Pese JL, Gutierrez PM, et l. Sleep prolems outperform depression nd hopelessness s cross-sectionl nd longitudinl predictors of suicidl idetion nd ehvior in young dults in the militry [pulished online Octoer 26, 2011]. J Affect Disord. 2012;136(3): doi: /j.jd Thse ME. Correltes nd consequences of chronic insomni. Gen Hosp Psychitry. 2005;27(2): Forl P, Knezevich J, Dewn N, Mlesker M. Mediction-induced sleep disturnces. Consult Phrm. 2011;26(6): doi: /tcp.n Tril GG, Wetter TC, Schredl M. Dreming under ntidepressnts: systemtic review on evidence in depressive ptients nd helthy volunteers [pulished online July 15, 2012]. Sleep Med Rev. 2013;17(2): doi: /j.smrv Fgiolini A, Comndini A, Cten Dell Osso M, Ksper S. Rediscovering trzodone for the tretment of mjor depressive disorder. CNS drugs. 2012;26(12): doi: /s Pgel JF, Helfter P. Drug induced nightmres n etiology sed review. Hum Psychophrmcol. 2003;18(1): Mthews M, Bsil B, Evcimen H, Adetunji B, Joseph S. Mirtzpine-induced nightmres. Prim Cre Compnion J Clin Psychitry. 2006;8(5): Sed G, Tsi S, Lee-Chiong T. Mediction effects on sleep nd rething [pulished online July 18, 2014]. Clin Chest Med. 2014;35(3): doi: /j.ccm Moul DE, Pilkonis PA, Miewld JM, Crey TJ, Buysse DJ. Preliminry study of the test-retest reliility nd concurrent vlidities of the Pittsurgh Insomni Rting Scle (PIRS) [strct 335.L]. Sleep. 2002;25(suppl):A246-A Johns MW. A new method for mesuring dytime sleepiness: the Epworth sleepiness scle. Sleep. 1991;14(6): Nicssio PM, Mendlowitz DR, Fussell JJ, Petrs L. The phenomenology of the pre-sleep stte: the development of the pre-sleep rousl scle. Behv Res Ther. 1985;23(3): Sunders JB, Aslnd OG, Bor TF, de l Fuente JR, Grnt M. Development of the Alcohol Use Disorders Identifiction Test (AUDIT): WHO Collortive Project on Erly Detection of Persons with Hrmful Alcohol Consumption II. Addiction. 1993;88(6): Zung WW. Fctors influencing the self-rting depression scle. Arch Gen Psychitry. 1967;16(5): Zung WW. The Depression Sttus Inventory: n djunct to the Self-Rting Depression Scle. J Clin Psychol. 1972;28(4): Zung WW. A rting instrument for nxiety disorders. Psychosomtics. 1971;12(6): Blnchrd EB, Jones-Alexnder J, Buckley TC, Forneris CA. Psychometric properties of the PTSD Checklist (PCL). Behv Res Ther. 1996;34(8): Png KP, Gourin CG, Terris DJ. A comprison of polysomnogrphy nd the WtchPAT in the dignosis of ostructive sleep pne. Otolryngol Hed Neck Surg. 2007;137(4): Brrer JE, Holrook AB, Sntos J, Popelk GR. Sleep MRI: novel technique to identify irwy ostruction in ostructive sleep pne. Otolryngol Hed Neck Surg. 2009;140(3): doi: /j.otohns Hedner J, White DP, Mlhotr A, et l. Sleep stging sed on utonomic signls: multi-center vlidtion study. J Clin Sleep Med. 2011;7(3): doi: /jcsm Erhim IO, Shpiro CM, Willims AJ, Fenwick PB. Alcohol nd sleep I: effects on norml sleep [pulished online Jnury 24, 2013]. Alcohol Clin ExpRes. 2013;37(4): doi: /cer Lnde RG, Grgnni C. Nonphrmcologic pproches to the mngement of insomni. J Am Osteopth Assoc. 2010;110(12): Americn Osteopthic Assocition The Journl of the Americn Osteopthic Assocition June 2015 Vol 115 No